Biweekly gemcitabine and cisplatin in platinum-resistant/refractory, paclitaxel-pretreated, ovarian and peritoneal carcinoma

OBJECTIVES: Synergism between gemcitabine and cisplatin is supported by preclinical and clinical data. The present study explores the efficacy of a biweekly regimen in platinum-resistant/refractory, paclitaxel-pretreated ovarian and peritoneal cancer. METHODS: 50 paclitaxel-pretreated patients with platinum-resistant/refractory ovarian or peritoneal carcinoma who had previously received paclitaxel chemotherapy, were treated with six cycles of gemcitabine 1000 mg/m(2) followed by cisplatin 40 mg/m(2) on days 1 and 15, repeated every 4 weeks. RESULTS: The median platinum-free interval (PFI) was 4 months while the median number of previous treatment lines was 2. Chemotherapy was well tolerated. Objective responses were observed in 31.5% of evaluable patients (n=35). CA125 response was observed in 68% of patients with elevated CA125 (n=41). Median overall survival (OS) was 13.2 months (95% Confidence Interval, CI: 10.2-16.2) while progression-free survival (PFS) was 4.9 months (95%CI: 3.5-6.4). A PFI of less than 3 months was associated with lower objective response rates (15.8% versus 50%, p=0.03). CONCLUSIONS: Biweekly gemcitabine and cisplatin is feasible for patients with platinum-resistant ovarian or peritoneal cancer and is associated with a favorable toxicity profile. In a population with recent exposure to platinum, a PFI of less than 3 months was the major factor influencing response to chemotherapy.     

Nasogastric aspiration/lavage in patients with gastrointestinal bleeding: a review of the evidence

Introduction: The usefulness of nasogastric aspiration and nasogastric lavage in patients with gastrointestinal bleeding is controversial, as evidenced by conflicting recommendations, both among and within society guidelines.

Areas covered: Considering these controversies, we reviewed the evidence regarding the following questions: 1) Can nasogastric lavage stop or slow down the bleeding and improve subsequent endoscopic visualization? 2) Is nasogastric aspiration helpful for the localization of bleeding? 3) Can nasogastric aspiration identify high risk patients that might benefit from earlier endoscopy? 4) Is there evidence for benefit in terms of outcomes from using nasogastric aspiration? 5) Is nasogastric intubation safe in patients with possible esophageal varices? Our review was conducted according to PRISMA guidelines.

Expert commentary: Based on the available literature, nasogastric lavage or aspiration cannot be routinely recommended unless a large properly designed randomized trial (which is currently lacking) proves otherwise. It is a painful and time-consuming procedure with no demonstrated benefit for the patient in terms of outcomes. Other clinical and laboratory parameters, and risk scores, are less invasive and are effective for guiding the stratification and management of patients, while pre-endoscopic erythromycin infusion is a good if not better alternative for improving visualization of the stomach.     

Pharmacological adjuncts to stop bleeding: options and effectiveness

Severe trauma and massive haemorrhage represent the leading cause of death and disability in patients under the age of 45 years in the developed world. Even though much advancement has been made in our understanding of the pathophysiology and management of trauma, outcomes from massive haemorrhage remain poor. This can be partially explained by the development of coagulopathy, acidosis and hypothermia, a pathological process collectively known as the “lethal triad” of trauma. A number of pharmacological adjuncts have been utilised to stop bleeding, with a wide variation in the safety and efficacy profiles. Antifibrinolytic agents in particular, act by inhibiting the conversion of plasminogen to plasmin, therefore decreasing the degree of fibrinolysis. Tranexamic acid, the most commonly used antifibrinolytic agent, has been successfully incorporated into most trauma management protocols effectively reducing mortality and morbidity following trauma. In this review, we discuss the current literature with regard to the management of haemorrhage following trauma, with a special reference to the use of pharmacological adjuncts. Novel insights, concepts and treatment modalities are also discussed.     

Comprehensive genomic profiling of metastatic collecting duct carcinoma,renal medullary carcinoma,and clear cell renal cell carcinoma

