USE THE ACTUAL WEIGHT TO CALCULATE PACLITAXEL DOSE

Gynecol Oncol. 2009 Apr 7. [Epub ahead of print]

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Chemotherapy toxicity in gynecologic cancer patients with a body surface area (BSA)>2 m(2).

Schwartz J, Toste B, Dizon DS.

Albany College of Pharmacy and Health Sciences, Vermont Campus, Colchester, Vermont, USA.

OBJECTIVES: Although many clinicians practice empiric dose reduction to prevent toxicity, it is unknown whether obese patients given chemotherapy dosed according to actual body weight (ABW) experience excess toxicity. At our institution, cancer patients receive chemotherapy dosed by ABW unless on a protocol capping doses at a maximum body surface area (BSA). We compared toxicities and dose modifications between women with a BSA>2 m(2) on uncapped versus capped paclitaxel as part of adjuvant paclitaxel/carboplatin for gynecologic malignancy. METHODS: In this retrospective study, women with a BSA>2 m(2) treated with paclitaxel (P) and carboplatin (C) for endometrial and ovarian cancer between January 1999 and July 2007 were identified using the chemotherapy database. Records were reviewed for patient age, BSA, diagnosis, stage, standardized and actual doses for each cycle, adverse drug reactions, and dosing modifications. Statistical comparisons were made using Fisher's exact test. RESULTS: We identified 59 women with BSA>2 m(2) on adjuvant P/C for endometrial and ovarian cancers. 50 received paclitaxel dosed by ABW and 9 received paclitaxel capped at a BSA of 2 m(2). There were no statistically significant differences in rates of toxicity or dose modification. CONCLUSIONS: Obese women with a BSA>2 m(2) on paclitaxel dosed by ABW do not experience excess toxicity in comparison to women on paclitaxel capped at a maximum BSA or women in published trials of adjuvant P/C. Empiric dose reduction is unnecessary and may result in suboptimal treatment of obese patients. However, as this was a retrospective review, more research is needed to make definitive recommendations on this topic.

AUTOLOGOUS STEM CELL TRANSPLANTATION AND TYPE 1 DIABETES

Stem Cell Transplantation May Be Helpful in Type 1 Diabetes

April 14, 2009 — Hematopoietic stem cell transplantation (HSCT) in patients with newly diagnosed type 1 diabetes mellitus (DM) helped patients achieve long-term insulin independence and improved beta-cell function, according to the results of a prospective phase 1/2 study reported in the April 15 issue of the Journal of the American Medical Association.

"In 2007, the effects of the autologous nonmyeloablative [HSCT] in 15 patients with type 1 [DM] were reported," write Carlos E.B. Couri, MD, PhD, from School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil, and colleagues. "Most patients became insulin free with normal levels of glycated hemoglobin A1c (HbA1c) during a mean 18.8-month follow-up. To investigate if this effect was due to preservation of beta-cell mass, continued monitoring was performed of C-peptide levels after stem cell transplantation in the 15 original and 8 additional patients."

The study sample consisted of 23 patients, aged 13 to 31 years, with type 1 DM diagnosed in the previous 6 weeks by clinical findings with hyperglycemia and confirmed by measurement of serum levels of anti–glutamic acid decarboxylase antibodies. Participants were enrolled from November 2003 to April 2008 and followed up until December 2008 at the Bone Marrow Transplantation Unit of the School of Medicine of Ribeirão Preto.

Hematopoietic stem cells were mobilized using the 2007 protocol. The main study endpoints were C-peptide levels measured during the mixed-meal tolerance test, both before and at different time points after HSCT. Secondary outcome measures included transplantation-related adverse events and death, temporal changes in requirements for exogenous insulin, and serum levels of HbA1c.

Mean follow-up was 29.8 months (median, 30 months; range, 7 – 58 months). During follow-up, 20 patients without previous ketoacidosis and who were not receiving corticosteroids during the preparative regimen became insulin-free. Of these 20 patients, 12 remained insulin-free for a mean duration of 31 months (range, 14 – 52 months), whereas 8 patients relapsed and again required insulin use at low doses of 0.1 to 0.3 U/kg.

In the group that continued to require insulin, HbA1c levels were less than 7.0%. Mean area under the curve (AUC) of C-peptide levels increased from 225.0 ± 75.2 ng/mL per 2 hours before transplantation to 785.4 ± 90.3 ng/mL per 2 hours at 24 months after transplantation (P < .001) and to 728.1 ± 144.4 ng/mL per 2 hours at 36 months after transplantation (P = .001).

In the group that was transiently insulin-free, mean AUC of C-peptide levels also increased from 148.9 ± 75.2 ng/mL per 2 hours before transplantation to 546.8 ± 96.9 ng/mL per 2 hours at 36 months after transplantation (P = .001), with this increase sustained at 48 months. Two patients in this group regained insulin independence after being treated with sitagliptin, and C-peptide levels concomitantly increased.

Adverse effects were bilateral nosocomial pneumonia in 2 patients, late endocrine dysfunction in 3 patients, and oligospermia in 9 patients. There were no deaths.

"After a mean follow-up of 29.8 months following autologous nonmyeloablative HSCT in patients with newly diagnosed type 1 DM, C-peptide levels increased significantly and the majority of patients achieved insulin independence with good glycemic control," the study authors write.

Limitations of this study include small sample size and lack of a control group.

"At the present time, autologous nonmyeloablative HSCT remains the only treatment capable of reversing type 1 DM in humans," the study authors write. "Randomized controlled trials and further biological studies are necessary to confirm the role of this treatment in changing the natural history of type 1 DM."

ORAL CONTRACEPTIVES AND SLE

Combined Oral Contraceptive Use Linked to Risk for Systemic Lupus Erythematosus

April 13, 2009 — Use of combined oral contraceptives (COCs) is linked to increased risk for systemic lupus erythematosus (SLE), according to the results of a population-based, nested case–control study reported in the April 15 issue of Arthritis Care & Research.

"Endogenous hormonal factors are believed to play an important part in the etiology of SLE," write Marie-Odile Bernier, MD, MSc, from McGill University in Montreal, Quebec, Canada, and colleagues. "Estrogen contained in contraceptives has been also questioned.... However, the role of exogenous estrogen as a trigger of SLE remains controversial because studies of the link between exogenous hormonal exposure and SLE risk have produced conflicting results."

The study population consisted of women aged 18 to 45 years identified from the United Kingdom's General Practice Research Database (GPRD). From 1994 to 2004, there were 786 patients with SLE found in the database and matched with up to 10 control individuals (n = 7817) among women without SLE at the time of the diagnosis of the patient with SLE.

The adjusted rate ratio (RR) of incident SLE associated with any use of COC was 1.19 (95% confidence interval [CI], 0.98 – 1.45). For current use of COC, adjusted RR was 1.54 (95% CI, 1.15 – 2.07). Current users who had only recently started COC use had a higher RR than did longer-term current users (RR, 2.52; 95% CI, 1.14 – 5.57 vs RR, 1.45; 95% CI, 1.06 – 1.99). Current exposure to first- or second-generation contraceptives was associated with especially increased risk (RR, 1.65; 95% CI, 1.20 – 2.26). Risk increased further with increasing dose of ethinyl estradiol (RR, 1.42, 1.63, and 2.92 for ≤30 µg, 31 – 49 µg, and 50 µg, respectively).

"The use of COCs is associated with an increased risk of SLE," the study authors write. "This risk is particularly elevated in women who recently started contraceptive use, suggesting an acute effect in a small subgroup of susceptible women."

Limitations of this study include lack of data on racial and socioeconomic status; incomplete information on gynecologic history, which could be a potential confounding factor; and lack of systematic collection of information concerning smoking or drinking habits.

"Although COC use may be associated with a significant increased risk of incident SLE, some have argued that the low relative risk of ~2 is probably insufficient to explain the 9:1 sex ratio in this disease," the study authors write. "Thus, although our findings add considerably to the existing literature, further studies on the acute effects of COCs will be needed to better identify the characteristics of women susceptible to developing SLE when exposed to COCs."

LESS THAN HALF PATIENTS RECEIVE SENTINEL NODE BIOPSY

Unchanging: Less Than Half of Melanoma Patients Receive Recommended Biopsy

April 14, 2009 — Less than half of melanoma patients with stage IB or II disease receive a sentinel lymph node biopsy, even though the procedure has been recommended in these patients by clinical practice guidelines since 1998.

This previously established finding has been confirmed by a new study, which also provides insight into the underuse of the procedure.

