Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.

BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data. METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated. RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5-11.0) and 1 year OS was 43% (95% CI 40-47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS. CONCLUSION: Benchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.

Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

WHAT IS KNOWN AND OBJECTIVE: Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor (KOR) agonists (pKORAs). METHODS: Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. RESULTS: The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. WHAT IS NEW AND CONCLUSIONS: The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile.

Synthesis and biological evaluation of 3-(4-chlorophenyl)-4-substituted pyrazole derivatives.

3-(4-Chlorophenyl)-4-substituted pyrazole derivatives were synthesised and tested for their in vitro antifungal activity. Some compounds showed very good antifungal activity against four pathogenic strains of fungi. The same compounds exhibited an interesting activity against the tested strain of Mycobacterium tuberculosis H37Rv. The results suggest that 1,3,4-oxadiazoles and 5-pyrazolinones bearing a core pyrazole scaffold may be promising antifungal and antitubercular agents.

Gabapentin for spasticity and autonomic dysreflexia after severe spinal cord injury.

STUDY DESIGN: Using a complete transection spinal cord injury (SCI) model at the fourth thoracic vertebral level in adult rats, we evaluated whether blocking noxious stimuli below the injury diminishes abnormal somatic and autonomic motor reflexes, manifested in muscular spasticity and hypertensive autonomic dysreflexia, respectively. Gabapentin (GBP) is well tolerated and currently used to manage neuropathic pain in the SCI population; evidence suggests that it acts to decrease presynaptic glutamate release. As clinical evidence indicates that GBP may suppress muscular spasticity in the chronic SCI population, we hypothesized that preventing neurotransmission of noxious stimuli with GBP eliminates a critical physiological link to these distinct, debilitating SCI-induced secondary impairments. OBJECTIVES: Behavioural assessments of tail muscle spasticity and mean arterial blood pressure responses to noxious somatic and/or visceral stimulation were used to test the effects of GBP on these abnormal reflexes. SETTING: Lexington, Kentucky. METHODS: We used femoral artery catheterization and radio-telemetric approaches to monitor blood pressure alterations in response to noxious colorectal distension (CRD) weeks after complete SCI. RESULTS: At 2-3 weeks post-SCI, acute GBP administration (50 mg kg(-1), i.p.) significantly attenuated both autonomic dysreflexia and tail spasticity induced by noxious stimuli compared with saline-treated cohorts. CONCLUSION: These results show, for the first time, that a single-pharmacological intervention, GBP, can effectively attenuate the manifestation of both muscular spasticity and autonomic dysreflexia in response to noxious stimuli.

Voluntary exercise may activate components of pro-survival risk pathway in the rat heart and potentially modify cell proliferation in the myocardium.

Although physical exercise is known to reduce size of infarction, incidence of ventricular arrhythmias, and to improve heart function, molecular mechanisms of this protection are not fully elucidated. We explored the hypothesis that voluntary running, similar to adaptive interventions, such as ischemic or remote preconditioning, may activate components of pro-survival (RISK) pathway and potentially modify cell proliferation. Sprague-Dawley adult male rats freely exercised for 23 days in cages equipped with running wheels, while sedentary controls were housed in standard cages. After 23 days, left ventricular (LV) myocardial tissue samples were collected for the detection of expression and activation of RISK proteins (WB). The day before, a marker of cell proliferation 5-bromo-2'-deoxyuridine (BrdU) was given to all animals to detect its incorporation into DNA of the LV cells (ELISA). Running increased phosphorylation (activation) of Akt, as well as the levels of PKC? and phospho-ERK1/2, whereas BrdU incorporation into DNA was unchanged. In contrast, exercise promoted pro-apoptotic signaling - enhanced Bax/Bcl-2 ratio and activation of GSK-3ß kinase. Results suggest that in the rat myocardium adapted to physical load, natural cardioprotective processes associated with physiological hypertrophy are stimulated, while cell proliferation is not modified. Up-regulation of pro-apoptotic markers indicates potential induction of cell death mechanisms that might lead to maladaptation in the long-term.

High birth weight, asthma and atopy at the age of 16 yr.

The association between high birth weight and asthma has been suggested. The Northern Finland Birth Cohort 1986, a longitudinal cohort originally including 9479 participants, has been followed up since birth until the age of 16 yr. Using the data of this study, we analyzed the association of high birth weight with asthma and atopic sensitization at the age of 16 yr. The analysis included the 5995 subjects with complete skin prick test data and the 5500 subjects with data on doctor-diagnosed asthma (written questionnaire) at the age of 16 yr. Atopy was defined as at least one positive skin prick test reaction, which definition was also used to separate atopic and non-atopic asthma. There was a significant association between high birth weight (>4510 g) and asthma among the atopic subjects (OR 2.40, 95% CI 1.33-4.32). When looking at atopy, the highest risk was observed among the subjects with highest birth weight category (>4510 g) (OR 1.44, 95% CI 1.05-1.97) and the adjacent (4200-4500 g) birth weight category (OR 1.24, 95% CI 1.01-1.53), when compared with the reference category (2500-3340 g). Our results support the notion that high birth weight is associated with an increased risk of asthma and suggest that the association is mostly explained by an increased risk of atopy. The biological mechanisms behind the associations are unknown, but they could be related to obesity.

