Prognostic significance of absolute lymphocyte count in patients with metastatic renal cell carcinoma receiving first-line combination immunotherapies: results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Lymphocytes are closely linked to mechanisms of action of immuno-oncology (IO) agents. We aimed to assess the prognostic significance of absolute lymphocyte count (ALC) in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Using the International mRCC Database Consortium (IMDC), patients receiving first-line IO-based combination therapy were analysed. Baseline patient characteristics, objective response rates (ORRs), time to next treatment (TTNT), and overall survival (OS) were compared. RESULTS: Of 966 patients included, 195 (20%) had lymphopenia at baseline, and they had a lower ORR (37% versus 45%; P < 0.001), shorter TTNT (10.1 months versus 24.3 months; P < 0.001), and shorter OS (30.4 months versus 48.2 months; P < 0.001). Among 125 patients with lymphopenia at baseline, 52 (42%) experienced ALC recovery at 3 months, and they had longer OS (not reached versus 30.4 months; P = 0.012). On multivariable analysis for OS, lymphopenia was an independent adverse prognostic factor (hazard ratio 1.68; P < 0.001). Incorporation of lymphopenia into the IMDC criteria improved OS prediction accuracy (C-index from 0.688 to 0.707). CONCLUSIONS: Lymphopenia was observed in one-fifth of treatment-naive patients with mRCC and may serve as an indicator of unfavourable oncologic outcomes in the contemporary IO era.

Electrohydrodynamics of diffuse porous colloids.

The present article deals with the electrohydrodynamic motion of diffuse porous particles governed by an applied DC electric field. The spatial distribution of monomers as well as the charge distribution across the particle are considered to follow sigmoidal distribution involving decay length. Such a parameter measures the degree of inhomogeneity of the monomer distribution across the particle. The diffuse porous particles resemble several colloidal entities which are often seen in the environment as well as in biological and pharmaceutical industries. Considering the impact of bulk pH and ion steric effects, we modelled the electrohydrodynamics of such porous particulates based on the modified Boltzmann distribution for the spatial distribution of electrolyte ions and the Poisson equation for electric potential as well as the conservation of mass and momentum principles. We adopt regular perturbation analysis with weak field assumption and the perturbed equations are solved numerically to calculate the electrophoretic mobility and neutralization fraction of the particle charge during its motion as well as fluid collection efficiency. We further deduced the closed form relation between the drag force experienced by the charged porous particle and the fluid collection efficiency. In addition to the numerical results, we further derived the closed form analytical results for all the intrinsic parameters indicated above derived within the Debye-Hückel electrostatic framework and homogeneous distribution of monomers within the particle for which the decay length vanishes. The deduced mathematical results as indicated above will be useful to analyze several electrostatic and hydrodynamic features of a wide class of porous particulate and environmental entities.

Potential of photoautotrophic microbial organisms in deciphering forensic issues.

In forensic pathology, solving the crime mystery of death due to drowning still remains a challenging issue. The amalgamation of autopsy findings and comparative study of diatoms recovered from the victim's body organs and suspected drowning site help to decipher the cause of death due to drowning or post-mortem immersion. Since the correct interpretation of the cause of death is an important criterion to provide justice to the victim, therefore, the main objective of our study is to throw light on the application of photoautotrophic micro-algal organisms, known as Diatoms, in solving seven cases of victims whose bodies were recovered from various water bodies of Himachal Pradesh, India. The diatom test was conducted by using reverse aqua regia solution (15 ml HNO3: 5 ml HCl) on the bone marrow extracted from the organs and water samples respectively. The informative outcomes of the experimental analysis demonstrated that the diatom test acts as a beneficial adjunct to solve drowning-related crimes where the exact cause of death remains hidden even after performing an autopsy of the victims. The protocol followed by the authors can be used conveniently to recover diatoms from bone marrow as well as from water samples. Our results showed that the maximum cases were of death due to accidental drowning but for one case of suicidal drowning in extremely cold water.

Photoplethysmography in postoperative monitoring of deep inferior epigastric perforator (DIEP) free flaps.

