Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.     

Understanding and clinical application of acute dilation of the left ventricle on ventricular arrhythmias

In this issue of the Journal of Geriatric Cardiology,Yin et al discussed the effects of calcium preconditioning (CPC) and streptomycin (S) on acute dilation of the left ventricle.……     

Sphenoid sinus mucocele (anterior clinoid variant) mimicking diabetic ophthalmoplegia and retrobulbar neuritis

Two patients (two men, 56 and 59 years old) had sphenoid sinus mucocele originating in the anterior clinoid process. In one case the mucocele initially mimicked diabetic ophthalmoplegia with pupil-sparing palsy of the oculomotor (third) nerve. After resolution of the palsy, severe visual loss developed with minimal recovery of vision after surgery. The second patient had recurrent episodes of retrobulbar optic neuropathy with optic atrophy and decreased vision. Visual loss from sphenoid sinus mucoceles is usually associated with a poor prognosis if surgical treatment is delayed more than seven to ten days.     

Theatre of paediatric surgery

In the 50 years since the first edition of this journal, operative paediatric surgery has undergone radical change. Many of the most common instruments are unchanged, both as a testament to their utility and in recognition of past surgeons remembered eponymously. Surrounding that basic core of instruments, theatre has changed radically as new tools and techniques have arisen. Surgeons have come down from their pedestals, recognising surgery as a team sport rather than a solo performance. More than half of the current paediatric surgical trainees are women, a higher proportion than in any other craft group of the Royal Australasian College of Surgeons. The appearance, and rapid development, of laparoscopy is to many observers the most notable change in surgery over the last 50 years. Placed in its context though, it is simply the most prominent example of a frameshift in surgical thinking. The patient as a whole is now the focus, rather than just the disease. Recent developments are as much about minimising harm to normal tissues as they are about extirpating pathology. As a surgical maxim, ‘Primum non nocere’ is even more in evidence in 2015 than it was in 1965.     

The perinatal autopsy: pertinent issues in multicultural Western Europe

Western Europe is in a demographic transition with increasing multicultural societies. Health professionals have to understand the background, religious and cultural aspects of parents to counsel them regarding an autopsy in the event of a perinatal loss. Autopsy rates have declined over the past decades, the major limiting factor being the granting of permission for an autopsy, possibly because of adverse publicity or reluctance of doctors to obtain consent. Autopsy has proved its value in revealing unsuspected findings. The public can be convinced of this utility by means of good information notwithstanding their religious or cultural background.     

Antioxidant capacity and phenolic content of selected commercially available cruciferous vegetables

Antioxidant activity, free radical scavenging activity and phenolic content of red cabbage (Brassica oleracea var. capitata rubra), Chinese cabbage (Brassica rapa pekinensis var cylindrica), green cabbage (Brassica oleracea var capitata), mustard cabbage (Brassica juncea var rugosa) and Chinese white cabbage (Brassica rapa var chinensis), grown in Malaysia, were evaluated. Red cabbage had the highest antioxidant activity and phenolic content compared to the other cruciferous vegetables studied (p < 0.05). The contributions of all cruciferous vegetables to the antioxidant activity was >79%. The radical scavenging activity was in the order of Chinese white cabbage > red cabbage > mustard cabbage > Chinese cabbage > green cabbage. There was a significant difference (p < 0.05) in the means of scavenging activity observed between cabbage, Chinese cabbage and Chinese mustard. Phenolic content was significantly different (p < 0.05) among all the cruciferous vegetables studied, and was in the order of red cabbage > Chinese white cabbage > green cabbage > Chinese cabbage >mustard cabbage. The study indicated that red cabbage possessed the highest antioxidant capacity and phenolic compounds concentration among all the cruciferous vegetables studied.     

Impact of pathological response after preoperative transcatheter arterial chemoembolization (TACE) on incidences of microvascular invasion and early tumor recurrence in hepatocellular carcinoma: a multicenter propensity score matching analysis

BackgroundTo study the influence of pathological responses (PR) after transcatheter arterial chemoembolization (TACE) on incidences of microvascular invasion (MVI) and early recurrence in hepatocellular carcinoma (HCC) patients.MethodsBetween 2013 to 2015, consecutive HCC patients who underwent liver resection with “curative” intent at three hospitals were enrolled in this study. Patients with different areas of PR after preoperative TACE were compared with those without preoperative TACE on the incidences of MVI, early recurrence rates and patterns of recurrence before and after propensity score matching (PSM).ResultsOf 1,970 patients, 737 patients who received preoperative TACE were divided into three groups according to the areas of PR: ≥90% (n=226), 60–90% (n=447), and <60% (n=64). PR ≥90% was an independent protective factor of incidences of MVI [odds ratio (OR), 0.144; 95% confidence interval (CI), 0.082–0.245, P<0.001) and early recurrence (HR, 0.742; 95% CI, 0.561–0.963, P=0.032); while PR<60% was an independent risk factor of incidences of MVI (OR, 6.076; 95% CI, 3.004–11.728, P<0.001) and early recurrence (HR, 1.428; 95% CI, 1.095–1.929; P=0.009). Furthermore, patients with PR <60% were significantly more likely to develop multiple intrahepatic recurrences involving multiple hepatic segments when compared with patients without preoperative TACE.ConclusionsThis study indicated the area of PR after TACE was closely associated with the incidences of MVI and early tumor recurrence. Patients with PR <60% were at significantly higher risks of having more MVI, early and multiple tumor recurrences     

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.Subject terms: Combination drug therapy, Cancer therapeutic resistance, Targeted therapies