Consolidation nivolumab and ipilimumab versus observation in limited-disease small-cell lung cancer after chemo-radiotherapy - results from the randomised phase II ETOP/IFCT 4-12 STIMULI trial.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. PATIENTS AND METHODS: STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. RESULTS: Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. CONCLUSIONS: The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results.

A plant endophyte Staphylococcus hominis strain MBL_AB63 produces a novel lantibiotic, homicorcin and a position one variant.

Here we report a jute endophyte Staphylococcus hominis strain MBL_AB63 isolated from jute seeds which showed promising antimicrobial activity against Staphylococcus aureus SG511 when screening for antimicrobial substances. The whole genome sequence of this strain, annotated using BAGEL4 and antiSMASH 5.0 to predict the gene clusters for antimicrobial substances identified a novel antimicrobial peptide cluster that belongs to the class I lantibiotic group. The predicted lantibiotic (homicorcin) was found to be 82% similar to a reported peptide epicidin 280 having a difference of seven amino acids at several positions of the core peptide. Two distinct peaks obtained at close retention times from a RP-HPLC purified fraction have comparable antimicrobial activities and LC-MS revealed the molecular mass of these peaks to be 3046.5 and 3043.2 Da. The presence of an oxidoreductase (homO) similar to that of epicidin 280- associated eciO or epilancin 15X- associated elxO in the homicorcin gene cluster is predicted to be responsible for the reduction of the first dehydrated residue dehydroalanine (Dha) to 2-hydroxypropionate that causes an increase of 3 Da mass of homicorcin 1. Trypsin digestion of the core peptide and its variant followed by ESI-MS analysis suggests the presence of three ring structures, one in the N-terminal and other two interlocking rings at the C-terminal region that remain undigested. Homicorcin exerts bactericidal activity against susceptible cells by disrupting the integrity of the cytoplasmic membrane through pore formation as observed under FE-SEM.

Correction to: NFATc2 is an intrinsic regulator of melanoma dedifferentiation.

In Fig. 6e, the authors noticed that wrong blots for MITF, MART-1 expression/modulation, and for ß-actin were presented, due to the similarity with experiments shown in Figure 5c. Correct MITF, MART-1, and ß-actin blots were added to the revised Fig. 6 shown in the associated Correction. The meaning of the results shown in Fig.6e, as well as the conclusions of this paper were not affected, and the authors regret for this error. These errors have not been fixed in the original Article.

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients

Background: Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need. Patients and methods: Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry. Results: A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0-1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months). Conclusion: Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic

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Correction to: Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.

Clinical and Translational Oncology.

Metal-Adapted Bacteria Isolated From Wastewaters Produce Biofilms by Expressing Proteinaceous Curli Fimbriae and Cellulose Nanofibers.

Bacterial biofilm plays a pivotal role in bioremediation of heavy metals from wastewaters. In this study, we isolated and identified different biofilm producing bacteria from wastewaters. We also characterized the biofilm matrix [i.e., extracellular polymeric substances (EPS)] produced by different bacteria. Out of 40 isolates from different wastewaters, only 11 (27.5%) isolates (static condition at 28°C) and 9 (22.5%) isolates (agitate and static conditions at 28 and 37°C) produced air-liquid (AL) and solid-air-liquid (SAL) biofilms, respectively, only on salt-optimized broth plus 2% glycerol (SOBG) but not in other media tested. Biomass biofilms and bacteria coupled with AL biofilms were significantly (P ≤ 0.001) varied in these isolates. Escherichia coli (isolate ENSD101 and ENST501), Enterobacter asburiae (ENSD102), Enterobacter ludwigii (ENSH201), Pseudomonas fluorescens (ENSH202 and ENSG304), uncultured Vitreoscilla sp. (ENSG301 and ENSG305), Acinetobacter lwoffii (ENSG302), Klebsiella pneumoniae (ENSG303), and Bacillus thuringiensis (ENSW401) were identified based on 16S rRNA gene sequencing. Scanning electron microscope (SEM) images revealed that biofilm matrix produced by E. asburiae ENSD102, uncultured Vitreoscilla sp. ENSG301, A. lwoffii ENSG302, and K. pneumoniae ENSG303 are highly fibrous, compact, and nicely interlinked as compared to the biofilm developed by E. ludwigii ENSH201 and B. thuringiensis ENSW401. X-ray diffraction (XRD) results indicated that biofilm matrix produced by E. asburiae ENSD102, uncultured Vitreoscilla sp. ENSG301, and A. lwoffii ENSG302 are non-crystalline amorphous nature. Fourier transform infrared (FTIR) spectroscopy showed that proteins and polysaccharides are the main components of the biofilms. Congo red binding results suggested that all these bacteria produced proteinaceous curli fimbriae and cellulose-rich polysaccharide. Production of cellulose was also confirmed by Calcofluor binding- and spectrophotometric assays. E. asburiae ENSD102, Vitreoscilla sp. ENSG301, and A. lwoffii ENSG302 were tested for their abilities to form the biofilms exposure to 0 to 2000 mg/L of copper sulfate (for Cu), zinc sulfate (for Zn), lead nitrate (for Pb), nickel chloride (for Ni), and potassium dichromate (for Cr), several concentrations of these metals activated the biofilm formation. The polysaccharides is known to sequester the heavy metals thus, these bacteria might be applied to remove the heavy metals from wastewater.

Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.

BACKGROUND: Immunotherapy increases overall response rate (ORR) and overall survival (OS) in patients with non-small-cell lung cancer (NSCLC). Prognostic and predictive factors are a high need. PATIENTS AND METHODS: Retrospective review of NSCLC patients treated with nivolumab was performed. Analyzed variables included age, sex, stage, performance status (PS), location of metastases, presence of tumour-related symptoms and comorbidities, number of metastasis locations, previous chemotherapy, anti-angiogenic and radiotherapy treatments, and analytical data from the standard blood count and biochemistry. RESULTS: A total of 175 patients were included. Median age was 61.5 years, 73.1% were men, 77.7% were ECOG-PS 0-1, and 86.7% were included with stage IV disease. Histology was non-squamous in 77.1%. Sixty-five received nivolumab in second line (37.1%). Thirty-eight patients had brain metastasis (22%), and 39 (22.3%) liver metastasis and 126 (72%) had more than one metastatic location. The ORR was 15.7% with median Progression free survival (PFS) 2.8 months and median OS 5.81 months. Stage III vs IV and time since the beginning of the previous line of treatment ≥ 6 vs < 6 months were associated with better response. PS 2, time since the previous line of treatment < 6 vs ≥ 6 months, and more than one metastatic location were independently associated with shorter OS in multivariable analysis (7.8 vs 2.7 months, 11.2 vs 4.6 months, and 9.4 vs 5.1 month). Finally, time since the previous treatment < 6 vs ≥ 6 months and more than one metastatic location were independently associated with shorter PFS in multivariable analysis (4.3 vs 2.3 months and 4.7 vs 2.3 months). CONCLUSION: Poor PS, short period of time since the previous treatment, and more than one metastatic location were associated with poorer prognostic.

NFATc2 is an intrinsic regulator of melanoma dedifferentiation.

Melanoma dedifferentiation, characterized by the loss of MITF and MITF regulated genes and by upregulation of stemness markers as CD271, is implicated in resistance to chemotherapy, target therapy and immunotherapy. The identification of intrinsic mechanisms fostering melanoma dedifferentiation may provide actionable therapeutic targets to improve current treatments. Here, we identify NFATc2 transcription factor as an intrinsic regulator of human melanoma dedifferentiation. In panels of melanoma cell lines, NFATc2 expression correlated inversely with MITF at both mRNA and protein levels. NFATc2(+/Hi) melanoma cell lines were CD271(+) and deficient for expression of melanocyte differentiation antigens (MDAs) MART-1, gp100, tyrosinase and of GPNMB, PGC1-α and Rab27a, all regulated by MITF. Targeting of NFATc2 by small interfering RNA, short hairpin RNA and by an NFATc2 inhibitor upregulated MITF, MDAs, GPNMB, PGC-1α, tyrosinase activity and pigmentation and suppressed CD271. Mechanistically, we found that NFATc2 controls melanoma dedifferentiation by inducing expression in neoplastic cells of membrane-bound tumor necrosis factor-α (mTNF-α) and that melanoma-expressed TNF-α regulates a c-myc-Brn2 axis. Specifically, NFATc2, mTNF-α and expression of TNF receptors were significantly correlated in panels of cell lines. NFATc2 silencing suppressed TNF-α expression, and neutralization of melanoma-expressed TNF-α promoted melanoma differentiation. Moreover, silencing of NFATc2 and TNF-α neutralization downmodulated c-myc and POU3F2/Brn2. Brn2 was strongly expressed in NFATc2(+/Hi) MITF(Lo) cell lines and its silencing upregulated MITF. Targeting of c-myc, by silencing or by a c-myc inhibitor, suppressed Brn2 and upregulated MITF and MART-1 in melanoma cells. The relevance of NFATc2-dependent melanoma dedifferentiation for immune escape was shown by cytolytic T-cell assays. NFATc2(Hi) MITF(Lo) MDA(Lo) HLA-A2.1(+) melanoma cells were poorly recognized by MDA-specific and HLA-A2-restricted CTL lines, but NFATc2 targeting significantly increased CTL-mediated tumor recognition. Taken together, these results suggest that the expression of NFATc2 promotes melanoma dedifferentiation and immune escape.

