Tal Sella

Activity of Cabazitaxel After Docetaxel and Abiraterone Acetate Therapy in Patients With Castration-Resistant Prostate Cancer

BACKGROUND Cabazitaxel and AA have been approved by the US Food and Drug Administration for use after docetaxel in mCRPC. Recently, CAB appeared to be active when given after AA. AA is capable of inducing AR splice variants that confer ligand-independent AR transactivation. Because microtubule-targeting agents impair AR nuclear transport and activity, we raised concerns about CAB efficacy after AA failure in mCRPC. PATIENTS AND METHODS One hundred thirty mCRPC patients received AA after docetaxel treatment in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data using conventional methods. RESULTS Twenty-four patients received a median of 4 (range, 1-13) CAB cycles. Nineteen (79.1%) of them received primary prophylaxis with growth factors. Median patient characteristics were: age 65 (range, 57-85) years; Gleason score: 8 (range, 6-10); and PSA: 128.1 (range, 0.01-1700) ng/mL. A PSA response (≥ 50% decrease from baseline) occurred in 6 (31.5%) of 19 evaluable patients (95% confidence interval [CI], 11.8-54.2%). CAB therapy obtained a partial response in 2 of the 13 (15.3%) evaluable patients (95% CI, 2.9-45.4%). Median survival from initiation of CAB was 8.2 (95% CI, 3.34-13.05) months, from AA 16.1 (95% CI, 11.56-20.64) and from docetaxel 32.0 (95% CI, 11.56-39.69). CONCLUSION A limited number of patients with mCRPC received CAB after docetaxel and AA treatment. In this selected population, CAB was active.

Incidence trends of keratinocytic skin cancers and melanoma in Israel 2006–11

The incidence of melanoma and keratinocyte cancers (KCs) is rising worldwide. Squamous cell carcinomas (SCCs) and basal cell carcinoma (BCCs) are the most common of all cancers.

Serum potassium levels predict blood pressure response to aldosterone antagonists in resistant hypertension.

The objective of this study was to identify factors associated with the blood pressure (BP) response to spironolactone—aldosterone receptor antagonist as an add-on therapy in patients with resistant hypertension (HTN). We retrospectively reviewed the data of subjects with resistant HTN who were treated with add-on spironolactone in a large HTN clinic. A paired Student’s t-test was used to assess the differences between the BP values before and during spironolactone administration, and multivariate analysis was used to assess the predictors of a satisfactory BP response (a decrease in systolic BP >10%). We analyzed the data of 48 hypertensive participants. The add-on spironolactone therapy had a significant BP-lowering effect in both systolic and diastolic BP values (P<0.01 for both). Baseline serum potassium levels of <4.5 mEq l−1 were associated with a satisfactory BP response (P<0.01). Furthermore, every decrement of 1 mEq l−1 of serum potassium was independently associated with a fivefold higher rate of achieving a satisfactory BP response to spironolactone therapy (P=0.024). Additional factors independently associated with an improved systolic BP response were old age (P=0.033), body mass index (P=0.033) and high baseline systolic BP (P=0.004). Our results support the use of add-on spironolactone therapy in patients with resistant HTN who are elderly and obese and have high systolic BP and serum potassium levels <4.5 mEq l−1.

Activity of cabazitaxel following docetaxel and abiraterone acetate in patients with castration-resistant prostate cancer.