Applicability of a single 5 color cytoplasmic markers tube as primary panel for immunophenotyping of acute leukemia: A Gujarat Cancer and Research Institute experience.

INTRODUCTION: Flow cytometry is highly sensitive for detection and quantitative analysis of surface and intracellular antigens in malignant hemopoietic cells. Immunophenotyping is a routine practice for classification and lineage assignment of acute leukemia. In the present study, our aim is to identify the role of a single 5 color, CD45, myeloperoxidase (MPO), cCD79a, cCD3, and Tdt, cytoplasmic markers combination as a primary tube. We compared with final diagnosis on the basis of morphology, cytochemistry, and primary and secondary panels of immunophenotyping and also with other study. MATERIALS AND METHODS: We have included 455 new cases of acute leukemias with applied primary and secondary panels of markers for immunophenotyping. We analyzed sensitivity and specificity of different subsets with combination of positive and negative markers. RESULTS: MPO was positive in 61.4% of acute myeloid leukemia (AML) cases. All 184 (100%) cases of the AML were negative for cCD3 and cCD79a co-expression. cCD79a expression was highly sensitive as 98.5% B-acute lymphoblastic leukemia (B-ALL) expressed it. cCD3 expression was detected in 100% cases of T-ALL, and its co-expression was not seen in B-ALL and AML. CONCLUSION: Our study indicates that there was very good correlation of 5-color cytoplasmic tube-based diagnosis versus final diagnosis based on morphology, cytochemistry, and flow cytometry. We can use this 5-color cytoplasmic tube method to make immunophenotyping cost-effective.

Chlorambucil-induced acute hepatic failure in a patient with membranous nephropathy.

We present the case of a 23-year-old woman with membranous nephropathy who developed acute hepatic failure after being administered chlorambucil for a month.

Recovery of gastrointestinal tract motility and myoelectric activity change after abdominal surgery.

OBJECTIVE: To investigate the relationship between fedstate gastrointestinal tract (GI) function and upper GI myoelectric changes seen after abdominal surgery. DESIGN: Twenty-one adult female mongrel dogs underwent either an open cholecystectomy, a laparoscopic cholecystectomy alone, or a laparoscopic cholecystectomy with peritoneal injury (n = 7 for each group). Bipolar recording electrodes were placed on the antrum and 3 sites of the proximal small intestine to record fasting myoelectric data each morning postoperatively. Solid-phase, technetium Tc 99m gastric emptying studies were performed on postoperative days 1 and 2. Radiopaque markers were ingested just before operation, and the excreted markers were counted using x-ray films of the feces. MAIN OUTCOME MEASURES: Postoperative fasting GI myoelectric activity, gastric emptying, and intestinal transit time. RESULTS: Migrating motor complexes (MMCs) in the small intestine were observed in 33.3% and 75.0% of the dogs on postoperative days 1 and 2, respectively. Gastric dysrhythmias were observed in 23.8% and 45.0% of the dogs on postoperative days 1 and 2, respectively. No relationship between type of surgery and the presence of MMCs or gastric dysrhythmias was noted. Gastric emptying was delayed on postoperative day 1 and was unrelated to the presence of MMCs. Transit time was not significantly delayed in dogs without MMCs on postoperative day 1 compared with that in dogs with MMCs on that day. The presence of gastric dysrhythmias did not affect transit time studies. CONCLUSION: Fasting GI myoelectric activity, including the return of MMCs and the presence of gastric dysrhythmias, does not accurately predict fed-state gastrointestinal GI function following abdominal surgery.

In vitro release of therapeutically active ingredients from polymer matrixes.

Several therapeutically active ingredients including benzocaine, cyclomethycaine, and methapyrilene hydrochloride were incorporated into ethylcellulose and polyamide films. The effect of cetyl alcohol and tributyl citrate upon the release of these ingredients was studied. The films containing the active ingredient and plasticizer were cast upon a mercury substrate, and the in vitro release of these drugs from each film into a desorbing medium of distilled water was measured. The results indicated that the film-forming agent and plasticizer affected the drug release rate and that the release followed first-order kinetics. Benzocaine was slowly released from polyamide-cetyl alcohol films and polyamide-cetyl alcohol-tributyl citrate films. Polyamide-tributyl citrate films showed enhanced release of benzoacaine and cyclomethycaine. Ethylcellulose films plasticized with tributyl citrate produced a fast drug release. Based upon these results, a water-soluble, highly polar, noncomplexing additive would tend to increase the drug release from the film. When the amount of benzocaine released from ethylcellulose was plotted as a function of the square root of time, a linear plot was obtained. Since this linear plot passed through the origin, ethylcellulose should be an ideal matrix for benzocaine according to the Higuchi diffusion-controlled model. These studies demonstrated the in vitro release of thf the solubility of the active agent in both the polymer film as a function of the solubility of the active agent in both the polymer matrix and the desorbing medium.

