Reversibility of liver failure secondary to metastatic breast cancer by vinorelbine and cisplatin chemotherapy

Purpose The development of liver metastases from breast cancer is associated with a very poor prognosis, estimated at 4 months median survival. Since treatment with many chemotherapeutic agents is relatively contraindicated, we assessed the safety, tolerability and potential efficacy of combination chemotherapy with vinorelbine and cisplatin (ViP).Method Pilot study in 11 patients with histologically confirmed breast carcinoma, radiological evidence of liver metastases and serum bilirubin greater than 1.5 times the upper limit of normal. Patients received up to six cycles of cisplatin (75 mg/m²) every 21 days and vinorelbine (20 mg/m²) on days 1 and 8 of every 21-day cycle. Measurement of liver lesions was performed on CT scan every 8 weeks into treatment.Results The most frequently reported adverse event was myelosuppression. Other adverse effects included nausea, vomiting and mild neurotoxicity. Two patients died after one treatment with ViP, one of whom suffered an intracerebral haemorrhage that was possibly treatment-related. Improvement in liver function tests was observed in 10 patients, and mean time to normalization of bilirubin levels was 36 days. Partial responses were documented radiologically in 7 out of 11 patients treated. Median overall survival from trial entry was 6.5 months (range 11–364 days), with one patient alive 13 months from trial entry.Conclusion Normalization of liver function is possible with ViP treatment of metastatic breast cancer, offering the potential to prolong survival. Phase II clinical trials of this regimen in this patient group should include measurement of quality of life in order to assess risk versus benefit.     

Reductive metabolism of the carcinogen 4-(5-nitro-2-furyl)thiazole to 1-(4-thiazolyl)-3-cyano-1-propanone by rat liver subcellular fractions

The reductive metabolism of 4-(5-nitro-2-furyl)thiazole (NFT), a rat mammary gland and forestomach carcinogen, was examined in vitro using rat liver tissues. NFT was reduced by rat liver cytosol or microsomes on anaerobic incubation with NADPH. The stoichiometry of microsomal reduction revealed that about 3 moles of NADPH were used per mole of NFT. Gas chromatographic analysis of the reaction mixture showed a major peak with a retention time of about 4.0 min in contrast to NFT with a retention time of about 6.5 min. Catalytic hydrogenation of NFT with palladium and activated carbon yielded a product with a retention time of 4.0 min. The component corresponding with the above metabolite was isolated from chemically reduced NFT and identified as 1-(4-thiazolyl)-3-cyano-l-propanone. The metabolite derived from enzymatic reduction had chromatographic and spectral properties and a mass spectral fragmentation pattern similar to those obtained chemically. These data establish that the enzymatically derived product is identical to that obtained by chemical reduction and that it corresponds to 1(4thiazolyl)3cyano1propanone.     

HIV risks among women who are married to men who have sex with men in India: a qualitative investigation

In countries such as India, men who have same-sex partnerships may marry women due to cultural pressures regardless of their sexual desires and preferences. The wives of such men may be at risk for HIV but limited existing research addresses this issue. This qualitative study used in-depth interviews to investigate HIV-related risk among married men who have sex with men (n = 34) and women who were aware of their husband’s same-sex behaviour (n = 13) from six research sites in five states and a Union Territory in India: Delhi (Delhi), Visakhapatnam (Andhra Pradesh), Hyderabad (Telangana), Bengaluru (Karnataka), Chennai and Madurai (Tamil Nadu). Thematic analysis revealed that wives of men who have sex with men were at risk for HIV from their husbands’ sexual practices, which are often hidden to avoid the potential consequences of stigmatisation, as well as from gender-based inequities that make husbands the primary decision-makers about sex and condom use, even when wives are aware of their husband’s same-sex behaviour. Innovative interventions are needed to address HIV-related risk in couples where wives remain unaware of their husband’s same-sex behaviour, and for wives who are aware but remain within these marriages.     

Evaluation of polymerase chain reaction (PCR) method and hybrid capture II (HCII) assay for the detection of human papillomavirus in cervical scrapings

In order to investigate the reliability of detecting HPV DNA in cervical smears, we compared the performance of nested MY/GP PCR and FDA approved-Hybrid Capture II (HCII) using clinical cervical scrapings from 40 patients. It was found that PCR was more sensitive (81.8%) in comparison to HCII (36.4%) in detecting HPV although specificity of HCII was much higher (96.6%) than PCR (58.6%). The Negative Predictive Value (NPV) of both the techniques were quite similar but Positive Predictive Value (PPV) of HCII was much higher (80.0%) compared to PCR (42.9%). While the HCII method showed good specificity for HPV detection, its lack of sensitivity as compared to PCR may be a drawback for diagnostic use.     

Interventional Procedures for Chronic Pain in Children and Adolescents: A Review of the Current Evidence

This review discusses the role of interventional procedures in the treatment of chronic pain in children and adolescents. Due to lack of scientific evidence, significant controversy surrounds the utility of invasive techniques for managing pediatric chronic pain states. Interventional procedures are a widely accepted modality for pain management in adults. The use of such techniques in children is supported only by case reports, case series, and very few randomized controlled studies. In addition, the potential for severe complications leaves open a debate on the safety of these invasive procedures, which must be confirmed by more extensive and accurate prospective studies.     

Mixture of trajectory models for neural decoding of goal-directed movements

Probabilistic decoding techniques have been used successfully to infer time-evolving physical state, such as arm trajectory or the path of a foraging rat, from neural data. A vital element of such decoders is the trajectory model, expressing knowledge about the statistical regularities of the movements. Unfortunately, trajectory models that both 1) accurately describe the movement statistics and 2) admit decoders with relatively low computational demands can be hard to construct. Simple models are computationally inexpensive, but often inaccurate. More complex models may gain accuracy, but at the expense of higher computational cost, hindering their use for real-time decoding. Here, we present a new general approach to defining trajectory models that simultaneously meets both requirements. The core idea is to combine simple trajectory models, each accurate within a limited regime of movement, in a probabilistic mixture of trajectory models (MTM). We demonstrate the utility of the approach by using an MTM decoder to infer goal-directed reaching movements to multiple discrete goals from multi-electrode neural data recorded in monkey motor and premotor cortex. Compared with decoders using simpler trajectory models, the MTM decoder reduced the decoding error by 38 (48) percent in two monkeys using 98 (99) units, without a necessary increase in running time. When available, prior information about the identity of the upcoming reach goal can be incorporated in a principled way, further reducing the decoding error by 20 (11) percent. Taken together, these advances should allow prosthetic cursors or limbs to be moved more accurately toward intended reach goals.     

FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia

Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven [including p210/p190(BCR/ABL)(T315I)] leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.