The use of the biopsy was associated with a variety of clinical factors, but was also associated with health-system factors, according to the authors of the study, which was published online March 9 in the Journal of Clinical Oncology.

"We found that the use of sentinel node biopsy is strongly associated with nonclinical factors, such as insurance coverage, type of hospital, and geographic region," senior author Julie Lange, MD, ScM, told Medscape Oncology. Dr. Lange is an associate professor of surgery, oncology and dermatology at Johns Hopkins Medicine, in Baltimore, Maryland.

She explained that patients who are either covered by Medicaid and Medicare (and not private insurance) or who live in the Northeast, the South, or the West were less likely to undergo the procedure. Also, stage IB and II patients were significantly more likely to undergo the procedure if they were treated at National Comprehensive Cancer Network (NCCN)- or National Cancer Institute (NCI)-designated hospitals.

"There obviously needs to be education of providers at multiple levels — the primary-care physician, the dermatologist, and even the surgeon — that sentinel lymph node biopsy is not only acceptable but is beneficial in staging and clinical decision-making for patients with stage IB or II melanomas," said lead author Karl Bilimoria, MD, in a statement. At the time of the study, Dr. Bilimoria was an American College of Surgeons Research Fellow at the Feinberg School of Medicine of Northwestern University, in Chicago, Illinois.

Sentinel lymph node biopsy is associated with improved regional disease control and improved disease-free survival, note the authors.

However, Dr. Lange noted that the procedure has not been proven to improve overall survival.

The researchers also found that the use of sentinel lymph node biopsy was less likely to be used in stage IB or II patients who were older than 75 years, had TIb tumors, and had no tumor ulcerations or head/neck/truncal ulcerations.

Differing Acceptance of Guidelines?

To uncover factors associated with sentinel lymph node biopsy use, the researchers used the National Cancer Data Base to identify 8525 patients treated for stage IB/II melanoma in 2004 and 2005. They also identified 8073 patients with stage IA disease to see what proportion were biopsied outside of the recommended NCCN guidelines.

For clinical stage IB or II melanoma, recommended sentinel lymph node biopsy use was reported in only 48.7% of patients. For clinical stage IA melanoma, 13.3% of patients had a biopsy.

The reasons behind the underuse of the biopsy in stage IB and II melanoma patients — which include Medicaid/Medicare status, regional preferences, and type of hospital — are not totally surprising, suggest the authors.

"Variance in cancer management related to socioeconomic and geographic factors has been shown in breast, colon, and prostate cancer, as well as other common malignancies," they write. However, before the current study, the factors associated with use and nonuse of the biopsy in melanoma were "poorly understood."

Sentinel lymph node biopsy is "widely accepted" in most high-volume melanoma centers, write the authors. Indeed, in the new study, 60% of patients with stage IB or II melanoma underwent sentinel lymph node biopsy if they were treated at NCCN- or NCI-designated centers, compared with 25% at Veterans Affairs centers and 43% at community hospitals.

Despite their findings about the factors associated with the less likely use of sentinel lymph node biopsy in appropriate patients, the authors searched for additional answers about the poor uptake of clinical guidelines on the matter.

"Reasons for the persistent underuse of [sentinel lymph node biopsy] in certain subsets is unclear," they write. "It is possible that the variances found in this study reflect a different level of acceptance of the stated guidelines among the different specialties," they add, noting that professionals involved in the care of these patients include dermatologists, general surgeons, surgical oncologists, plastic surgeons, otolaryngologists, medical oncologists, and radiation oncologists.

The purpose of the procedure might not be well understood, suggest the authors. "Some still question whether [sentinel lymph node biopsy] should be used routinely in the absence of clear documentation of an improvement in overall survival, even though the primary purpose of the procedure is to provide prognostic and staging information," they write.

Dr. Lange does not believe that underuse of the biopsy can be explained by the harm/benefit ratio of the procedure.

"Sentinel node biopsy is a low-risk procedure, but not a no-risk procedure. It adds some time to the surgical procedure (compared with wide excision alone) and there are minor risks of infection and lymphocoele," she said. Furthermore, the risk for limb edema from a sentinel node biopsy is low, she said, adding that it was not, however, 0. "There are some cases in which, based on a patient's own medical history and concerns, a decision not to do a sentinel node biopsy is perfectly rational," she observed.

LOWER SURVIVAL WITH BREAST NHL

Lower Survival With Primary Breast Non-Hodgkin's Lymphoma

NEW YORK (Reuters Health) Apr 10 - Women with primary breast non-Hodgkin's lymphoma (PBL) have lower survival than do individuals with aggressive nodal lymphomas, according to a report in the March issue of the American Journal of Hematology.

PBL represents less than 1% of non-Hodgkin's lymphomas and only about 2% of extranodal presentations, the authors explain, and its natural history has yet to be elucidated.

Dr. Patricia Validire and colleagues from Institut Curie in Paris used data from 45 women with malignant lymphoma with a primary breast site of disease to define the initial pathological and clinical characteristics of PBL, their natural history, and the prognostic factors regarding disease-free survival and overall survival.

Most patients (38 women) had diffuse large B-cell lymphoma (DLBCL), the authors report, and just over half of these were classified in the low-risk group. The rest were evenly divided among the low- to intermediate-risk, intermediate- to high-risk, and high-risk groups.

All 38 women with DLBCL received chemotherapy, 27 received radiotherapy, and 20 received CNS prophylactic radiotherapy.

Thirty-four of these patients achieved complete response at the end of initial therapy, 3 achieved partial response, and 1 progressed during treatment.

The 2- and 5-year disease-free survival rates were 65% and 54%, respectively, and the 2- and 5-year overall survival rates were 75% and 61%, respectively.

These survival rates were significantly lower than those in a comparison series of patients with localized nodal lymphoma but not significantly different from those in patients with disseminated DLCL with or without breast involvement, the investigators say.

Adverse prognostic factors in a multivariate analysis included two or more extranodal sites, a performance score of 2 or higher, and an erythrocyte sedimentation rate of at least 30.

"Initial breast localization has a pejorative impact on the outcome of patients with non-Hodgkin's lymphoma (NHL) with an impressive adverse influence of additional extranodal sites," the investigators conclude. "These results suggest a specific management of NHL with breast involvement."

TRIPLE NEGATIVE CANCER INCREASED IN BLACK WOMEN

April 13, 2009 — Triple-negative breast cancers (negative for estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]), are 3-fold more common in black women than in nonblack women, regardless of age or body mass index (BMI), according to the results of a study reported in the March 25 issue of Breast Cancer Research.

"We investigated clinical and pathologic features of breast cancers (BC) in an unselected series of patients diagnosed in a tertiary care hospital serving a diverse population," write Lesley A. Stead, from Boston University Medical Center in Massachusetts, and colleagues. "We focused on [Tneg] tumours ([ER], [PR] and HER2 negative), which are associated with poor prognosis."

Between 1998 and 2006, 415 women were diagnosed with invasive breast cancers and had available data on tumor grade and stage; ER, PR, and HER2 status; and patient age, BMI, and self-identified racial/ethnic group. Using contingency tables and multivariate logistic regression, the investigators evaluated associations between patient and tumor characteristics.

The patient sample had a wide range of racial and ethnic origins, with birthplace representing a total of 44 countries; 36% were white, 43% black, 10% Hispanic, and 11% other. Obesity, defined as BMI higher than 30 kg/m², was present in 47%. Tumor receptor status was ER+ and/or PR+ in 72%, triple-negative tumors in 20%, and HER2+ in 13%.

Triple-Negative Breast Cancers Are Increased in Black Women

Compared with white women, black women had 3-fold higher odds of having a triple-negative tumor (95% confidence interval [CI], 1.6 - 5.5; P = .0001). In black women diagnosed before and after age 50 years, triple-negative tumors were equally prevalent (31% vs 29%; P = not significant). Similarly, prevalence of triple-negative tumors was similar in black women who were obese and nonobese (29% vs 31%; P = not significant). In the overall patient sample, the proportion of triple-negative tumors decreased as BMI increased (P = .08).

Limitations of this study include relatively small sample size and lack of data on clinical outcome or on potential confounders, such as parity.

"Black women of diverse background have 3-fold more Tneg tumours than non-black women, regardless of age and BMI," the study authors write. "Other factors must determine tumour subtype. The higher prevalence of Tneg tumours in black women in all age and weight categories likely contributes to black women's unfavorable breast cancer prognosis."