186 Background: Cabazitaxel (CAB) and abiraterone-acetate (AA) have been approved after docetaxel in castration resistant prostate cancer (CRPC). Both exhibit hormonal effects. AA depletes androgen in microenvironment; taxanes affect the microtubule-dependent trafficking of the androgen receptor. Recently, clinical cross-resistance has been suggested between AA and taxanes. This prompted evaluation of CAB following docetaxel and AA in CRPC. METHODS Over 13 months until December 2011, 130 CRPC patients received AA after docetaxel in compassionate programs. Of them, 24 (18.4%) subsequently received CAB. We retrospectively reviewed their data (PCWG2/RECIST and NCI toxicity criteria). RESULTS Fourteen (58.3%) received CAB/prednisone at 20 mg/m2 and 10 patients 25 mg/m2, overall a median of 4 (1-13) cycles. Nineteen (79.1%) received primary G-CSF support. Patient characteristics (median, range in parenthesis): Age 65 (57-85) years, Gleason- 8 (6-10), K.S- 80 (50-90) %. Metastatic sites: liver- 5 (20.8%), visceral- 8 (33.3%), osseous- 22 (91.6%), No. sites involved- 2 (1-4). Lab-work: PSA- 128.1 (0.01-1700) ng/ml, PSA Doubling time- 2.16 (0.64-7.41) months, alkaline phosphatase 129 (35-1200) u/L. Castration sensitive period - 16.2 (2.0-92.1) months. Using Cox univariate analysis, only K.S was near-significant for prediction of survival after initiating CAB, p=0.075, OR=0.315, 95% C.I (0.88-1.125). A PSA response of 30%, 95% C.I (11,8-54,2)% was observed after CAB with non progression occurring in 6 (26%) out of 23 evaluable patients, 95% CI (10.2-48.4)%. At analysis 11 patients are alive. Median survival from initiation of CAB was 8.2 (95% C.I 3.34-13.05) months, from AA 16.1 (95 C.I 11.56-20.64) and from docetaxel 32.0 (95% C.I 11.56-39.69). Non-progression with docetaxel (but not AA) was associated with longer survival with CAB, p=0.049, 43.1 v.s 17.4 months. Four (16.6%) patients developed infectious complications, including one death due to septic shock. CONCLUSIONS Limited number of patients with CRPC received CAB following docetaxel and AA. In this selected population CAB was active. Response to prior docetaxel was associated with prolonged survival to CAB therapy.

The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews.

BACKGROUND The p.I1307K adenomatous polyposis coli (APC) gene variant, prevalent among Ashkenazi Jews, may increase the risk for colorectal neoplasia. We studied the clinical importance of screening for this polymorphism in 3305 Israelis undergoing colonoscopy. PATIENTS AND METHODS Clinical data regarding potential risk factors for colorectal cancer (CRC) were collected from individuals undergoing colonoscopic examination at the Tel-Aviv medical center. The APC p.I1307K was detected using real-time PCR (polymerase chain reaction) from DNA extracted from peripheral mononuclear cells. RESULTS The overall prevalence of the p.I1307K polymorphism was 8.0% (10.1% among Ashkenazi and 2.7% among Sephardic Jews, p<0.001). The overall adjusted odds ratio (OR) for colorectal neoplasia among carriers was 1.51 (95% confidence intervals (CI), 1.16-1.98). Among average risk Ashkenazi Jews, the adjusted OR was 1.75 (95% CI 1.26-2.45). A multiplicative interaction was identified between Ashkenazi ethnicity and APC p.I1307K carrier status (P(INTERACTION) = 0.055). The histopathological features of adenomas and carcinomas did not differ between carriers and non-carriers. CONCLUSIONS The APC p.I1307K gene variant is an important risk factor for colorectal neoplasia in average risk Ashkenazi Jews. Carriers in this group should be considered for screening colonoscopy at the age of 40, to be repeated every 5 years, similar to recommendations in individuals with family history of colorectal cancer.

Screening for gestational diabetes in the 21st century: a population-based cohort study in Israel

Objective: Studies indicate that gestational diabetes mellitus (GDM) prevalence is increasing worldwide. We aimed to examine secular trends in GDM prevalence and screening practices over the last decade in Israel, and to identify changes in GDM risk factors. Methods: We collected data on all 367,247 pregnant women who were screened for GDM between 2000 and 2010 in Israel’s second largest healthcare organization. Multivariable logistic regression analysis was used to identify risk factors for GDM. Results: GDM prevalence increased by 12%, from 3.8% in 2000 to 4.3% in 2010 and was accompanied by a 37% rise in the proportion screened directly by 100-gram oral glucose tolerance test without a prior 50-gram glucose challenge test (from 6.5% to 8.9%). During the study period there was an on-going increment in the proportion of pregnant women with one or more GDM risk factor, such as older age, low socioeconomic level, history of polycystic ovary syndrome or in vitro fertilization, which was all significantly (p < 0.05) associated with the risk of GDM. Conclusions: The increasing risk of GDM in Israel can be explained by both rising prevalence of women with established risk factors, as well as shifting screening practices.

