Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

A Phase Ib/II Study Evaluating the Combination of Weekly Docetaxel and Cisplatin Together with Capecitabine and Bevacizumab in Patients with Advanced Esophago-Gastric Cancer.

INTRODUCTION: Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. METHODS: Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part). RESULTS: The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5-52.2 months) and the median progression-free survival was 7.6 months (range, 1.3-26.6 months). The 2-year OS rate reached 23.7%. CONCLUSIONS: AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00845884.

The impact of oxaliplatin on the gonads: from bedside to the bench.

STUDY HYPOTHESIS: What is the impact of oxaliplatin on gonadal function? STUDY FINDING: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. WHAT IS KNOWN ALREADY: Recent studies have indicated a significant increase in survivorship of colorectal cancer patients of reproductive age, who may then face fertility concerns. The impact of oxaliplatin on gonadal function is yet to be discovered. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Eleven female (<43 years) and eight male (<45 years) patients recently diagnosed with colorectal cancer, who were candidates for oxaliplatin-based protocol, were enrolled into the study. FSH, estradiol, anti-Müllerian hormone (AMH) and menstrual pattern were measured in female patients, whereas FSH, inhibin-B, testosterone, and steroid-hormone binding globulin were measured in male patients. Hormones were measured at baseline and 6 months post-treatment (last chemotherapy administration) in men and women. In the animal model, pubertal mice were injected with oxaliplatin and sacrificed 1 week, 1 month and 3 months later. Ovarian reserve was estimated by serum AMH measurements. Testicular function was evaluated by serum inhibin-B and sperm evaluation. Gonadal apoptosis (TUNEL), proliferation (Ki-67), repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL) were measured by immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: In all women, AMH decreased post-treatment, but remained above the detection limit in 9/11 patients (P < 0.05). FSH was elevated, but did not exceed the premenopausal range in 9/11 patients. All patients remain menstruating or resumed menstruation post-treatment. In female mice oxaliplatin induced transient apoptosis at 1-month post-treatment. In men Inhibin-B was slightly reduced post-treatment. In male mice oxaliplatin did not affect spermatozoa concentration, but was associated with transient, moderate reductions of spermatocytes-spermatogonia numbers and spermatozoa motility. LIMITATIONS, REASONS FOR CAUTION: Future prospective large-scale studies are warranted in order to affirm these outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Due to high survival rates of colorectal cancer patients of reproductive age that were diagnosed at early stages of the disease, the issue of treatment-induced gonadotoxicity gains significance. Since at the individual level there might be a risk of infertility, a detailed discussion and referral to fertility preservation prior to initiation of treatment is recommended. Nevertheless, oxaliplatin-based protocols appear to be less gonadotoxic than other chemotherapeutic protocols. LARGE SCALE DATA: None. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by the Israeli Science Foundation (ISF) grant 13-1816 (I.B.-A.). There is no conflict of interest.

Adjuvant Docetaxel and Cyclophosphamide (DC) with prophylactic granulocyte colony-stimulating factor (G-CSF) on days 8 &12 in breast cancer patients: a retrospective analysis.

PURPOSE: Four cycles of docetaxel/cyclophosphamide (DC) resulted in superior survival than doxorubicin/cyclophosphamide in the treatment of early breast cancer. The original study reported a 5% incidence of febrile neutropenia (FN) recommending prophylactic antibiotics with no granulocyte colony-stimulating factor (G-CSF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events. We explored the use of growth factor (GF) support on days 8 and 12 of the cycle with the original DC protocol. METHODS: Our study included all consecutive patients with stages I-II breast cancer who were treated with the DC protocol at the Institute of Oncology, Davidoff Center (Rabin Medical Center, Petah Tikva, Israel) from April, 2007 to March, 2012. Patient, tumor characteristics, and toxicity were reported. RESULTS: In total, 123 patients received the DC regimen. Median age was 60 years, (range, 25-81 years). Thirty-three patients (26.8%) were aged 65 years and older. Most of the women (87%) adhered to the planned G-CSF protocol (days 8 &12). 96% of the patients completed the 4 planned cycles of chemotherapy. Six patients (5%) had dose reductions, 6 (5%) had treatment delays due to non-medical reasons. Thirteen patients (10.6%) experienced at least one event of FN (3 patients had 2 events), all requiring hospitalization. Eight patients (6.5%) required additional support with G-CSF after the first chemotherapy cycle, 7 because of FN and one due to neutropenia and diarrhea. IN CONCLUSION: Primary prophylactic G-CSF support on days 8 and 12 of the cycle provides a tolerable option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.