Ένα ...ολοκάθαρο πρωτάθλημα!

Στο ολοκάθαρο Ελληνικό ποδόσφαιρο δεν αρκεί μία ομάδα να κάνει αυτό που πρέπει για να μπορέσει να διεκδικήσει στα ίσια αυτό που «κυνηγάει» Πρέπει να μπορεί να παλέψει και με τα διάφορα «σενάρια» για να επιτύχει το στόχο της.

Κι αν ο ΑΡΗΣ σήμερα κέρδισε δύο αντιπάλους μαζί, την Αεκ και τον Κάκκο, δεν μπόρεσε – και δεν ήταν δυνατόν – να κερδίσει και τους πολλούς και διάφορους (αναμφίβολα επιτυχημένους) σεναριογράφους του πρωταθλήματος.

Χωρίς ντροπή, δίχως ίχνος τσίπας, έκαναν ότι έπρεπε να κάνουν (ή και ότι δεν έπρεπε να κάνουν μέσα στο γήπεδο) για να ολοκληρώσουν ένα εμετικό σχέδιο το οποίο φαίνεται ότι είχε καταστρωθεί με κάθε λεπτομέρεια και είχαν προβλεφθεί και οι ασφαλιστικές δικλείδες, σε περίπτωση που ...κέρδιζε ο ΑΡΗΣ, όπως και έγινε.

Ο ΑΡΗΣ στάθηκε στο ύψος των απαιτήσεων, έπαιξε το ποδόσφαιρο που έπρεπε, το ποδόσφαιρο που θέλουμε να βλέπουμε, το ποδόσφαιρο που μπορεί και θα έπρεπε να παίζει σε όλη τη διάρκεια της χρονιάς.

Το φιλμ του αγώνα

Το παιχνίδι ξεκίνησε με τους γηπεδούχου να προσπαθούν να πιέσουν στη μεσαία γραμμή τους παίκτες του ΑΡΗ, ώστε να μπορούν να βγούνε μπροστά με αξιώσεις και να απειλήσουν την εστία του Σηφάκη.

Η πρώτη καλή στιγμή, όμως, του αγώνα ήταν στο 2ο λεπτό, με ένα μακρινό σουτ από το Βανγκέλι, δεκαπέντε μέτρα έξω από τη μεγάλη περιοχή και από τον άξονα, το οποίο πέρασε ελάχιστα έξω από το αριστερό κάθετο δοκάρι της εστίας των γηπεδούχων.

Ο τρόπος ανάπτυξης των γηπεδούχων ήταν από τα άκρα και προσπαθούσαν είτε με σέντρες είτε με ατομικές ενέργειες των επιθετικών τους, να διασπάσουν την άμυνα του ΑΡΗ. Στο 5ο λεπτό, είχαμε ένα σουτ του Καφέ, μέσα από τη μεγάλη περιοχή, στα αριστερά της άμυνας του ΑΡΗ, αλλά με σωστή τοποθέτηση ο Σηφάκης μπλόκαρε εύκολα τη μπάλα.

Η ομάδα μας είχε ενισχυμένο το κέντρο, αφού εκτός από το Μπατιόν και τον Πρίττα, υπήρχε η επικουρική βοήθεια των Ρεγκέιρο (αριστερά) και του Κόκε (δεξιά), οι οποίοι είχαν οπισθοχωρήσει σε σχέση με αυτό που έχουμε συνηθίσει, ώστε να βοηθούν το παιχνίδι και την πίεση στο κέντρο.

Ο ΑΡΗΣ είχε ένα τρίλεπτο (9-12), πίεσης στο κέντρο και επιθετικής δραστηριότητας από την αριστερή πλευρά με πρωταγωνιστές το Βανγκέλι και το Ρεγκέιρο, αλλά το μόνο κέρδος ήταν ένα κόρνερ στο 10ο λεπτό, χωρίς όμως να δημιουργηθεί κάτι αξιόλογο στα «καρέ» της αεκ.

Από την άλλη, ο Κάκκος, για άλλο ένα παιχνίδι προκάλεσε από νωρίς τις αντιδράσεις των παικτών μας, αφού δεν έδινε φάουλ στα «ανορθόδοξα» μαρκαρίσματα των παικτών της αεκ, με αποτέλεσμα να υπάρχει πίεση έξω από τη μεγάλη περιοχή της ομάδας του ΑΡΗ.

Ο Κάκκος συνέχιζε να εκνευρίζει τους παίκτες μας, αυτή τη φορά όμως με τη μη υπόδειξη φάουλ σε ολοφάνερα σκληρά μαρκαρίσματα έξω από τη μεγάλη περιοχή (περίπτωση Χαβίτο 18ο λεπτό)

Στο 21ο λεπτό είχαμε μια καλή στιγμή για τον ΑΡΗ, όταν ο Ρεγκέιρο έβγαλε τη σέντρα από την δεξιά πλευρά της άμυνας των γηπεδούχων, αλλά πριν από το Κάμπορα που ήταν μέσα στη μικρή περιοχή αμαρκάριστος, κατάφερε ο Σάχα με υπερένταση να απομακρύνει.

ΓΚΟΛ!!! Στο 22ο λεπτό είχαμε το «άνοιγμα» του σκορ για τον ΑΡΗ. Ο Νέτο έβγαλε τη σέντρα από τα δεξιά, η μπάλα έφτασε στο Χαβίτο, που έπιασε λίγο έξω από τη μικρή περιοχή την κεφαλιά-«ψαράκι», η μπάλα πήγε στο δεξί κάθετο δοκάρι της εστίας της αεκ, αλλά στην επαναφορά ο Κόκε με «ψύχραιμο» πλασαριστό σουτ από τη γραμμή της μικρής περιοχής, έκανε το 0-1 για τον ΑΡΗ.

Ο Κάκκος συνέχιζε να μη δίνει φάουλ σε παραβάσεις των παικτών της αεκ, αλλά με πολύ άνεση έβγαλε την κίτρινη κάρτα στον (αρχηγό) Κόκε, που διαμαρτυρήθηκε στο 27ο λεπτό, επειδή δε δόθηκε φάουλ σε χτύπημα πάνω στο Χαβίτο.

Ο ΑΡΗΣ δεν «κλείστηκε» πίσω, αλλά προσπαθούσε να βγαίνει με αξιώσεις προς τα αντίπαλα καρέ, κυρίως από τη δεξιά πλευρά των γηπεδούχων.

Στο 30ο λεπτό, ο Ρεγκέιρο έβγαλε τη σέντρα, αλλά ο Κόκε που ήταν στο ύψος του πέναλτι δεν πρόλαβε να σουτάρει τη μπάλα, αφού πέρασε μπροστά του με μεγάλη δύναμη.

Στο 32ο λεπτό, πάλι ίδιο σκηνικό με τους δύο παίκτες, ο Κόκε έπιασε την κεφαλιά, η οποία έφυγε όμως ψηλά πάνω από το οριζόντιο δοκάρι της εστίας του Σάχα.

Η πίεση των παικτών μας ήταν ασφυκτική στο δικό μας «μισό» και με μαν-του-μαν σε Εντίνιο και Μπλάνκο, οι οποίοι δε μπορούσαν να απεγκλωβιστούν από τους Κουλουχέρη και Ρομπέρζ.

Από την άλλη, στο κέντρο υπήρχε ο έλεγχος και η επιθετική ανάπτυξη, όπως είχαμε πει γίνονταν από την αριστερή μας πλευρά με το Ρεγκέιρο να είναι ο αποδέκτης της τελικής πάσας των μέσων μας.

Τα διαιτητικά «όργια» και η ανοχή υπέρ των παικτών της αεκ εκτός από τον Κάκκο είχαν και την ανοχή των βοηθών Γενναίου και Ευθυμιάδη, οι οποίοι έδιναν πάντα με τις υποδείξεις τους τη μπάλα στους γηπεδούχους.

Η αεκ, ελέω των παραπάνω «καταστάσεων», είχε ένα τρίλεπτο πίεσης από το 38ο ως το 41ο λεπτό, αφού είχαμε υποδείξεις «φάουλ» έξω από την περιοχή του ΑΡΗ και λανθασμένες υποδείξεις δύο…..κόρνερ….

Στο 43ο λεπτό, βέβαια, ο Κάκκος δε μπορούσε να μην αντιδράσει στο σκληρό μαρκάρισμα του Αλεξόπουλου πάνω στο Χαβίτο, που του έκανε προσποίηση και τον «άδειασε», και έτσι έδειξε την κίτρινη κάρτα στον αμυντικό της αεκ.