Oral absorption efficiency of acid-labile antibiotics from lipid-drug delivery systems.

The utility of cholesterol, cholesteryl acetate, and beta-sitosterol in protecting and improving the oral absorption efficiency of acid-labile antibiotics is discussed. The potassium salts of penicillin G and penicillin V and erythromycin lactobionate were studied. The stability of the two penicillins in simulated gastric fluid was determined iodometrically. The rank order of acid protective activity was: cholesteryl acetate greater than beta-sitosterol greater than cholesterol. Oral administration of erythromycin lactobionate coated with cholesteryl acetate produced a twofold increase in human urinary excretion of erythromycin when compared with the uncoated material. Potassium salts of penicillin G and penicillin V coated with cholesteryl acetate yielded 1.6- and 2-fold higher urine levels, respectively, as compared with the uncoated candidates.

The relationship between disgust sensitivity, anxiety and obsessions.

Three hundred participants, including volunteers from an obsessional support group, filled in questionnaires relating to disgust sensitivity, health anxiety, anxiety, fear of death, fear of contamination and obsessionality as part of an investigation into the involvement of disgust sensitivity in types of obsessions. Overall, the data supported the hypothesis that a relationship does exist between disgust sensitivity and the targeted variables. A significant predictive relationship was found between disgust sensitivity and total scores on the obsessive compulsive inventory (OCI; Psychological Assessment 10 (1998) 206) for both frequency and distress of symptomatology. Disgust sensitivity scores were significantly related to health anxiety scores and general anxiety scores and to all the obsessional subscales, with the exception of hoarding. Additionally, multiple regression analyses revealed that disgust sensitivity may be more specifically related to washing compulsions: frequency of washing behaviour was best predicted by disgust sensitivity scores. Washing distress scores were best predicted by health anxiety scores, though disgust sensitivity entered in the second model. It is suggested that further research on the relationship between disgust sensitivity and obsessionality could be helpful in refining the theoretical understanding of obsessions.

Suicide among immigrants from the Indian subcontinent: a review.

OBJECTIVE: Studies of suicide among immigrants from the Indian subcontinent (India, Pakistan, Bangladesh, and Sri Lanka) were examined to increase awareness of suicide risk and to better understand social and psychological factors contributing to suicide in this group. METHODS: An online search was conducted of MEDLINE for the years 1966 to 1994 and Psychological Abstracts for the years 1974 to 1994, and all references on completed suicides in the target population were selected for review. RESULTS: Suicide rates of young women immigrants from the Indian subcontinent are consistently higher than those of their male counterparts and of young women in the indigenous populations of the countries to which they immigrate. Suicide rates among older men in this immigrant group have been reported to be low, although reports are less consistent. Use of violent methods such as hanging, burning, and poisoning is common among both men and women. A disproportionately higher number of immigrant Hindus commit suicide. Family conflict appears to be a precipitating factor in many suicides, whereas mental illness is rarely cited as a cause. Depression, anxiety, and domestic violence may contribute to the high rates. Affective disorders may be underdiagnosed in this population. CONCLUSIONS: More research is needed on the epidemiology of psychiatric illnesses and their contribution to suicide in this group.

Acetyl-L-carnitine treatment following spinal cord injury improves mitochondrial function correlated with remarkable tissue sparing and functional recovery.

We have recently documented that treatment with the alternative biofuel, acetyl-L-carnitine (ALC, 300 mg/kg), as late as 1 h after T10 contusion spinal cord injury (SCI), significantly maintained mitochondrial function 24 h after injury. Here we report that after more severe contusion SCI centered on the L1/L2 segments that are postulated to contain lamina X neurons critical for locomotion (the "central pattern generator"), ALC treatment resulted in significant improvements in acute mitochondrial bioenergetics and long-term hind limb function. Although control-injured rats were only able to achieve slight movements of hind limb joints, ALC-treated animals produced consistent weight-supported plantar steps 1 month after injury. Such landmark behavioral improvements were significantly correlated with increased tissue sparing of both gray and white matter proximal to the injury, as well as preservation of choline acetyltransferase (ChAT)-positive neurons in lamina X rostral to the injury site. These findings signify that functional improvements with ALC treatment are mediated, in part, by preserved locomotor circuitry rostral to upper lumbar contusion SCI. Based on beneficial effects of ALC on mitochondrial bioenergetics after injury, our collective evidence demonstrate that preventing mitochondrial dysfunction acutely "promotes" neuroprotection that may be associated with the milestone recovery of plantar, weight-supported stepping.