Introduction and ObjectiveUnlike clear cell renal cell carcinoma (CCRCC), collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) are rare tumors that progress rapidly and appear resistant to current systemic therapies. We queried comprehensive genomic profiling to uncover opportunities for targeted therapy and immunotherapy.Material and MethodsDNA was extracted from 40 microns of formalin-fixed, paraffin-embedded specimen from relapsed, mCDC (n = 46), mRMC (n = 24), and refractory and metastatic (m) mCCRCC (n = 626). Comprehensive genomic profiling was performed, and Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated. We analyzed all classes of genomic alterations.ResultsmCDC had 1.7 versus 2.7 genomic alterations/tumor in mCCRCC ( = 0.04). Mutations in VHL (P < 0.0001) and TSC1 (P = 0.04) were more frequent in mCCRCC. SMARCB1 (P < 0.0001), NF2 (P = 0.0007), RB1 (P = 0.02) and RET (P = 0.0003) alterations were more frequent in mCDC versus mCCRCC. No VHL alterations in mRMC and mCDC were identified. SMARCB1 genomic alterations were significantly more frequent in mRMC than mCDC (P = 0.0002), but were the most common alterations in both subtypes. Mutations to EGFR, RET, NF2, and TSC2 were more frequently identified in mCDC versus mRMC. The median TMB and MSI-High status was low with <1% of mCCRC, mCDC, and mRMC having ≥ 20 mut/Mb.ConclusionGenomic alteration patterns in mCDC and mRMC differ significantly from mCCRCC. Targeted therapies for mCDC and mRMC appear limited with rare opportunities to target alterations in receptor tyrosine kinase and MTOR pathways. Similarly, TMB and absence of MSI-High status in mCDC and mRMC suggest resistance to immunotherapies.     

Natural history of descending thoracic and thoracoabdominal aortic aneurysms

ObjectivesElucidating critical aortic diameters at which natural complications (rupture, dissection, and death) occur is of paramount importance to guide timely surgical intervention. Natural history knowledge for descending thoracic and thoracoabdominal aortic aneurysms is sparse. Our small early studies recommended repairing descending thoracic and thoracoabdominal aortic aneurysms before a critical diameter of 7.0 cm. We focus exclusively on a large number of descending thoracic and thoracoabdominal aortic aneurysms followed over time, enabling a more detailed analysis with greater granularity across aortic sizes.MethodsAortic diameters and long-term complications of 907 patients with descending thoracic and thoracoabdominal aortic aneurysms were reviewed. Growth rates (instrumental variables approach), yearly complication rates, 5-year event-free survival (Kaplan–Meier), and risk of complications as a function of aortic height index (aortic diameter [centimeters]/height [meters]) (competing-risks regression) were calculated.ResultsEstimated mean growth rate of descending thoracic and thoracoabdominal aortic aneurysms was 0.19 cm/year, increasing with increasing aortic size. Median size at acute type B dissection was 4.1 cm. Some 80% of dissections occurred below 5 cm, whereas 93% of ruptures occurred above 5 cm. Descending thoracic and thoracoabdominal aortic aneurysm diameter 6 cm or greater was associated with a 19% yearly rate of rupture, dissection, or death. Five-year complication-free survival progressively decreased with increasing aortic height index. Hazard of complications showed a 6-fold increase at an aortic height index of 4.2 or greater compared with an aortic height index of 3.0 to 3.5 (P < .05). The probability of fatal complications (aortic rupture or death) increased sharply at 2 hinge points: 6.0 and 6.5 cm.ConclusionsAcute type B dissections occur frequently at small aortic sizes; thus, prophylactic size-based surgery may not afford a means for dissection protection. However, fatal complications increase dramatically at 6.0 cm, suggesting that preemptive intervention before that criterion can save lives.     

Lack of association between low HDL-cholesterol and elevated circulating cellular adhesion molecules in normolipidemic CAD patients and healthy subjects

High plasma HDL-cholesterol (HDL-c) is a well-established protective factor in coronary artery disease (CAD). One of its potential protective mechanisms is the inhibition of the cytokine-induced upregulation of expression of cellular adhesion molecules (CAMs). High sCAM levels were found to be associated with low HDL-c in some studies performed mostly in hyperlipidemic subjects, but this association has not yet been investigated in CAD patients. In addition, conflicting results were obtained from in vitro studies that explored the proposed HDL effect on cytokine-induced CAM expression. The aim of the present case-control study was to investigate whether low HDL-c values are associated with CAM overexpression in normolipidemic CAD patients and healthy individuals, matched according to age and gender. Plasma HDL-c, sICAM-1, sVCAM-1, and sE-selectin were measured in 37 normolipidemic patients with angiographically verified coronary artery disease and in 52 healthy normolipidemic subjects. The sCAM values obtained in the subjects (patients or controls) with low HDL-c levels (< 1.03 mmol/L) were compared with the values in the subjects with high HDL-c (>or= 1.03 mmol/L). No significant difference was found between sICAM-1, sVCAM-1, and E-selectin values obtained in subjects with low and high HDL-c, either among the patients or the healthy controls. In conclusion, low HDL-c levels are not associated with CAM overexpression in normolipidemic CAD patients and healthy subjects.     

SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF‐β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF‐β signaling pathway exhibit arterial aneurysms and dissections as key features