Τα υπόλοιπα λεπτά που ακολούθησαν ως και το τελευταίο σφύριγμα του Κάκκου για το πρώτο ημίχρονο δεν είχαν κάτι το αξιοσημείωτο, με τον ΑΡΗ να πηγαίνει στα αποδυτήρια για την ανάπαυλα του ημιχρόνου, προηγούμενος με 0-1.

Το δεύτερο ημίχρονο ξεκίνησε με τους παίκτες της γηπεδούχου να προσπαθούν να πιέσουν σε όλο το γήπεδο για να δημιουργηθεί το λάθος στο κέντρο, κυρίως, και κάποιο «ρήγμα» στην άμυνα του ΑΡΗ, όμως η αμυντική διάταξη των παικτών μας ήταν πολύ καλή και δε δημιουργήθηκε κάτι επικίνδυνο στα «καρέ» του Σηφάκη.

Η πρώτη καλή στιγμή για το δεύτερο ημίχρονο ήταν στο 58ο λεπτό και ανήκε στην αεκ, όταν ύστερα από εκτέλεση φάουλ του Μαντούκα, ο Μαϊστόροβιτς έπιασε την κεφαλιά από το ύψος του πέναλτι, αλλά ο Σηφάκης μπλόκαρε με θεαματικό τρόπο τη μπάλα.

Στο αμέσως επόμενο λεπτό, οι γηπεδούχοι είχαν άλλη μια καλή στιγμή, όταν ο Μπλάνκο παρενεβλήθη σε μια σέντρα σουτ μέσα στη μικρή περιοχή, αλλά η μπάλα απομακρύνθηκε από τον Ρομπέρζ, που ήταν πάνω στη γραμμή.

Η απάντηση του ΑΡΗ σε όλα τα παραπάνω ήταν το σουτ του Χαβίτο στο 61ο λεπτό, μέσα από τη μεγάλη περιοχή και δεξιά, αλλά η μπάλα πήγε στην εξωτερική πλευρά των διχτύων και λίγο έξω από το αριστερό κάθετο δοκάρι της εστίας των γηπεδούχων.

Στο 62ο λεπτό, ο Κάμπορα βρέθηκε με τη μπάλα μέσα στη μεγάλη περιοχή, απέφυγε με κλειστή ντρίμπλα τον προσωπικό του αντίπαλο και πάσαρε στην αμαρκάριστο Χαβίτο, ο οποίος από το ύψος του πέναλτι έστειλε τη μπάλα λίγο πάνω από το οριζόντιο δοκάρι.

Στο 67ο λεπτό ο Κόκε με το Χαβίτο έπαιξαν το 1-2 με ωραίο τρόπο, ο τελευταίος έβγαλε τη σέντρα μέσα στη μεγάλη περιοχή και αριστερά, αλλά ο Κάμπορα την τελευταία στιγμή έχασε το κοντρόλ και δεν έπιασε το σουτ, όπως θα ήθελε, με αποτέλεσμα η μπάλα να μπλοκαριστεί με εύκολο τρόπο από το Σάχα.

Στο 68ο λεπτό, ο Μαντούκα σούταρε με το αριστερό μέσα από τη μεγάλη περιοχή του ΑΡΗ και από τη δεξιά πλευρά, αλλά ο Σηφάκη με καλή τοποθέτηση μπλόκαρε τη μπάλα.

Στο 70ο λεπτό είχαμε την εκτέλεση ενός φάουλ 30 μέτρα έξω από τη μεγάλη περιοχή, από τον Εντίνιο, αλλά η μπάλα έφυγε πάνω από το οριζόντιο δοκάρι του Σηφάκη.

Ο Κάκκος συνέχιζε να βοηθάει τους γηπεδούχους στο να αμύνονται, αφού δεν έδινε ολοκάθαρα φάουλ (πάνω σε Χαβίτο και Νέτο) έξω από τη μεγάλη περιοχή της αεκ, δίνοντας έτσι την ευκαιρία στους αμυντικούς της αεκ να κερδίζουν τη μπάλα με εύκολο τρόπο.

Στο 75ο λεπτό είχαμε την εκτέλεση φάουλ από τον Κόκε, δέκα μέτρα έξω από τη μεγάλη περιοχή και αριστερά, αλλά η μπάλα, αν και έφυγε με δύναμη και φάλτσο, δεν ανησύχησε τον τερματοφύλακα της αεκ.

Ο ρυθμός του παιχνιδιού ως και το 83ο λεπτό, «έπεσε» κάπως, αφού είχαμε συνεχή φάουλ εκατέρωθεν και έτσι δε μπορούσε καμία από τις δύο ομάδες να έχει σταθερό ρυθμό και να επιβάλει το παιχνίδι της.

Στο 85ο λεπτό ο Κάκκος θεώρησε αντικανονικό το μαρκάρισμα το Κόκε στο Χουαφράν, είκοσι μέτρα έξω από τη μεγάλη περιοχή των γηπεδούχων, και έτσι τον απέβαλε με απ΄ευθείας κόκκινη κάρτα.

Ο παίκτης της αεκ, ύστερα από ένα λεπτό δε μπόρεσε να συνεχίσει και έτσι η ομάδα του έμεινε και αυτή με 10 παίκτες στον αγωνιστικό χώρο, αφού είχαν συμπληρωθεί οι τρεις αλλαγές.

Στο 2ο λεπτό των καθυστερήσεων ο Χαβίτο έπιασε το σουτ από τη δεξιά πλευρά της μεγάλης περιοχής, αλλά η μπάλα έφυγε με δύναμη αρκετά μέτρα έξω από το αριστερό κάθετο δοκάρι της εστίας των γηπεδούχων.

Το παιχνίδι έληξε με τον ΑΡΗ να πετυχαίνει μια μεγάλη νίκη μεν με 0-1, νίκη που επισκιάστηκε από το …αξιοπερίεργο διπλό της Λάρισας μέσα στο Καραϊσκάκη.

HYPOTHYROIDISM AND TYROSINE KINASE INHIBITORS

Hypothyroidism related to tyrosine kinase inhibitors

An emerging toxic effect of targeted therapy

Despite their inherent selectivity, targeted therapies such as tyrosine kinase inhibitors (TKIs) can cause unusual adverse effects. Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction. Retrospective studies indicate that sunitinib can induce hypothyroidism in 53–85% of patients, and in prospective studies this complication has been reported in 36–71% of patients. Sorafenib has been reported to be responsible for hypothyroidism in 18% of patients with metastatic renal-cell carcinoma. Axitinib induced hypothyroidism in preclinical studies, but this result has not yet been reported in clinical trials. Furthermore, imatinib and sunitinib seem to increase the requirement of levothyroxine in hypothyroid patients. The management of thyroid dysfunction and possible related symptoms, such as fatigue, represents a challenge to oncologists. Dr Francesco Torino from the Medical Oncology Division, San Filippo Neri Hospital, Rome, Italy and colleagues proposed a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism in the latest issue of Nature Reviews Clinical Oncology.

Several possible mechanisms that lead to sustained TKI-related thyroid toxic effects have been suggested, but pharmacological and preclinical data are lacking. Understanding whether sunitinib-related or sorafenib-related hypothyroidism is dependent on the drug's direct mechanism of action (i.e. inhibition of VEGFR-2, KIT, BRAF, RET etc.), or because of indirect effects on other targets (mechanism-independent toxic effects) will be important to optimize therapy. Accurate studies on the mechanism-dependent and mechanism-independent toxic effects of new cancer drugs in clinical settings will not only lead to safer treatment with targeted agents, but could also provide the opportunity to achieve a better therapeutic index in individual patients. Unfortunately, the majority of published studies on hypothyroidism as an adverse effect of TKIs are observational. A common problem shared by all the studies is the small number of patients evaluated, which reduces the statistical power of each single study and the reliability of the conclusions.

Prospective trials are needed to explore the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and other TKIs. To this aim, epidemiological and biological features of thyroid function should be carefully tested. TSH levels progressively rise with age. The prevalence of subclinical hypothyroidism might, therefore, be significantly overestimated unless an age-specific range for TSH is used. In future studies biological correlative features (such as the role of key genes for thyroid function) would help to define the molecular mechanisms of TKI-induced damage of thyroid function.