Gestational diabetes and the risk of cryptorchidism and hypospadias.

To the Editor: Gestational diabetes mellitus is the onset of glucose intolerance during pregnancy. Pregnancies complicated with diabetes are at increased risk for many maternal and fetal complications, including cesarean delivery, macrosomia, neonatal hypoglycemia, stillbirth, shoulder dystocia, and congenital malformations.1 However, few epidemiologic studies have evaluated associations between gestational diabetes and the risk of cryptorchidism (failure of one or both testicles to descend into the scrotum) or hypospadias (urethral opening on the ventral side of the penis). shared risk factors for cryptorchidism and hypospadias include intrauterine growth restriction (small for gestational age), low birth weight, preterm delivery, and concomitant genital abnormalities. these two defects are commonly associated with testicular cancer risk in adult life2; thus, gaining a better understanding of their etiology that may provide new means of identifying men at risk of developing testicular cancer. In Israel, universal gestational diabetes screening is conducted in accordance with American Diabetes Association guidelines, and approximately 90% of the pregnancies in the Maccabi Healthcare services healthcare maintenance organization (HMO) between 2000 and 2010 were screened.3 Using administrative and clinical data, we conducted a populationbased retrospective cohort study in this HMO to evaluate the association between gestational diabetes and two common male congenital anomalies, cryptorchidism and hypospadias, in male offspring. Details on the study methods and characteristics of the study cohort are provided in the eAppendix (http://links. lww.com/eDe/A737) and the etable (http://links.lww.com/eDe/A737). Associations between gestational diabetes and the risk of cryptorchidism and hypospadias were estimated separately, using unconditional logistic regression analyses adjusting for year of birth, maternal age at oral glucose tolerance test, maternal birthplace, socioeconomic status, history of infertility, use of in vitro fertilization, and history of polycystic ovarian syndrome. the study included 150,144 mother-infant pairs. the frequency of diabetes was 40.3 per 1000 pregnancies; 3649 cases of cryptorchidism (24.2 per 1000 male births) and 2342 cases of hypospadias (15.6 per 1000 male births) were identified. Maternal diabetes was not associated with cryptorchidism (odds ratio = 0.93 [95% confidence interval = 0.77– 1.10]) or hypospadias (0.83 [0.66–1.04]) (table). Furthermore, among male children of mothers with gestational diabetes (n = 5,497), neither of the indices of diabetes severity (number of abnormal glucose tolerance test values and the use of insulin during pregnancy) was associated with the risk of either anomaly (table). the current retrospective cohort study does not support an association of gestational diabetes with cryptorchidism or hypospadias. Consistent with our study, a swedish registry-based study (1973– 1982) reported no association between gestational diabetes and cryptorchidism.4 In contrast, one case-control study reported a positive association between gestational diabetes, diagnosed based on medical record reports of diet-controlled diabetes or abnormal glucose tolerance test, and cryptorchidism.5 However, that study was based on relatively small numbers (125 cases), and only 30% of cases and 22% of controls had a glucose tolerance test during pregnancy. In the current study, all pregnancies included in the analysis were screened for gestational diabetes mellitus and approximately 90% of pregnancies in the MHs HMO during the study time period were screened.3 We are aware of three previous studies that evaluated the association of gestational diabetes with hypospadias and, consistent with our results, all reported a null association.6–8 An important strength of the current study is the direct ascertainment of gestational diabetes based on laboratory glucose tolerance tests, avoiding issues concerning self-report and inconsistent diagnostic criteria. Additional strengths of the study include its large size, retrospective cohort design, and the systematic and comprehensive collection of personal data. the study adds persuasive evidence that gestational diabetes is not associated with the risk of cryptorchidism or hypospadias.

