Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors.

Heterozygous activin receptor-like kinase 1 (ALK1) mutations are associated with two vascular diseases: hereditary hemorrhagic telangiectasia (HHT) and more rarely pulmonary arterial hypertension (PAH). Here, we aimed to understand the impact of ALK1 mutations on BMP9 and BMP10 transcriptomic responses in endothelial cells. Endothelial colony-forming cells (ECFCs) and microvascular endothelial cells (HMVECs) carrying loss of function ALK1 mutations were isolated from newborn HHT and adult PAH donors, respectively. RNA-sequencing was performed on each type of cells compared to controls following an 18 h stimulation with BMP9 or BMP10. In control ECFCs, BMP9 and BMP10 stimulations induced similar transcriptomic responses with around 800 differentially expressed genes (DEGs). ALK1-mutated ECFCs unexpectedly revealed highly similar transcriptomic profiles to controls, both at the baseline and upon stimulation, and normal activation of Smad1/5 that could not be explained by a compensation in cell-surface ALK1 level. Conversely, PAH HMVECs revealed strong transcriptional dysregulations compared to controls with > 1200 DEGs at the baseline. Consequently, because our study involved two variables, ALK1 genotype and BMP stimulation, we performed two-factor differential expression analysis and identified 44 BMP9-dysregulated genes in mutated HMVECs, but none in ECFCs. Yet, the impaired regulation of at least one hit, namely lunatic fringe (LFNG), was validated by RT-qPCR in three different ALK1-mutated endothelial models. In conclusion, ALK1 heterozygosity only modified the BMP9/BMP10 regulation of few genes, including LFNG involved in NOTCH signaling. Future studies will uncover whether dysregulations in such hits are enough to promote HHT/PAH pathogenesis, making them potential therapeutic targets, or if second hits are necessary.

Effectiveness and safety of cabazitaxel chemotherapy for metastatic castration-resistant prostatic carcinoma on Turkish patients (The Anatolian Society of Medical Oncology).

OBJECTIVE: Prostate cancer is among the most common cancers in males. Prostate cancer is androgen dependent in the beginning, but as time progresses, it becomes refractory to androgen deprivation treatment. At this stage, docetaxel has been used as standard treatment for years. Cabazitaxel has become the first chemotherapeutic agent which has been shown to increase survival for patients with metastatic Castrate Resistant Prostate Cancer (mCRPC) that progresses after docetaxel. Phase 3 TROPIC study demonstrated that cabazitaxel prolongs survival. PATIENTS AND METHODS: In this study, we evaluated a total of 103 patients who took cabazitaxel chemotherapy for mCRPC diagnosis in 21 centers of Turkey, retrospectively. This study included patients who progressed despite docetaxel treatments, had ECOG performance score between 0-2, and used cabazitaxel treatment. Patients received cabazitaxel 25 mg/m2 at every 3 weeks, and prednisolone 5 mg twice a day. RESULTS: Median number of cabazitaxel cures was 5.03 (range: 1-17). Cabazitaxel response evaluation detected that 34% of the patients had a partial response, 22.3% had stable disease and 32% had a progressive disease. Grade 3-4 hematological toxicities were neutropenia (28.2%), neutropenic fever (14.5%), anemia (6.7%), and thrombocytopenia (3.8%). In our study, median progression-free survival (PFS) was 7.7 months and overall survival (OS) was 10.6 months. CONCLUSIONS: This study reflects toxicity profile of Turkish patients as a Caucasian race. We suggest that cabazitaxel is a safe and effective treatment option for mCRPC patients who progress after docetaxel. Moreover, ethnicity may play important roles both in treatment response and in toxicity profile.

Evaluation of changes in the attitudes and behaviors of relatives of lung cancer patients toward cancer prevention and screening.

BACKGROUND: Cancer diagnosis affects all the relatives living with the patient; however, whether the behavior of family members changes or not is unknown. To end this we evaluated the relatives of lung cancer patients. MATERIALS AND METHODS: Forty-one questions were used to collect data from the relatives of lung cancer patients who had been living with them for at least one year, to evaluate changes in their attitudes and behaviors related to cancer prevention. RESULTS: The study included 246 lung cancer patients' relatives, of them 172 (69.9%) were women and 74 (30.1%) were men. The median age was 46 years (range: 20-83 years). Patients and their relatives had been living together for an average of 28 years (range: 1-68 years), and 88 (35.7%) of the patients' relatives were their children. We found changes in the attitudes and behaviors toward prevention and screening for cancer in 92 (37.4%) of the relatives. Fifty-two (21.1%) of them changed their smoking habits, 34 (13.8%) altered their eating habits, 25 (10.2%) changed their exercise habits, 13 (5.3%) visited a doctor due to a suspicion of having cancer, 12 (4.9%) changed their lifestyles, seven (2.8%) underwent cancer screening tests, three (1.2%) started using alternative medicines, and three (1.2%) started using vitamins for cancer prevention. CONCLUSIONS: Important changes occur in the attitudes and behaviors of patients' relatives toward cancer prevention and screening after the patients are diagnosed with lung cancer. Being aware of how patients' relatives react to a family member's cancer diagnosis may provide healthcare professionals with more incentive to address the relatives' special needs.

A modified DCF regimen as primary treatment for patients with metastatic gastric cancer.