OBJECTIVE: Deep inferior epigastric perforator (DIEP) free flaps are widely used as a reconstruction option following mastectomy in breast cancer. During such cases partial tissue necrosis can occur due to the insufficient blood supply to the transplanted tissue site. Therefore, monitoring of flap perfusion and early detection of flap failure is a prerequisite to flap survival. There is a need to develop a non-invasive, easy to use, reproducible and inexpensive monitoring device to assess flap perfusion postoperatively. APPROACH: A three-wavelength reflective optical sensor and processing system based on the principle of photoplethysmography (PPG) has been developed to investigate blood volumetric changes and estimate free flap blood oxygen saturation continuously and non-invasively in DIEP free flaps in the postoperative period. The system was evaluated in 15 patients undergoing breast reconstructive surgery using DIEP free flap. Main results and Significance: Good quality red, infrared and green PPG signals were obtained in the postoperative period. Initial estimation of blood oxygen saturation values estimated from the free flap PPGs seem to be in broad agreement with the commercial finger pulse oximeter used in this study. This pilot study has demonstrated that PPG has the potential to be used as a monitoring technique in assessing free flap viability.

Effects of meteorological parameters on COVID-19 transmission trends in Bangladesh.

Abstract: Understanding the influence of meteorological parameters in relation to COVID-19 transmission may be a convenient way to predict the ongoing pandemic towards its adaptive control measures. This study aims to explore the association between COVID-19 cases and meteorological parameters and to predict COVID-19 transmission for an extended period covering different climatic patterns. The number of COVID-19 cases, daily records of rainfall, temperature, relative humidity and wind speed data were collected for April and May 2020 from the eight major divisions in Bangladesh. The basic statistical analyses and auto regressive integrated moving average (ARIMA) using SPSS tool were applied to evaluate and explore association between meteorological parameters and COVID-19 cases and its transmission trend. A greater number of significant positive associations (r = 0.24-0.58) is found to exist between the relative humidity and COVID-19 cases across the cities, while with temperature both positive and negative associations (r = - 0.23 to 0.72) were revealed. Furthermore, both the rainfall and wind speed exhibit positive correlations. ARIMA model portrayed predictive trend of COVID-19 transmission, from its inception on 8 March 2020 to September 2020, in Bangladesh. The month of July showed the highest daily COVID-19 cases prior to lowering at steady rate till September illustrating the influnce of meteorological parameters. Supplementary Information: The online version contains supplementary material available at 10.1007/s42398-021-00195-5.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.

BACKGROUND: Enzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel. METHODS: We conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel. RESULTS: Of 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide. CONCLUSIONS: The activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.

Potentially toxic elements in lignite and its combustion residues from a power plant.

The presence of potentially toxic elements in lignite and coal is a matter of global concern during energy extraction from them. Accordingly, Barsingsar lignite from Rajasthan (India), a newly identified and currently exploited commercial source of energy, was evaluated for the presence of these elements and their fate during its combustion. Mobility of these elements in Barsingsar lignite and its ashes from a power plant (Bikaner-Nagaur region of Thar Desert, India) is presented in this paper. Kaolinite, quartz, and gypsum are the main minerals in lignite. Both the fly ash and bottom ash of lignite belong to class-F with SiO2 > Al2O3 > CaO > MgO. Both the ashes contain quartz, mullite, anhydrite, and albite. As, In, and Sr have higher concentration in the feed than the ashes. Compared to the feed lignite, Ba, Co, U, Cu, Cd, and Ni are enriched (10-5 times) in fly ash and Co, Pb, Li, Ga, Cd, and U in bottom ash (9-5 times). Earth crust-normalization pattern showed enrichment of Ga, U, B, Ag, Cd, and Se in the lignite; Li, Ba, Ga, B, Cu, Ag, Cd, Hg, Pb, and Se, in fly ash; and Li, Sr, Ga, U, B, Cu, Ag, Cd, Pb, and Se in bottom ash. Hg, Ag, Zn, Ni, Ba, and Se are possibly associated with pyrite. Leaching test by toxicity characteristic leaching procedure (TCLP) showed that except B all the elements are within the safe limits prescribed by Indian Standards.