The impact of snake bite on household economy in Bangladesh.

The present study aims to assess the different types of costs for treatment of snake bite patients, to quantify household economic impact and to understand the coping mechanisms required to cover the costs for snake bite patients in Bangladesh. The patients admitted to four tertiary level hospitals in Bangladesh were interviewed using structured questionnaires including health-care-related expenditures and the way in which the expenditures were covered. Of the snakes which bit the patients, 54.2% were non-venomous, 45.8% were venomous and 42.2% of the patients were given polyvalent antivenom. The total expenditure related to snake bite varies from US$4 (US$1 = Taka 72) to US$2294 with a mean of US$124 and the mean income loss was US$93. Expenditure for venomous snake bite was US$231, which is about seven times higher than non-venomous snake bite (US$34). The treatment imposes a major economic burden on affected families, especially in venomous snake bite cases.

Study on heavy metals levels and its risk assessment in some edible fishes from Bangshi River, Savar, Dhaka, Bangladesh.

Concentrations of eight heavy metals (Pb, Cd, Ni, Cr, Cu, Zn, Mn, and As) in the muscles of ten species of fish collected from Bangshi River at Savar in Bangladesh were measured in two different seasons. The concentrations of the studied heavy metals, except Pb in Corica soborna, were found to be below the safe limits suggested by various authorities and thus gave no indication of pollution. The present study also showed that, Zn was the most and Cd was the least accumulated metal in the studied fish muscles. ANOVA analysis clearly revealed that there was a significant variation (CI=95%) of the heavy metal concentrations in different fish species in the Bangshi River. Significant positive correlations between the heavy metal concentrations in fish muscles were also observed in both seasons. From the human health point of view, this study showed that there was no possible health risk to consumers due to intake of studied fishes under the current consumption rate.

Reassessment of suicide attempters at home, shortly after discharge from hospital.

BACKGROUND: Assessment of suicide attempters in a general hospital may be influenced by the condition of the patient and the unfavorable circumstances of the hospital environment. AIMS: To determine whether the results of a reassessment at home shortly after discharge from hospital differ from the initial assessment in the hospital. METHODS: In this prospective study, systematic assessment of 52 suicide attempters in a general hospital was compared with reassessment at home, shortly after discharge. RESULTS: Reassessments at home concerning suicide intent, motives for suicide attempt, and dimensions of psychopathology did not differ significantly from the initial hospital assessment. However, patients' motives for the suicide attempt had changed to being less impulsive and more suicidal, worrying was significantly higher, and self-esteem was significantly lower. A third of the patients had forgotten their aftercare arrangements and most patients who initially felt no need for additional help had changed their mind at reassessment. CONCLUSIONS: Results from this group of suicide attempters suggest that a brief reassessment at home shortly after discharge from hospital should be considered.

Diarrhoeagenic Escherichia coli are not a significant cause of diarrhoea in hospitalised children in Kuwait.

BACKGROUND: The importance of diarrhoeagenic Escherichia coli (DEC) infections in the Arabian Gulf including Kuwait is not known. The prevalence of DEC (enterotoxigenic [ETEC], enteropathogenic [EPEC], enteroinvasive [EIEC], enterohemorrhagic [EHEC] and enteroaggregative [EAEC]) was studied in 537 children < or = 5 years old hospitalised with acute diarrhoea and 113 matched controls from two hospitals during 2005-07 by PCR assays using E. coli colony pools. RESULTS: The prevalence of DEC varied from 0.75% for EHEC to 8.4% for EPEC (mostly atypical variety) in diarrhoeal children with no significant differences compared to that in control children (P values 0.15 to 1.00). Twenty-seven EPEC isolates studied mostly belonged to non-traditional serotypes and possessed beta and theta intimin subtypes. A total of 54 DEC isolates from diarrhoeal children and 4 from controls studied for antimicrobial susceptibility showed resistance for older antimicrobials, ampicillin (0 to 100%), tetracycline (33 to 100%) and trimethoprim (22.2 to 100%); 43.1% of the isolates were multidrug-resistant (resistant to 3 or more agents). Six (10.4%) DEC isolates produced extended spectrum beta-lactamases and possessed genetic elements (blaCTX-M, blaTEM and ISEcp1) associated with them. CONCLUSION: We speculate that the lack of significant association of DEC with diarrhoea in children in Kuwait compared to countries surrounding the Arabian Gulf Region may be attributable to high environmental and food hygiene due to high disposable income in Kuwait.

Risk factors for Nipah virus encephalitis in Bangladesh.

