Lack of Cumulative Toxicity Associated With Cabazitaxel Use in Prostate Cancer

Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3–4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed “per cycle” incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis.“Per cycle” incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86–0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34–0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86–1; P = 0.07). Patients with a body surface area >2 m² presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86–1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.     

Pooled Analysis of Phase II Trials Evaluating Weekly or Conventional Cisplatin as First-Line Therapy for Advanced Urothelial Carcinoma

BackgroundWeekly gemcitabine with GC every 3-4 weeks is considered conventional first-line chemotherapy for advanced urothelial carcinoma (UC). Weekly split-dose cisplatin with wGC might be less toxic and have similar activity, but has not been compared with GC. We pooled published phase II trials of GC and wGC to compare efficacy and safety.Patients and MethodsTwo trials of wGC and 3 trials of GC were identified. Because the data were not derived from randomized trials, GC and wGC were not formally compared, and exact 95% quasi-binomial confidence intervals (CI), for response rates and grade ≥ 3 toxicities were calculated.ResultsThe 95% CI overlapped, suggesting agreement between wGC and GC. No clear difference in response rates and grade ≥ 3 toxicities between GC and wGC were observed.ConclusionGemcitabine combined with day 1 cisplatin and wGC yielded similar responses and grade ≥ 3 toxicities in advanced UC in a hypothesis-generating pooled analysis of phase II trials. Considering the probable lower nephrotoxicity of fractionated cisplatin, prospective evaluation of wGC might be warranted across cisplatin-eligible and -ineligible patients to develop a single chemotherapy template for the development of combinations with biological agents in a broad population of patients.     

The Impact of Gender on Outcomes in Patients With Metastatic Urothelial Carcinoma

BackgroundAlthough urothelial cancer is more common in men, women with urothelial cancer have inferior survival outcomes. The potential existence of gender-related disparities in patients with metastatic urothelial cancer has not been extensively explored.Patients and MethodsIndividual patient data were pooled from 8 phase II and phase III trials evaluating first-line cisplatin-based combination chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between male and female patients.ResultsOf the 543 patients included in the analysis, 100 patients (18%) were women. There was no significant difference in the number of cycles of chemotherapy administered or in the proportions of patients experiencing severe toxicities when comparing male and female patients. There was no difference in the survival distributions between male and female patients (P = .08); the median survival of male patients was 11.7 months (95% confidence interval [CI], 10.5-13.2) compared with 16.2 months for female patients (95% CI, 12.8-20.4). There was no significant difference in survival between men and women when controlling for baseline performance status and/or the presence of visceral metastases.ConclusionFemale patients with metastatic urothelial cancer tolerate cisplatin-based chemotherapy similarly to male patients and achieve comparable clinical outcomes. Although gender-associated survival disparities in patients with metastatic urothelial cancer cannot be completely ruled out, if such disparities exist, they are unlikely related to tolerability or efficacy of chemotherapy.     

Mixed-Micellar Proliposomal Systems for Enhanced Oral Delivery of Progesterone

The objective of our study was to develop a mixed-micellar proliposomal formulation of poorly water-soluble drug progesterone and evaluate the dissolution profile and membrane transport. Several formulations of proliposomes were prepared by mixing different concentrations of lipid, progesterone, polysorbate 80, and microcrystalline cellulose. The mixed-micellar formulation of drug:dimyristoyl-phosphatidycholine:polysorbate 80 (1:20:3.3) exhibited the maximum dissolution (75.27%), while pure progesterone resulted in low dissolution. The above formulation showed a 4-fold increase in transport in Caco-2 cells and a 6-fold increase in transport across the everted rat intestinal sac experiments compared with control. Proliposomal formulations enhance the extent of dissolution and membrane transport of progesterone and serve as ideal carriers for oral delivery of drugs with low water solubility.     

Does Squatting Worsen Lower Limb Ischemia in Patients with Peripheral Arterial Disease?

Peripheral arterial disease (PAD) is an important cause of morbidity and mortality in the world affecting up to 20% in people over 70?years of age. The prevalence is increasing in India due to combined effects of increased life expectancy, increased tobacco smoking and increased prevalence of diabetes mellitus. The aim of the study was to examine the hypothesis whether squatting posture reduces blood flow to lower limbs resulting in worsening of symptoms of lower limb ischemia in patients with PAD. 10 patients with arterial disorders due to thromboangiitis obliterans (TAO), atherosclerosis and diabetic macro vascular disease were selected for patients and were compared with 10 healthy volunteers as controls. Clinical examination and duplex scan of posterior tibial artery (PTA) and dorsalis pedis artery (DPA) performed in standing and squatting position in a clinical environment. They were asked about symptoms of numbness, ischemic pain and the results were noted. Results were tabulated and analysed using Microsoft Excel?. Members in the control group complained of numbness of both the limbs after a period of 30?min on an average. In the patients group, members while squatting complained of numbness in the involved limb within 5?min. They complained of ischemic pain in the involved limb within 10?min and developed numbness in the opposite limb in within 15?min. Posterior tibial artery and dorsalis pedis artery pulsations disappeared for the entire duration of squatting in both groups as confirmed by duplex scanning. It may be recommended that patients with established peripheral vascular disease should avoid squatting position, even if it is for a very short period of time. It is desirable to advice such patients to use appropriate structures as supports which will allow them to work without squatting. This may also necessitate a change in occupation.     

The molecular structure of 4-(dimethylmaleimido)phenyl methacrylate

The molecular structure of 4-(dimethylmaleimido)phenyl methacrylate was determined by means of X-ray diffraction. Crystals are orthorhombic, space group F2dd, a = 3,993(1) Å, b = 36,650(6) Å, c = 39,460(8) Å and Z = 16; d_calc = 1,360 g · cm^?3, V = 5774,7 ų, M = 285,3, λ = 0,7107 Å, μ (MoK_α) = 1,06 cm^?1, F(000) = 2400. The structure was solved by direct methods and refined to R = 0,062 for 304 observed reflections. The molecule has a synperiplanar conformation as to the C?C and C?O double bonds about C(7)? C(8) and also as to the C?O and C? O bonds about C(7)? O(1).