It would be of interest to compare the incidence of thyroid toxic effects induced by TKIs when used as first-line treatment to that following sequential therapy. If thyroid dysfunction is more frequent in patients after second-line or third-line treatments, a 'summation effect' related to the sequential treatments might be responsible. In addition, because TKI-related hypothyroidism seems to be a long-term adverse effect, the investigational use of TKIs in the adjuvant setting should take into account this issue, and monitoring thyroid function in patients treated with sunitinib or sorafenib should be mandatory.

The clinical relevance of overt hypothyroidism, the value of thyroid hormone replacement in individuals with abnormal TSH after TKI therapy, and the correct timing of replacement therapy need to be defined more accurately and should be evaluated prospectively with appropriately designed clinical trials. To this aim, a closer collaboration between oncologists and endocrinologists will improve the majority of the above issues and improve the therapies used and quality of life for patients with cancer.

LAB SUCCESS

Sunitinib Effective in Metastatic Renal Cell Cancer

NEW YORK (Reuters Health) Apr 07 - Sunitinib shows substantial activity in most patients with metastatic clear-cell renal carcinoma, Greek researchers report in a March 12th on-line paper in BMC Cancer. As yet, however, there are no clear indictors of which patients will gain benefit.

Dr. Konstantinos T. Papazisis told Reuters Health, "We report favorable outcomes and a good safety profile, similar to what has been observed in the pivotal trials. We also showed that shrinking the tumor doesn't really matter as long as we are able to stop it growing; patients with disease stabilization or disease remission have a similar overall survival."

Dr. Papazisis, of Theagenion Cancer Hospital, Thessaloniki, and colleagues report on treatment responses in 39 patients, 30 of whom obtained clinical benefit. Median progression-free survival was almost 9 months and median overall survival was more than 16 months.

In investigating possible indicators of response, the researchers found that patients with clinical benefit had significantly lower plasma VEGF increases compared to those with progression after 2 cycles of treatment. However, in patients with initial clinical benefit, subsequent progression did not lead to an increase in plasma VEGF.

Because sunitinib does not benefit every patient, Dr. Papazisis said, "We are on a search for markers that would predict outcome early on in the course of treatment. This would save unnecessary treatment-related side effects and costs."

BMC Cancer. 2009 Mar 12;9:82.

Related Articles, References for this PMC Article, Free in PMC, LinkOut

Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers.

Kontovinis LF, Papazisis KT, Touplikioti P, Andreadis C, Mouratidou D, Kortsaris AH.

3rd Department of Medical Oncology, Theagenion Cancer Hospital, Al Simeonidi str. 2, 54007, Thessaloniki, Greece. loukas.kontovinis@gmail.com

BACKGROUND: Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution. METHODS: We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA. RESULTS: At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression. CONCLUSION: Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.

AMIODARONE EFFECTIVE FOR PERSISTENT ATRIAL FIBRILLATION

Amiodarone Effective for Persistent Atrial Fibrillation

NEW YORK (Reuters Health) Apr 02 - Pooled data from studies involving more than 5000 patients indicate that amiodarone is effective and safe in patients with persistent atrial fibrillation, Australian researchers report in the March issue of Mayo Clinic Proceedings.

Drs. James F. Doyle and Kwok M. Ho of the Royal Perth Hospital note that although the agent is useful in achieving and maintaining sinus rhythm, it also has serious systemic adverse events.

To gain more information on the benefits and risks, the investigators initially reviewed more than 200 randomized controlled trials of amiodarone versus a rate control drug or placebo. Twelve studies that involved a total of 5060 patients with persistent AF ultimately met their inclusion criteria and underwent meta-analysis.

Compared to beta blockers, digoxin or placebo, amiodarone was significantly more successful in achieving sinus rhythm (relative risk 3.2). There was no increase in long-term mortality associated with its use (relative risk, 0.95).

However, cessation of therapy because of intolerable adverse events was much more common in amiodarone patients than those given rate control drugs or placebo (relative risk, 3.0). Nevertheless, there was no increased risk of hospitalization in these patients.

"Our findings," Dr. Ho told Reuters Health, "suggest that long-term amiodarone can be considered as a treatment option for those who have disturbing symptoms from persistent atrial fibrillation. Lower doses of amiodarone -- less than 200 mg per day -- also appears to be equally effective but with less side effects."

However, the researchers add that whether long-term low-dose therapy with the agent "is more cost-effective and better tolerated than new analogues of amiodarone, such as dronedarone, remains uncertain and merits further investigation."

HOT TEA AND ESOPHAGEAL CANCER

Hot Tea Consumption Linked to Higher Risk for Esophageal Cancer

April 3, 2009 — Drinking hot tea was strongly associated with a higher risk for esophageal cancer according to the results of a northern Iranian population-based case-control study reported online first on March 27 in the British Medical Journal.

"An association between drinking hot beverages and risk of oesophageal cancer has been reported in several studies from different parts of the world," write Farhad Islami, MD, from Shariati Hospital, Tehran University of Medical Sciences in Iran, and colleagues. "In Golestan, tea and water are the only drinks commonly consumed, with comparable average intake. An ecological study showed that inhabitants of Golestan drank more tea and at a higher temperature than people living in a nearby area with a low incidence of oesophageal cancer."

The goal of this study was to evaluate the relationship between characteristics of tea drinking habits in Golestan province in northern Iran, which is an area with a high incidence of esophageal squamous cell carcinoma (SCC), and risk for that disease. Patterns of tea drinking and temperature at which tea was usually drunk were also determined for healthy persons enrolled in a cohort study.

Tea drinking among 300 patients with histologically proven esophageal SCC was compared with that in 571 matched neighborhood controls in the case-control study and in 48,582 participants in the cohort study. The primary study endpoint was the odds ratio (OR) of esophageal SCC associated with drinking hot tea.

Regular drinking of black tea was reported by 98% of the cohort participants, with mean daily volume more than 1 L. Reported temperature of tea was less than 60°C in 39.0% of participants, 60°C to 64°C in 38.9%, and 65°C or higher in 22.0%. Reported temperature agreed moderately with actual temperature measurements (weighted κ, 0.49).

In the case-control study, risk for esophageal cancer was increased for drinking hot tea (OR, 2.07; 95% confidence interval [CI], 1.28 – 3.35) or very hot tea (OR, 8.16; 95% CI, 3.93 – 16.9) vs lukewarm or warm tea. Risk was also significantly increased for drinking tea 2 to 3 minutes after pouring (OR, 2.49; 95% CI, 1.62 – 3.83) or less than 2 minutes after pouring (OR, 5.41; 95% CI, 2.63 – 11.1) vs drinking tea at least 4 minutes after being poured. Responses to the questions about temperature at which tea was drunk agreed strongly with interval from tea being poured to being drunk (weighted κ, 0.68).

"Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer," the study authors write.

Limitations of this study include possible information bias regarding the amount and temperature of consumed tea, validation study performed among healthy people, possible selection bias, and some missing data.

"A large proportion of Golestan inhabitants drink hot tea, so this habit may account for a substantial proportion of the cases of oesophageal cancer in this population," the study authors write. "Informing the population about the hazards of drinking hot tea may be helpful in reducing the incidence of oesophageal cancer in Golestan and in other high risk populations where similar habits are prevalent."

In an accompanying editorial, David C, Whiteman, from Queensland Institute of Medical Research at Royal Brisbane Hospital in Australia, recommends allowing tea to cool for 5 minutes before drinking.

"The mechanism through which heat promotes the development of tumours warrants further exploration and might be given renewed impetus on the basis of these findings," Dr. Whiteman writes. "These findings are not cause for alarm, however, and they should not reduce public enthusiasm for the time honoured ritual of drinking tea. Rather, we should follow the advice � [that suggests] a five to 10 minute interval between making and pouring tea, by which time the tea will be sufficiently flavoursome and unlikely to cause thermal injury."

GEMCITABINE CISPLATIN COMBINATION FOR BREAST CANCER?

Gemcitabine-Cisplatin Could Be Clinically Useful in Metastatic Breast Cancer

NEW YORK (Reuters Health) Apr 03 - The combination of gemcitabine and cisplatin is active against metastatic breast cancer, whether prior treatment has been minimal or aggressive, according to two phase 2 studies published online on March 23 by the Journal of Clinical Oncology.

The parallel studies, designed by the California Cancer Consortium and Loyola University Chicago and led by Dr. Helen K. Chew at the University of California Davis, Sacramento, enrolled 136 patients with histologically confirmed metastatic or locally recurrent breast cancer. Their median age was 46 years.