Mycosis fungoides: an overview.

Mycosis fungoides (MF) is a lymphoma that appears to have a unique relationship with the skin. In recent years our knowledge about this disease has increased considerably, in particular regarding the nature of the malignant cells and their functional characteristics. Furthermore, there is mounting evidence suggesting a viral etiology. Since its first description by Alibert in the early part of the past century, MF has been the subject of much controversy in regard to fundamental issues such as clinical and histological criteria for the establishment of the diagnosis [1] as well as its relationship to other lymphomas and skin diseases. Some of this controversy remains today. Mycosis fungoides is a relatively uncommon disease, the incidence being in the order of 1-2 million per year [1,2]. As is the case with most neoplastic diseases, the incidence increases with age; however, relatively speaking MF is not exceptional among individuals in their twenties or thirties. As for sex distribution there is a slight preponderance of men [3-5].

Neuropsychiatric features of acute disseminated encephalomyelitis: a review.

Acute disseminated encephalomyelitis is a disorder associated with significant morbidity and mortality. A description and literature review are presented to focus attention on the myriad neuropsychiatric manifestations of this disease. Common psychiatric symptoms include lethargy, irritability, and confusion. Ataxia, seizures, and other signs representing involvement of various areas of the brain and spinal cord are common neurologic presentations. The cerebrospinal fluid shows only nonspecific abnormalities, whereas magnetic resonance imaging may show various lesions in the white matter representing demyelination. The treatment of choice is steroids, but there can be significant residual sequelae of the disease, including intellectual and behavioral abnormalities.

Decision-making in acute asthma.

The management of an eight-year-old child with acute asthma was investigated by putting a semi-structured patient management problem (PMP) to 618 general practitioners. Of the 321 (52 per cent) who replied, 112 (35 per cent) would arrange for immediate admission to hospital and a further 154 (48 per cent) would have the child admitted after 30 minutes when initial home treatment appeared not to be working. Among those who would treat at home there was considerable variation in the type and intensity of treatment given. The more recently qualified were more likely to admit immediately or to treat vigorously at home (with intravenous steroids and/or aminophylline); no other characteristic of the doctor or the practice was related to admission decision or to treatment. Expectations concerning the immediate hospital management of the patient also varied widely. Comparison of the expected hospital management with actual management recorded in hospital case-notes suggested that general practitioners overestimate the use of intensive treatments (steroids, intravenous drip, oxygen) and investigations (blood gases, lung function tests, chest radiograph).

Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986.

Thirty laboratories from institutions in Britain, France, Italy, The Netherlands, New Zealand, Sweden and the USA participated in a workshop to evaluate the anti-cardiolipin (aCL) test. Participants were asked to measure IgG and IgM aCL in seven samples on each of three separate days. The seven samples were prepared so that IgG and IgM aCL concentrations were known before distribution. Twenty-three of 30 laboratories measuring IgG aCL had significant regression slopes (P less than 0.001) when optical absorbance readings or counts per minute were compared with IgG aCL concentration. Twenty-four of 28 laboratories measuring IgM aCL had significant regression slopes (P less than 0.001). Coefficient of determination (R2) ranged from 81.1% to 98.7% for laboratories with valid IgG aCL assays and from 48.0% to 96.7% for valid IgM aCL assays. Valid assays had in common the use of 10% fetal calf or 10% adult bovine serum in PBS. Assays that were not valid had in common the use of PBS, PBS-Tween, or 0.3% gelatin as diluents. All laboratories with valid assays defined samples with high and moderate aCL levels as positive but there was no consensus about low positive samples. This study shows that properly performed ELISA or SRIA assays can be used to provide an accurate, reproducible, and quantitative measure of IgG and IgM aCL concentration in serum samples.

Depression in general practice: case thresholds and diagnosis.

Using multiple diagnostic and epidemiological criteria, three samples of general practice (GP) depressives were studied: those prescribed a new course of antidepressants, those given other treatment, and those missed by the GP. The majority of patients qualified as psychiatric cases on the PSE Index of Definition, the Bedford College Criteria, and the Research Diagnostic Criteria. Most satisfied diagnostic criteria for depression, or (fewer) anxiety. The disorders were relatively mild and often borderline on all three systems. Depressives given other treatment most often failed to meet diagnostic criteria. About half the antidepressant treated patients received RDC diagnoses of major depression. Among the other treatment sample, only one-fifth met these criteria, and half had non-depressive diagnoses. Most cases of depression treated by GPs satisfy criteria for psychiatric disorder, but tend to be relatively mild and borderline in quality.