Nipah virus (NiV) is a paramyxovirus that causes severe encephalitis in humans. During January 2004, twelve patients with NiV encephalitis (NiVE) were identified in west-central Bangladesh. A case-control study was conducted to identify factors associated with NiV infection. NiVE patients from the outbreak were enrolled in a matched case-control study. Exact odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by using a matched analysis. Climbing trees (83% of cases vs. 51% of controls, OR 8.2, 95% CI 1.25-infinity) and contact with another NiVE patient (67% of cases vs. 9% of controls, OR 21.4, 95% CI 2.78-966.1) were associated with infection. We did not identify an increased risk for NiV infection among persons who had contact with a potential intermediate host. Although we cannot rule out person-to-person transmission, case-patients were likely infected from contact with fruit bats or their secretions.

Nonbacterial thrombotic endocarditis associated with lung adenocarcinoma.

Nonbacterial thrombotic endocarditis (NBTE) is a rather frequent neoplasic complication, most often occurring in adenocarcinomas of the lung and pancreas. The most frequent clinical manifestation is one of multiple cerebral infarcts, but other ischaemic events can occur. Diagnosis is frequently missed on transthoracic ultrasound, making transoesophagic ultrasound a more reliable diagnostic tool. We present a case of NBTE associated with lung adenocarcinoma.

Nonbacterial thrombotic endocarditis associated with lung adenocarcinoma

Nonbacterial thrombotic endocarditis (NBTE) is a rather frequent neoplasic complication, most often occurring in adenocarcinomas of the lung and pancreas. The most frequent clinical manifestation is one of multiple cerebral infarcts, but other ischaemic events can occur. Diagnosis is frequently missed on transthoracic ultrasound, making transoesophagic ultrasound a more reliable diagnostic tool. We present a case of NBTE associated with lung adenocarcinoma (AU)

Genotypic characterization of rotaviruses and prevalence of serotype-specific serum antibodies in children in Kuwait.

There are no data on the serotypes of rotaviruses prevalent in Kuwait, which has a large expatriate population and hence a focal point for transmission of pathogens. The serotype information will contribute to the fund of knowledge on the world epidemiology of rotavirus serotypes and will predict the outcome of vaccination in Kuwait. Of the 75 rotavirus-positive samples from 172 children (aged <5 years) with severe diarrhoea, 69 were genotyped. The distribution of genotypes was G1 (63.8%) followed by G9 (10.2%), G2 (7.3%), G4 (7.3%) and G3 (4.4%). Among the P types, P[8] was the most common type found across all G types. By fluorescent focus neutralization test, serum antibodies to genotypes G1 (94%), G4 (68%) and G9 (46%) were found in 120 other children. These results show that G1 is the predominant serotype in Kuwait and that a vaccine that contains G1 will be most effective.

Iodine status among pregnant women in Kuwait.

UNLABELLED: Up to now, little has been known about iodine intake and the prevalence of iodine deficiency (ID), if any, in Kuwait. Urinary iodine excretion (UIE) and changes in thyroid function during pregnancy were thus evaluated. METHODS: Urinary iodide level was measured in random urine samples collected from 326 pregnant women at different gestational trimesters. Blood samples were drawn for free T4 (FT4) and TSH level determination. RESULTS: Median UIE levels fall within the normal range during all gestational trimesters i.e. >100 microg/l. However, if the new suggested recommendation for pregnant women <140 microg/l, is applied, median UIE values during trimesters 2 and 3 indicate ID. Mean serum TSH levels increased between trimesters 1 and 3 (p<0.05), whereas serum FT4 decreased between first and second trimesters (p<0.05), and this reduction continued at the third trimester. Furthermore, an increase in TSH levels for subjects with mild and moderate ID (Mi and Mo, respectively) were noticed (p<0.05) during the second trimester. However, FT4 levels dropped in subjects with Mi and Mo ID during the first trimester (p<0.05). In conclusion, these results suggest that 56.8% of pregnant women had median UIE level <145 microg/l, associated with high TSH and low FT4 levels. CONCLUSION: Data obtained may indicate insufficient iodine intake among pregnant women in Kuwait.

Flegmasia cerulea dolens en paciente con carcinoma testicular / Phlegmasia cerulea dolens in patients with testicular carcinoma

Describimos un caso de flegmasia cerulea dolens secundaria a una trombosis venosa profunda por compresión de la vena cava inferior, en un varón de 31 años con un tumor germinal. Necesitó un tratamiento urgente con agentes fibrinolíticos, heparina intravenosa y quimioterapia. Con el tratamiento obtuvo una respuesta completa tumoral y una completa revascularización de la vena cava y vena femoral derecha

We describe a case of phlegmasia cerulea dolens secondary to venous thrombosis due to compression of inferior vena cava, in a 31-year-old man with a germ cell tumour. He was treated with systemic thrombolytic agents, intravenous heparin and urgent chemotherapy He presented a complete tumoral response and complete revascularization of the vena cava and right femoral vein