One of the two study populations comprised 74 women who had been heavily pretreated, with at least two chemotherapy regimens for metastatic disease or disease progression after bone marrow or hematopoietic cell transplantation. In addition, all had received anthracycline or taxane therapy.

The 62 women in the minimally treated population had received no more than one prior regimen, without either cisplatin or gemcitabine.

Treatment during the study was a 21-day cycle with cisplatin 25 mg/m daily on days 1 through 4 and gemcitabine 1,000 mg/m on days 2 and 8. Participants in the heavily pretreated group received a median of three cycles of protocol therapy, while those in the minimally pretreated group received a median of four.

The overall response rate was 26% in both groups. The duration of response was 5.3 months in the heavily pretreated group and 5.9 months in the minimally pretreated. Median overall survival was 10.8 months in the heavily pretreated group and 13.1 months in the minimally pretreated.

In a subset of 55 patients, the study also analyzed polymorphisms in 10 genes relevant to gemcitabine and cisplatin, including those involved in DNA repair, drug metabolism and cell-cycle control.

The XPD-751 polymorphism was associated with significantly increased overall survival, among participants who carried the Lys allele rather than the Gln allele.

The XRCC3 polymorphism was associated with significantly better response rate and progression-free survival among patients who carried the Thr/Thr genotype instead of the heterozygous Met/Thr genotype.

"Our findings," the researchers write, "implicate the potential importance of DNA repair enzymes and drug metabolism enzymes in the prediction of clinical outcome to chemotherapy in metastatic breast cancer."

ENERGY DRINKS AND PATIENTS WITH CARDIOVASCULAR DISEASE

"Energy Drinks" Potentially Harmful to Patients With Cardiovascular Disease

NEW YORK (Reuters Health) Apr 03 - Consumption of energy drinks increases blood pressure and heart rate, and should therefore be avoided by people with hypertension or heart disease, according to results of a small prospective study.

The beverages, marketed to enhance cognitive function and stamina, usually contain caffeine, taurine, sugars, vitamins, and other nutritional supplements, Dr. James S. Kalus, at Henry Ford Hospital in Detroit, and co-authors note in The Annals of Pharmacotherapy for April. The potential hemodynamic or electrocardiographic effects of energy drinks have not been studied.

To look into this, the researchers studied 15 healthy volunteers, 20-39 years of age, who abstained from other dietary sources of caffeine, beginning 48 hours prior to baseline.

The subjects drank 500 mL (2 cans, each containing 100 mg taurine and 100 mg caffeine) of an energy drink over 30 minutes daily for 7 days. On days 1 and 7, blood pressure, heart rate, and electrocardiograms were obtained prior to consuming the drinks and 5 times during the 4 hours afterward.

Mean heart rate increased significantly from baseline by 7.8% on day 1 and by 11.0% on day 7; corresponding increases for systolic blood pressure were 7.9% and 9.6%, and for diastolic blood pressure, 7.0% and 7.8%. EKG parameters did not change significantly.

"Increases in blood pressure and heart rate of the magnitude observed in our study could be significant in persons with known cardiovascular disease," Dr. Kalus and his associates maintain, especially in patients who exhibit impaired baroreflex buffering in response to vasoactive substances. Young individuals with undiagnosed, premature cardiovascular disease could also be at risk.

They advise clinicians that "consumption of these drinks could, theoretically, be a frequently overlooked cause of altered medication effectiveness or even hospital admissions or emergency department visits."

SERUM AMYLOID A AND MELANOMA PROGNOSIS

Worse Melanoma Prognosis With Higher Serum Amyloid A

NEW YORK (Reuters Health) Apr 08 - Higher serum amyloid A (SAA) levels in patients with melanoma are associated with worse progression-free and overall survival, according to a report in the March 23rd online issue of the Journal of Clinical Oncology.

Currently recognized serum biomarkers of melanoma are powerful predictors of outcome in metastatic disease, but weak in early-stage patients, the authors explain.

Dr. Peter Findeisen from University of Heidelberg in Germany and colleagues investigated the prognostic value of SAA in comparison to S100B, lactate dehydrogenase (LDH), and C-reactive protein (CRP) in patients comprising all clinical stages of melanoma.

Patients with SAA levels below 10 mg/L showed a favorable survival compared with patients with higher SAA levels, the authors report.

S100B, SAA and CRP were all independent prognostic factors.

SAA was a significant prognostic marker among patients in stage I-III and in patients in stage IV.

Among patients in earlier stages (I-III), only SAA and CRP proved to be significant prognostic markers.

The combination of SAA and CRP proved significantly better than SAA or CRP alone in predicting outcomes, the researchers note.

"The significant interaction found between CRP and SAA by multivariate analysis deserves particular notification, as far as we observed a significant decrease in the probability of survival starting from patients showing normal values of both markers, followed by patients showing elevated levels of SAA, then followed by patients showing elevated levels of CRP, and finally ending with the worst prognosis in patients showing elevated levels of both SAA and CRP," the investigators report.

"These results indicate that SAA and CRP combined could serve as useful prognostic serum biomarkers in melanoma, particularly in early-stage patients," the authors conclude. "In this patient group these new markers could help to identify patients at high risk of disease progression in strong need of adjuvant treatment."

LYNCH SYNDROME DETECTED WITH SIMPLE IMMUNOHISTOCHEMISTRY

Lynch Syndrome Detectable Using Microsatellite Instability

NEW YORK (Reuters Health) Apr 08 - Lynch syndrome - also called hereditary non-polyposis colorectal cancer (HNPCC) -- can be detected in young colorectal cancer patients using microsatellite instability (MSI) as the initial test, according to a report in the March 1st International Journal of Cancer.

"A relatively simple lab test will allow the identification of younger colorectal cancer patients who are likely to have Lynch syndrome," Dr. Barry Iacopetta from University of Western Australia, Nedlands, told Reuters Health. "If this is confirmed by further genetic tests, it will allow other affected family members who have the mutant gene to undergo regular surveillance."

Dr. Iacopetta and colleagues used MSI as the initial screen to ascertain previously unrecognized cases of Lynch syndrome out of all patients diagnosed with colorectal cancer in Western Australia between 2000 and 2006.

MSI was found in 8.7% of colorectal tumors from patients under age 60 years, the authors report, but the frequency of MSI was higher (15.7%) among patients under 45 years old.

In 97 cases evaluated using immunohistochemistry, 95 (98%) showed loss of expression in at least one mismatch repair protein.

Similarly, among 35 patients for whom germline mutation data could be obtained, likely pathogenic mutations were found in 11 cases and unclassified variants in 2 cases.

Using all the available data, the total number of germline mutation carriers in the entire cohort of 1344 patients under 60 years old was estimated at 48 (3.6%), including 25 already known, 11 newly discovered, and 12 extrapolated to exist in patients who were not tested.

"Thanks to this test, there is no reason why Lynch syndrome families should go undetected in the population," Dr. Iacopetta said. "We recommend that all colorectal cancer patients aged less than 55 years should undergo MSI testing."

"This strategy avoids the reliance on clinicians to routinely obtain a family history of cancer as the screening method for determining referral to familial cancer clinics," the investigators explain. "Although this MSI-based approach cannot identify 100% of Lynch syndrome cases, and further comparisons with an immunohistochemistry-based approach are required, we believe it represents an effective strategy for detecting the maximum number of cases with minimal use of resources."

"In the state of Western Australia this test is now being offered to all younger patients at no cost," Dr. Iacopetta added.

SORAFENIB NOT USEFUL FOR MELANOMA

J Clin Oncol. 2009 Apr 6. [Epub ahead of print]

Related Articles, LinkOut

Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma.

Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U.

University of Kiel, Kiel; Charité Berlin; University Hospital Benjamin Franklin, Berlin; Johannes Gutenberg Clinic-Mainz University, Mainz, Germany; Johann Wolfgang Goethe University, Frankfurt am Main; Klinikum rechts der Isar, Munich; University Hospital of Mannheim, Mannheim, Germany; University Hospital of Tuebingen, Tuebingen, Germany; St Luke's Hospital and Health Network, Bethlehem; University of Pittsburgh Cancer Institute, Pittsburgh, PA; University of Colorado Cancer Center, Aurora, CO; The Angeles Clinic and Research Institute, Santa Monica; Onyx Pharmaceuticals, Emeryville, CA; H. Lee Moffitt Cancer Center, Tampa, FL; Bayer AG, West Haven, CT; University of Toronto and Princess Margaret Hospital, Toronto, Ontario, Canada; Institut Gustave-Roussy, Villejuif Cedex, France; Newcastle Mater Misericordiae Hospital, Newcastle, New South Wales, Australia; and the Erasmus University Medical Center-Daniel den Hoed Cancer Centre, Rotterdam, Netherlands.