PURPOSE: To retrospectively assess the efficacy and toxity of a modified docetaxel, cisplatin, fluorouracil (mDCF) regimen as primary treatment in patients with metastatic gastric cancer (MGC). METHODS: mDCF included folinic acid 400 mg/m(2) (day 1) + 5-fluorouracil (5-FU) 400 mg/m(2) i.v. bolus (day 1) + 5-FU 2400 mg/m(2) 46-h infusion (days 1 and 2) + docetaxel 60 mg/m(2) (day 1) + cisplatin 50 mg/m(2) (day 1) and was administered once every two weeks in MGC patients. RESULTS: Eighty-nine patients (median age 59 years, range 31-79) were enrolled. The median number of courses was 6 (range 2-12), and the total number was 492. The median follow-up duration was 8.6 months (range 2-14). Three (3.3%) patients showed complete response, 21 (23.6%) partial response, 36 (40.4%) stable disease, and progression was observed in 29 (32.6%) patients. The median progression- free survival (PFS) rate was 7 months (95% CI 5.7-8.2), and the median overall survival (OS) rate was 11 months (95% CI 9.7-12.2). The most common toxicity was neutropenia, which was observed in 52 (58.4%) patients. CONCLUSION: mDCF with reduced drug doses, given every two weeks, is a rather efficient regimen for MGC patients.

Prognostic factors affecting recurrence and survival in patients with locally advanced rectal cancer.

PURPOSE: This study aimed at investigating the factors that are likely to affect recurrence and survival in patients with locally advanced rectal cancer. METHODS: The study included patients treated and followed- up between January 1999 and August 2009. Patient and disease data were retrieved from the patients' hospital charts. RESULTS: A total of 221 patients were evaluated. Their median age was 58 years (range 18-83); 69 (31.2%) patients had clinical stage II and 152 (68.8%) clinical stage III. Median follow-up was 40 months (range 8-136). Median disease free survival (DFS) was 77 months and median overall survival (OS) 95 months. The factors affecting local recurrence were pathological lymph node involvement (pN+), pathological T4 (pT4) tumors, and postoperative high serum level of carcinoembryonic antigen (CEA). pN (+) tumors, postoperative high serum CEA level, and perineural invasion increased the risk of both local and distant metastasis. The factors affecting mortality were pN+ tumors, pT4 tumors, poor tumor differentiation, high postoperative CEA level, age > 60 years, and no postoperative adjuvant chemotherapy (CT). The factors affecting DFS were pN+ tumors, pT4 tumors, poor tumor differentiation, postoperative high serum CEA level, perineural invasion, and surgical margin positivity. The factors affecting OS were pN+ tumors, postoperative high serum CEA level, poor tumor differentiation, perineural invasion and no adjuvant CT. CONCLUSION: Some prognostic factors are important in the assessment of prognosis of locally advanced rectal cancer.

Mitomycin-C in combination with fluoropyrimidines in the treatment of metastatic colorectal cancer after oxaliplatin and irinotecan failure.

PURPOSE: To retrospectively evaluate the efficacy and tolerability of mitomycin-C (MMC) in combination with fluoropyrimidines as salvage 3rd -or 4th-line therapy in metastatic colorectal cancer (MCRC) patients. METHODS: All patients in this study had previously failed oxaliplatin and irinotecan-based chemotherapy. Patients were treated with MMC (6 mg/m(2) intravenously/i.v.) on day 1 in combination with either oral UFT (500 mg/m(2)) and oral leucovorin (LV) (30 mg) on days 1-14 every 3 weeks (group A) or infusional 5-fluorouracil (5-FU) by deGramont regimen with i.v. LV (200 mg/m(2)) on days 1 and 2, every 2 weeks (group B). RESULTS: Thirty-nine MCRC patients were analyzed. Twenty-two of them were in group A and 17 in group B. Thirty-three were evaluable for clinical efficacy. The clinical benefit in the intent-to-treat (ITT) population was 30.8%. Median progression free survival (PFS) was 6 months (95% confidence interval/ CI 4-8) and median overall survival (OS) 9 months (95% CI 6.5-11.5). Median PFS was 3 months (95% CI 2.4-3.6) in group A and 7 months (95% CI 5.1-8.9) in group B (p=0.009). Median OS was 7 months (95% CI 4.3-9.7) in group A and 12 months (95% CI 5.4-18.6) in group B (p=0.422). The combination of MMC and fluoropyrimidines was generally well tolerated. The most common severe toxicities were nausea and vomiting, neutropenia, hepatotoxicity and diarrhea. CONCLUSION: MMC in combination with fluoropyrimidines is safe and active in heavily-pretreated MCRC patients. This combination remains a viable option in these patients. However, better therapies are urgently needed.

Reduced jugular venous oxygen saturation during rewarming from deep hypothermic circulatory arrest: cerebral overextraction?

Deep hypothermic circulatory arrest may impair cerebral cellular functions, and physiological parameters following circulatory arrest may deviate from the normal. The intention of this study was to monitor jugular venous oxygen saturation during cardiopulmonary bypass before and after deep hypothermic circulatory arrest. Jugular venous oxygen saturation were obtained on 18 patients by using a retrograde jugular vein catheter during replacement of the ascending aorta. Indications for operations were ascending aortic dilatation (n=15) and acute aortic dissection (n=3). Hypothermic cardiopulmonary bypass (233+/-60 min), cardioplegic arrest (105+/-37 min) and circulatory arrest (22+/-7 min) were utilized during the operations. Jugular venous oxygen saturation increased during hypothermia and decreased during rewarming. Compared with cooling, jugular venous oxygen saturation during the initial part of rewarming were significantly lower (87+/-5% vs. 97+/-1%, 89+/-4% vs. 95+/-2%, 81+/-4% vs. 87+/-5% at 16, 20 and 24 degrees C respectively, p<0.05). One patient required re-exploration because of bleeding. All patients were found neurologically normal before being discharged from the hospital (mean 14+/-7 days). In conclusion, jugular venous oxygen saturation is inversely related to the body temperature in patients undergoing hypothermic cardiopulmonary bypass. Significantly decreased jugular venous oxygen saturation during the initial part of rewarming may signify an increased cerebral extraction of oxygen.