The clinical research office of the endourological society percutaneous nephrolithotomy global study: Outcomes in the morbidly obese patient - a case control analysis.

BACKGROUND: Efficacy and safety of percutaneous nephrolithotomy (PCNL) have been demonstrated in obese individuals. Yet, there is a paucity of data on the outcomes of PCNL in morbidly obese patients (body mass index [BMI] >40). METHODS: Perioperative and stone-related outcomes following PCNL in morbidly obese patients was assessed using a prospective database administered by the Clinical Research Office of the Endourological Society (CROES). A multidimensional match of 97 morbidly obese patients with those of normal weight was created using propensity score matching. Student's t-test and Chi-square tests were used to assess for differences between the groups. RESULTS: In total, 97 patients with a BMI >40 kg/m(2) were matched by stone characteristics with 97 patients of normal weight. The morbidly obese population demonstrated higher rates of diabetes mellitus (43% vs. 6%, p < 0.001) and cardiovascular disease (56% vs. 18%, (p < 0.001). Access was achieved more frequently by radiologists in the morbidly obese group (19% vs. 6%, p = 0.016). Mean operative duration was longer in the morbidly obese group (112 ± 56 min vs. 86 ± 43.5 min, p < 0.001). Stone-free rates were lower in the morbidly obese group (66% vs. 77%, p = 0.071). There was no significant difference in length of hospital stay or transfusion rate. Morbidly obese patients were significantly more likely to experience a postoperative complication (22% vs. 6%, p = 0.004). INTERPRETATION: PCNL in morbidly obese patients is associated with longer operative duration, higher rates of re-intervention and an increased risk of perioperative complications. With this knowledge, urologists should seek to develop strategies to optimize the perioperative management of such patients.

A phase I study of cabozantinib (XL184) in patients with renal cell cancer.

BACKGROUND: Cabozantinib targets tyrosine kinases including the hepatocyte growth factor receptor (MET) and vascular endothelial growth factor (VEGF) receptor 2, which are important drug targets in renal cell carcinoma (RCC). PATIENTS AND METHODS: This single-arm open-label phase I trial evaluated the safety and tolerability of cabozantinib in heavily pretreated patients with metastatic clear cell RCC. RESULTS: The study enrolled 25 RCC patients for whom standard therapy had failed. Patients received a median of two prior systemic agents, and most patients had previously received at least one VEGF pathway inhibiting therapy (22 patients [88%]). Common adverse events included fatigue, diarrhea, nausea, proteinuria, appetite decreased, palmar-plantar erythrodysesthesia, and vomiting. Partial response was reported in seven patients (28%). Median progression-free survival was 12.9 months, and median overall survival was 15.0 months. CONCLUSION: Cabozantinib demonstrates preliminary anti-tumor activity and a safety profile similar to that seen with other multitargeted VEGFR tyrosine kinase inhibitors in advanced RCC patients. Further evaluation of cabozantinib in RCC is warranted. ClinicalTrials.gov identifier: NCT01100619.

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Free flap pulse oximetry utilizing reflectance photoplethysmography.

The successful salvage of a free flap is dependent on the continuous monitoring of perfusion. To date there is no widely accepted and readily available post-operative monitoring technique to reliably assess the viability of free flaps by continuously monitoring free flap blood oxygen saturation. In an attempt to overcome the limitations of the current techniques a reflectance photoplethysmographic (PPG) processing system has been developed with the capability of real-time estimation of arterial oxygen saturation (SpO2) levels implemented in LabVIEW. This system was evaluated in clinical measurements on five patients undergoing breast reconstruction using Deep Inferior Epigastric Perforator (DIEP) flap. Good quality PPG signals were obtained from the flaps and fingers simultaneously. The estimated free flap SpO2 values were in broad agreement with the oxygen saturation readings from the commercial pulse oximeter. The results suggest that reflectance free flap photoplethysmography can be used as a continuous monitoring technique to non-invasively monitor the perfusion of free flaps.