PURPOSE: This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. PATIENTS AND METHODS: A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m(2) plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. RESULTS: The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3 thrombocytopenia, diarrhea, and fatigue were more common in patients treated with sorafenib plus CP versus placebo plus CP. CONCLUSION: In this study, the addition of sorafenib to CP did not improve any of the end points over placebo plus CP and cannot be recommended in the second-line setting for patients with advanced melanoma. Both regimens had clinically acceptable toxicity profiles with no unexpected adverse events. A trial of similar design for the first-line treatment of patients with advanced melanoma (intergroup trial E2603) is currently ongoing.

BROCCOLI AND GASTRIC CANCER

Broccoli Sprouts May Protect Against Gastric Cancer

April 8, 2009 — Preliminary research suggests that broccoli sprouts have chemopreventive properties. In a pilot clinical trial and an animal study, researchers found that the consumption of broccoli sprouts can reduce colonization of Helicobacter pylori, which is associated with the development of gastritis and gastric cancer. In addition, consuming broccoli sprouts appears to enhance antioxidant and anti-inflammatory enzymes in the stomach.

The study, published in the April issue of Cancer Prevention Research, builds on earlier research about the potential value of sulforaphane, a naturally occurring biochemical that is found in relative abundance in fresh broccoli sprouts. Laboratory experiments using purified sulforaphane have shown that it displays antibacterial properties against helicobacter and even kills strains that are resistant to commonly used antibiotics (Proc Natl Acad Sci U S A. 2002;99:7610-7615).

"In our 2002 study, sulforaphane killed helicobacter directly in the test tube," said study author Jed W. Fahey, MS, ScD, a nutritional biochemist in the Lewis B. and Dorothy Cullman Cancer Chemoprotection Center at the Johns Hopkins University School of Medicine, in Baltimore, Maryland. "It also reduced the rate of gastric cancer in mice."

Although the pure compound effectively eliminated helicobacter, it was not clear whether the same effect could be reproduced with dietary sources of sulforaphane. The current study showed that a dietary source might to exert a similar but milder effect.

"The key take-home message harkens back to the old message — eat veggies," Dr. Fahey told Medscape Oncology. "We're now giving people the science that shows why eating fruits and vegetables is good for your health."

Research has shown that fruits and vegetables contain phytonutrients, which might have a protective effect. "Right now," said Dr. Fahey, "we're providing the evidence that shows that broccoli is good for you."

The current research is actually 2 complementary studies — 1 in mice and 1 in humans infected with H. pylori — in which sulforaphane-rich broccoli sprouts were added to the diet.

Reduction Seen in Biomarkers of Inflammation and H. pylori Colonization

The human trial was conducted in Japan, where there is a high incidence of chronic H. pylori infection. A cohort of 48 people with H. pylori infection were randomized to consume either 70 g/day of broccoli sprouts (containing 420 μmol of sulforaphane precursor) for 8 weeks, or an equal amount of alfalfa sprouts. Although rich in phytochemicals, alfalfa sprouts do not contain sulforaphane.

All study participants had blood, stool, and urine samples collected on days 0, 28, 56, and 112. In stool samples, H. pylori stool antigen (HpSA), which is a biomarker of H. pylori colonization, was analyzed, and in blood samples, serum pepsinogens (PG)I and PGII, biomarkers of gastric inflammation, were measured. The severity of current H. pylori colonization was assessed using the urea breath test.

The researchers found that the level of HpSA was reduced by more than 40% in the broccoli-sprout group but was unchanged in the alfalfa group. During the intervention period, there were also significant reductions in both PGI and PGII (P < .05), but only in the broccoli-sprout group.

However, values for HpSA and PGI/II returned to baseline levels 2 months after the intervention. Broccoli-sprout consumption does reduce H. pylori colonization, the researchers note, but does not completely eradicate the pathogen.

Data From Experimental Model

In the first experiment of the mouse trial, C57BL/6 female mice infected with H. pylori Sydney strain 1 were maintained on a high-salt diet (7.5% NaCl) and were fed broccoli sprouts. The result was reduced gastric bacterial colonization and attenuated mucosal expression of tumor necrosis factor-α and interleukin-1β, which are major proinflammatory cytokines that are elevated in gastric mucosa by H. pylori infection. Broccoli sprouts added to the diet suppressed the upregulation of these cytokines.

They also observed that the protective effect against gastric mucosa inflammation was paralleled by significant inhibition of gastric atrophy and reduced levels of both 8-OHdG and single-stranded DNA, which are markers of apoptosis.

A second experiment was conducted using H. pylori–infected mice that had been genetically engineered to lack the Nrf2 gene, which activates protective enzymes. Consumption of broccoli sprouts did not appear to offer the same protection to this group of mice. This finding confirmed previous findings that Nrf2 plays a role in protecting against H. pylori–induced inflammation and gastritis, according to the researchers.

Possible Reduction of Cancer

"In our study, we reduced levels of H. pylori," said Dr. Fahey. "Reducing the risk of stomach cancer was not the outcome, but the progression is clear — the risk of cancer is 3- to 6-fold higher with H. pylori infection."

"If you reduce colonization, then you can reduce infection," he added. "We didn't cure anyone, but we never expected dietary intervention alone to do that."

As the population ages, the incidence of cancer is expected to increase. "The number of new cases will double in the next 25 years, so the burden on the health system will be intolerable," said Paul Talalay, MD, the John Jacob Abel Distinguished Service Professor of Pharmacology and director of the Laboratory for Molecular Sciences at Johns Hopkins University School of Medicine.

"It is not a choice to look at prevention or protection against cancer, it is a mandate," said Dr. Talalay in a statement.

Although not involved in this study, Dr. Talalay is a pioneer in the study of dietary phytochemicals that might help protect against cancer, and he is scheduled to receive the Linus Pauling Institute Prize for Health Research on May 18, 2009. The award is one of the leading honors in the world for scientists studying micronutrients, diet, and other natural approaches to disease prevention or therapy.

WHERE STATISTICS MATTERS

Medical Errors Still Common in US Hospitals: HealthGrades Study

NEW YORK (Reuters Health) Apr 07 - While patient safety in US hospitals is improving, "medical mistakes still occur at an alarming rate," according to the Sixth Annual HealthGrades Patient Safety in American Hospitals Study, released today.

Between 2005 and 2007, medical errors cost Medicare over $6.9 billion and were responsible for more than 92,000 potentially preventable in-hospital deaths among Medicare beneficiaries, report Dr. Rick May and co-authors at HealthGrades, a healthcare ratings organization in Golden, Colorado.

Dr. May's group used a Medicare inpatient database to evaluate 12 patient safety indicators at nearly 5000 hospitals. The 242 best-performing hospitals were recognized with the HealthGrades 2009 Patient Safety Excellence Award.

More than 913,000 total patient safety events occurred, representing 2.3 percent of the nearly 38 million Medicare hospitalizations. Patients who experienced at least one event had a one-in-ten chance of dying, the report indicates.

The investigators observed that, on average, Medicare patients treated at award-winning hospitals were 43% less likely to experience one of the assessed medical errors compared with those at bottom-ranking hospitals. "This finding of better performance was consistent across all 12 patient safety indicators studied," the authors write.

Errors with the highest incidence rates were failure to rescue, defined as death among surgical inpatients with serious treatable complications (96.2 per 1000 patients); decubitus ulcer (32 per 1000); postoperative respiratory failure (17.2 per 1000); and postoperative sepsis (14.9 per 1000).

"The good news is that there are hospitals that are doing an amazing job when it comes to patient safety," Dr. May says in a press release. "Patients need to know that they have a substantially lower risk of experiencing a medical error and therefore a lower risk of death or complications when they are admitted to one of these exceptional top-performing hospitals."

Individual hospital ratings can be viewed for free at www.healthgrades.com.

IP AS EFFECTIVE AS EP FOR SMALL CELL LUNG CANCER

J Clin Oncol. 2009 Apr 6. [Epub ahead of print]

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Phase III Trial of Irinotecan/Cisplatin Compared With Etoposide/Cisplatin in Extensive-Stage Small-Cell Lung Cancer: Clinical and Pharmacogenomic Results From SWOG S0124.

Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, Jett J, Langer CJ, Kuebler JP, Dakhil SR, Chansky K, Gandara DR.

University of California Davis Cancer Center, Sacramento; Cedars Sinai Cancer Center; University of Southern California Norris Cancer Center, Los Angeles, CA; Southwest Oncology Group Statistical Center, Seattle, WA; North Shore-Long Island Jewish Health System, Manhasset, NY (Cancer and Leukemia Group B); Mayo Clinic, Rochester, MN (North Central Cancer Treatment Group); University of Pennsylvania Abramson Cancer Center, Philadelphia, PA (Eastern Cooperative Oncology Group); Columbus Community Clinical Oncology Program, Columbus, OH; and Wichita Community Clinical Oncology Program, Wichita, KS.

PURPOSE: Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC. PATIENTS AND METHODS: Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks). Blood specimens for genomic DNA analysis were collected before random assignment in 169 patients. RESULTS: Of 671 patients, 651 were eligible (324 and 327 patients in the IP and EP arms, respectively). Response rates with IP and EP were 60% and 57%, respectively (P = .56). Median progression-free survival for IP and EP was 5.8 and 5.2 months, respectively (P = .07). Median overall survival for IP and EP was 9.9 and 9.1 months, respectively (P = .71). Severe diarrhea was more common with IP (19% v 3%); severe neutropenia and thrombocytopenia were higher with EP versus IP (68% v 33% and 15% v 4%, respectively). PG analysis showed that ABCB1 (C3435T)T/T (membrane transport) was associated with IP-related diarrhea; UGT1A1 (G-3156A)A/A (drug metabolism) was associated with IP-related neutropenia. CONCLUSION: This large North American trial failed to confirm the previously reported survival benefit observed with IP in Japanese patients. Both regimens produced comparable efficacy, with less hematologic and greater gastrointestinal toxicity with IP. These results emphasize the potential importance of PG in interpreting trials of cancer therapy.

ADDING IXABEPILONE TO CAPECITABINE IS NOT COSTT EFFECTIVE

J Clin Oncol. 2009 Mar 30. [Epub ahead of print]

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Cost Effectiveness of Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment.

Reed SD, Li Y, Anstrom KJ, Schulman KA.

Center for Clinical and Genetic Economics and Outcomes Research and Assessment Group, Duke Clinical Research Institute; and Departments of Medicine and Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC.

PURPOSE: Using data from a recent randomized trial, we evaluated the cost effectiveness of ixabepilone plus capecitabine versus capecitabine alone in patients with predominantly metastatic breast cancer considered to be taxane-resistant and previously treated with or resistant to an anthracycline. METHODS: We developed a stochastic decision-analytic model to represent data collected in the trial on medical resource use, health-related quality of life, and clinical outcomes. Estimates of overall survival were conditional on level of tumor response. We assigned monthly costs and utility weights according to periods defined by the duration of study treatment, time from discontinuation of the study drug until disease progression, and from progression until death and were specific to the level of response and receipt of subsequent therapy. Medical resources were valued in 2008 US dollars. We performed Monte Carlo simulations and sensitivity analyses to evaluate model uncertainty. RESULTS: Overall survival was significantly associated with level of tumor response (P < .001). Total costs were estimated at $60,900 for patients receiving ixabepilone plus capecitabine and $30,000 for patients receiving capecitabine alone. The estimated gain in life expectancy with ixabepilone was 1.96 months (95% CI, 1.36 to 2.64 months); the estimated gain in quality-adjusted survival was 1.06 months (95% CI, 0.09 to 2.03 months). The resulting incremental cost-effectiveness ratio was $359,000 per quality-adjusted life-year (95% CI, $183,000 to $4,030,000). In sensitivity analyses, the results were robust to changes in numerous inputs and assumptions. CONCLUSION: Addition of ixabepilone to capecitabine adds approximately $31,000 to overall medical costs and affords approximately 1 additional month of quality-adjusted survival.

COFFEE IMPROVES GLUCOSE TOLERANCE

March 27, 2009 — Chlorogenic acid and trigonelline, which are present in coffee, may improve glucose tolerance, according to the results of a randomized cross-over trial reported online March 26 in Diabetes Care.

"In prospective cohort studies, higher coffee consumption has been associated with a lower risk of type 2 diabetes," write Aimιe E van Dijk, MSc, from the Institute for Health Sciences, VU University Amsterdam, in the Netherlands, and colleagues. "Associations have been similar for caffeinated and decaffeinated coffee suggesting that coffee components other than caffeine have beneficial effects on glucose homeostasis. Coffee is a major source of the phenolic compound chlorogenic acid and the vitamin B3 precursor trigonelline that have been shown to reduce blood glucose concentrations in animal studies."

The goal of this study was to determine the acute effects of decaffeinated coffee, chlorogenic acid, and trigonelline on glucose tolerance in 15 overweight men. During a 2-hour oral glucose tolerance test (OGTT), the investigators studied the effects on glucose and insulin concentrations of 12 g decaffeinated coffee, 1 g chlorogenic acid, 500 mg trigonelline, and placebo (1 g mannitol).

Coffee Components May Improve Glucose Tolerance

Compared with placebo, chlorogenic acid and trigonelline ingestion were associated with significant reductions in glucose (−0.7 ΅mol/L [P = .007] and −0.5 ΅mol/L [P = .024], respectively) and insulin (−73 pmol/L [P = .038] and −117 pmol/L [P = .007], respectively) concentrations 15 minutes after an OGTT. However, insulin and glucose area under the curve values during the OGTT were similar for each of the treatments vs placebo.

Limitations of this study include that multiple tests were conducted for different time points, increasing the likelihood of chance findings, and difficulty comparing the treatment effects because the decaffeinated coffee supplement contained substantially less chlorogenic acid and trigonelline than the doses given in isolation.

"Chlorogenic acid and trigonelline reduced early glucose and insulin responses during an OGTT," the study authors write. "This finding is consistent with the hypothesis that these compounds may contribute to the putative beneficial effect of coffee on development of type 2 diabetes."

BIOSIMILARS ARE HERE

BioDrugs. 2009;23(1):43-51. doi: 10.2165/00063030-200923010-00005.

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Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim Neupogen: single-blind, randomized, crossover trial.

Lubenau H, Bias P, Maly AK, Siegler KE, Mehltretter K.

BioGeneriX AG, Mannheim, Germany. heinz.lubenau@t-online.de

OBJECTIVE: Filgrastim XM02 is a biosimilar non-glycosylated recombinant methionyl form of human granulocyte colony-stimulating factor (r-MetHuG-CSF) expressed in Escherichia coli for subcutaneous and intravenous administration in the treatment of different forms of neutropenia and stem cell mobilization. This study was conducted to compare the pharmacokinetic and pharmacodynamic characteristics of the new biosimilar filgrastim XM02 with the marketed filgrastim (Neupogen). METHODS: Two filgrastim doses (5 and 10 microg/kg) of the new biosimilar filgrastim XM02 and the marketed filgrastim were administered either as intravenous infusion or subcutaneous injection in four single-dose, crossover, randomized substudies, conducted in 36 subjects each. Serum concentrations of filgrastim were determined using an enzyme-linked immunosorbent assay test kit on samples taken at intervals up to 48 hours after administration. The CD34+ stem cell count up to 15 days after administration was determined by flow cytometry using a validated CD34+ cell enumeration kit, and the absolute neutrophil count (ANC) up to 96 hours after dosing was determined by the Beckman Coulter AcT differential automated hematology analyzer. The primary pharmacokinetic endpoint was the AUC (48 h) (area under the serum concentration-time curve) of filgrastim serum concentration determined by the linear trapezoidal rule. Equivalence (biosimilarity) between the two filgrastim products was assessed by 90% confidence limits obtained from analyses of variance of log-transformed pharmacokinetic and pharmacodynamic endpoints, applying 80-125% equivalence intervals. RESULTS: The mean serum concentration profiles of filgrastim, ANC and CD34+ cells over time were similar for the two filgrastims. The 90% confidence intervals for all test/reference ratios for pharmacokinetic and pharmacodynamic endpoints lay within the accepted bioequivalence range of 80-125%. Both filgrastims showed similar safety profiles and were well tolerated. CONCLUSIONS: Equivalence of the two filgrastims was clearly demonstrated for all four dose/route of administration groups. Equivalence could be demonstrated for the serum concentration profile, for the ANC profile and, even more importantly, for the CD34+ cell count, which is a marker for the ability of the granulocyte colony-stimulating factor to mobilize stem cells.