Short- and Long-Term Survival in Metastatic Pancreatic Adenocarcinoma, 1993–2013

Background: During the past 2 decades, numerous clinical trials have focused on improving outcomes in patients with metastatic pancreatic cancer (mPDAC). The efficacy of new treatments has been demonstrated among highly selected patients in randomized phase III trials; hence, it is not clear to what extent these advances are reflected within the broader mPDAC population. Materials and Methods: Survival statistics were extracted from the SEER database for patients diagnosed with mPDAC between 1993 and 2013. Survival was analyzed using the Kaplan-Meier method and proportional hazard models. Results: The study population consisted of 57,263 patients diagnosed with mPDAC between 1993 and 2013; 52% were male, with a median age of 69 years (range, 15-104). Superior prognosis correlated with younger age, being married, tumor located within the head of the pancreas, lower grade disease, and more recent year of diagnosis. Median overall survival (OS) remained stable at 2 months between 1993 and 2013. Improvements in OS were seen for younger patients (age <50 years) and those with a more recent year of diagnosis (2009-2013). The percentage of patients who died within 2 months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%; P<.0001). The percentage of patients surviving ≥12 months improved from 4.9% in 1993 to 12.7% in 2013 (P<.0001). Conclusions: In recent years a modest improvement in OS has been seen among younger patients with mPDAC. The percentage of patients living beyond 1 year has significantly increased over time; however, the percentage of those dying within 2 months remains substantial.

Preferences for disclosure of disease related information among thoracic cancer patients.

OBJECTIVE Cancer patients in developed countries increasingly express a preference for more detailed information and involvement in decisions about their care. However, data is sparse and conflicting on preferences of ethnic minorities and immigrants. We aimed to identify preferences for illness related information and correlates with clinical characteristics among patients with thoracic cancers. METHODS Two hundred and fifty two consecutive cancer patients seen at the Thoracic Oncology Unit, Sheba Medical Center, Israel, participated in the study. Prior to their first oncologist visit, patients completed a questionnaire eliciting their preferences for disclosure of illness related information - full, partial or none - as well as additional demographic information. RESULTS Eighty four percent of subjects requested full disclosure of disease related information including bad news. Patient age, gender, marital status, birth country, immigration status and smoking status were not associated with disclosure preferences. Patients who refused complete-disclosure were more likely to have metastatic disease with a 2.72 odds ratio (95% confidence interval 1.29-5.74). CONCLUSIONS Most Israeli thoracic cancer patients request full disclosure of illness related information. This preference seems more significantly correlated to disease stage than demographic characteristics.

Evaluation of tolerability and efficacy of incorporating carboplatin in neoadjuvant anthracycline and taxane based therapy in a BRCA1 enriched triple-negative breast cancer cohort

PURPOSE The addition of carboplatin (Cb) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) has been demonstrated to improve pathologic complete response (pCR) at the expense of increased toxicity. We aimed to evaluate the effectiveness and tolerability of dose-dense anthracycline & cyclophosphamide (ddAC) followed by weekly paclitaxel (wT) in combination with weekly Cb. METHODS Retrospective data was collected on patients with clinical stage I-III TNBC treated with neoadjuvant ddAC-wTCb (four cycles of ddA 60 mg/m2 and ddC 600 mg/m2 every 2 weeks followed by 12 cycles of wT 80 mg/m2 with Cb AUC 1.5). Indices of tolerability and pCR were evaluated and compared to a historical cohort (n = 76) treated with ddAC-T. A secondary objective was to evaluate the rates of pCR by BRCA status. RESULTS For 43 eligible patients, mean age was 41.5 years, 51% had clinical stage II disease, 81.4% were clinically node positive and 32.6% carried a deleterious BRCA1 mutation. Only 35% completed all scheduled doses of chemotherapy. Grade 3/4 neutropenia was observed in 42.5% of patients. Overall pCR was 51.2%; 44.8% in BRCA wild-type compared to 64.3% in BRCA-associated TNBC (p = 0.232). pCR rates with ddAC-wTCb were similar to historic institutional rates with ddAC-T (51.2% vs. 51.3%, p = 0.987) and were comparable when stratified by BRCA status. In pooled multivariate analysis, only BRCA status (HR 4.00, 95%CI 1.65-9.75, p = 0.002) was significantly associated with pCR. CONCLUSION Neoadjuvant ddAC-wTCb is less tolerable in clinical practice compared to most clinical trials, with a pCR comparable to historic rates using non-platinum regimen. The role of Cb in neoadjuvant chemotherapy for BRCA mutated TNBC remains uncertain.