Global sampling of the photochemical reaction paths of bromoform by ultrafast deep-UV through near-IR transient absorption and ab initio multiconfigurational calculations.

Ultrafast deep-ultraviolet through near infrared (210-950 nm) transient absorption spectroscopy complemented by ab initio multiconfigurational calculations offers a global description of the photochemical reaction pathways of bromoform following 255-nm excitation in methylcyclohexane and acetonitrile solutions. Photoexcitation of CHBr3 leads to the ground-state iso-CHBr3 product in a large quantum yield (∼35%), formed through two different mechanisms: concerted excited-state isomerization and cage-induced isomerization through the recombination of the nascent radical pair. These two processes take place on different time scales of tens of femtoseconds and several picoseconds, respectively. The novel ultrafast direct isomerization pathway proposed herein is consistent with the occurrence of a conical intersection between the first excited singlet state of CHBr3 and the ground electronic state of iso-CHBr3. Complete active space self-consistent field calculations characterize this singularity in the vicinity of a second order saddle point on the ground state which connects the two isomer forms. For cage-induced isomerization, both the formation of the nascent radical pair and its subsequent collapse into ground-state iso-CHBr3 are directly monitored through the deep-ultraviolet absorption signatures of the radical species. In both mechanisms, the optically active (i.e., those with largest Franck-Condon factors) C-Br-Br bending and Br-Br stretching modes of ground-state iso-CHBr3 have the largest projection on the reaction coordinate, enabling us to trace the structural changes accompanying vibrational relaxation of the non-equilibrated isomers through transient absorption dynamics. The iso-CHBr3 photoproduct is stable in methylcyclohexane, but undergoes either facile thermal isomerization to the parent CHBr3 structure through a cyclic transition state stabilized by the polar acetonitrile medium (∼300-ps lifetime), and hydrolysis in the presence of water.

Protein-encapsulated gold cluster aggregates: the case of lysozyme.

We report the evolution and confinement of atomically precise and luminescent gold clusters in a small protein, lysozyme (Lyz) using detailed mass spectrometric (MS) and other spectroscopic investigations. A maximum of 12 Au(0) species could be bound to a single Lyz molecule irrespective of the molar ratio of Lyz : Au(3+) used for cluster growth. The cluster-encapsulated protein also forms aggregates similar to the parent protein. Time dependent studies reveal the emergence of free protein and the redistribution of detached Au atoms, at specific Lyz to Au(3+) molar ratios, as a function of incubation time, proposing inter-protein metal ion transfer. The results are in agreement with the studies of inter-protein metal transfer during cluster growth in similar systems. We believe that this study provides new insights into the growth of clusters in smaller proteins.

Luminescent, bimetallic AuAg alloy quantum clusters in protein templates.

We report the synthesis of luminescent AuAg alloy quantum clusters (QCs) in bovine serum albumin (BSA), for the first time, with experimentally determined atomic composition. Mixing of the as-synthesized protein-protected Au and Ag clusters resulted in the formation of alloy AuAg clusters within the BSA. Mass spectrometric analysis of the product of a 1 : 1 molar ratio reaction mixture of Au(QC)@BSA and Ag(QC)@BSA suggested that the alloy clusters could be Au(38-x)Ag(x)@BSA. Further analyses by standard techniques revealed that the alloy cluster core of ∼1.2 nm diameter is composed of nearly zero valent Au and Ag atoms that exhibit distinctly different steady state and time resolved excited state luminescence profiles compared to the parent clusters. Tuning of the alloy composition was achieved by varying the molar ratio of the parent species in the reaction mixture and compositional changes were observed by mass spectrometry. In another approach, mixing of Au(3+) ions with the as-synthesized Ag(QC)@BSA also resulted in the formation of alloy clusters through galvanic exchange reactions. We believe that alloy clusters with the combined properties of the constituents in versatile protein templates would have potential applications in the future. The work presents interesting aspects of the reactivity of the protein-protected clusters.