The impact of Bevacizumab (Avastin) on survival in metastatic solid tumors--a meta-analysis and systematic review.

PURPOSE: To evaluate the effect of Bevacizumab in combination with chemotherapy on overall survival of patients with metastatic solid tumors. DESIGN: A systematic literature search to identify randomized trials comparing chemotherapy with and without Bevacizumab in metastatic cancer. The primary end point was overall survival (OS) and the secondary end points were progression free survival (PFS) and toxicity. A meta-analysis was performed for each tumor type and for the combination of all tumors. RESULTS: 24 randomized trials with 8 different types of malignancies were included in this meta-analysis. Patients treated with Bevacizumab had an OS benefit, hazard ratio (HR) 0.89 (95% CI 0.84-0.93, P<0.00001 I(2)-4%). The combined analysis showed a PFS benefit with a HR 0.71 (95% CI 0.68-0.74, P<0.00001, I(2)-54%). The toxicity analysis showed a statistically significant increase in fatal adverse events (FAEs) in the Bevacizumab treatment arm, risk ratio (RR) 1.47 (95% CI 1.1-1.98). A separate analysis of the lung cancer trials showed an increased risk of fatal pulmonary hemorrhage with a RR of 5.65 (95% CI 1.26-25.26). The risk of G3-4 adverse events was increased: RR 1.2 (95% CI 1.15-1.24). CONCLUSION: in this combined analysis Bevacizumab improved OS (with little heterogeneity) and PFS. These results should be considered in the light of lack of markers predictive of response and the increased severe and fatal toxicity seen with Bevacizumab treatment.

Duration of vancomycin treatment for coagulase-negative Staphylococcus sepsis in very low birth weight infants.

AIM: Vancomycin is widely used to treat late onset coagulase-negative Staphylococcus (CoNS) sepsis in very low birth weight (VLBW) infants. Although vancomycin is associated with a risk of toxicity and bacterial resistance, the appropriate duration of use has not been established. This study sought to investigate the association between the duration of vancomycin therapy and clinical outcome in VLBW infants with CoNS sepsis. METHODS: The files of all VLBW infants treated for CoNS sepsis at a tertiary paediatric medical centre from 1995-2003 were reviewed for clinical data, laboratory variables and outcome. Only patients with two positive diagnostic blood cultures were included. The findings were analyzed by duration of vancomycin treatment after the last positive blood culture. RESULTS: The study cohort included 126 infants, 48 treated for 5 days, 32 for 6-7 days, 31 for 8-10 days and 15 for >10 days. There were no differences among the groups in perinatal characteristics, central catheter dwell time, laboratory data including haematologic, renal and liver function tests, or rate of complications of prematurity. Five infants were diagnosed with infective endocarditis or aortic thrombi and were treated for >10 days. CoNS sepsis recurred in two infants (1.6%). No toxicity of vancomycin treatment was observed. CONCLUSIONS: In VLBW infants with uncomplicated CoNS sepsis, treatment with vancomycin for 5 days after the last positive blood culture appears to be associated with a satisfactory outcome and no adverse effects. A well-controlled prospective multicentre study is needed to confirm these findings.

Persistent coagulase-negative staphylococci bacteremia in very-low-birth-weight infants.

This study sought to expand current knowledge on the clinical and epidemiological characteristics of persistent coagulase-negative Staphylococcus (CoNS) bacteremia in very-low-birth-weight (VLBW) infants. Background and disease-related data were collected prospectively on 143 VLBW infants diagnosed with CoNS bacteremia at a pediatric tertiary medical center in 1995-2003. Findings were compared between those with persistent (positive blood cultures for >72 h under appropriate treatment ) and nonpersistent disease. Fifty-eight infants (40.6%) were found to have persistent bacteremia. There were no between-group differences in maternal characteristics, mode of delivery, newborn characteristics, dwell time of central venous and umbilical catheters, complications of prematurity, or mean hospital stay. The persistent bacteremia group had significantly higher rates of hypothermia at presentation (37.9% vs. 17.6%, p < 0.04), creatinine >1.2 mg% on treatment day 7 (13.7% vs. 2.4%, p < 0.02; transient phenomenon), and endocarditis (p < 0.03); one infant had an aortic thrombus. Predominantly breast-fed infants had a higher rate of negative cultures within 72 h of appropriate treatment than predominantly formula-fed infants (60% vs. 19%, p < 0.02). In conclusion, persistence of CoNS bacteremia is common in VLBW infants. Endocarditis should be excluded in all infants with persistent disease. Breast-feeding is associated with a shorter disease duration.