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There is a paucity of data on the safety of cabozantinib use in combination with radiotherapy.To report the practice patterns, safety, and efficacy of cabozantinib with radiotherapy in metastatic renal cell carcinoma (mRCC).An international multicenter retrospective study was conducted. Patients with mRCC treated with cabozantinib at any line of therapy and who received radiotherapy between 30 d prior to the start date of cabozantinib and 30 d following discontinuation of cabozantinib, from 2014 to 2020, were included. Concurrent use was defined as the use of cabozantinib on radiotherapy treatment days during any course of radiotherapy.The primary outcomes of interest were the rate of grade ≥3 adverse events (AEs) occurring within 90 d of receipt of radiotherapy. Secondary outcomes included hospitalization rate and patterns of cabozantinib and radiotherapy use. Baseline characteristics and AEs were presented descriptively.A total of 127 consecutive patients were included. Most patients had clear cell histology (88%), had International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk disease (57%), and had received at least one prior line of therapy (93%). Of 127 patients, 67 (53%) received concurrent cabozantinib with radiotherapy, while the remaining held cabozantinib on radiotherapy days. Overall, grade 3-4 AEs occurred in 6.3% (n = 8/127) of patients. No grade 5 events were observed. In patients treated with conventional palliative radiotherapy (n = 88), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 6.3% (n = 3/48) versus 5.0% (n = 2/40). No patient was hospitalized due to radiotherapy-related toxicity. In patients treated with stereotactic ablative body radiotherapy (SABR; n = 50), the rate of grade 3-4 AEs in those who had concurrent versus those who had nonconcurrent cabozantinib was 3.6% (n = 1/28) versus 9.1% (n = 2/22). One patient in the nonconcurrent group was hospitalized due to muscle weakness suspected to be related to associated vasogenic edema 19 d after SABR for multiple brain metastases.In this real-world study of patients with mRCC treated with cabozantinib, 53% of patients received radiotherapy concurrently, with few grade 3-4 AEs reported within 90 d of receiving radiotherapy. The use of radiotherapy and cabozantinib requires a risk-benefit assessment of patient and disease characteristics to optimize therapy regimens.Our study reports the real-world experience of using radiotherapy in patients receiving cabozantinib for metastatic kidney cancer. Over half of the patients continued taking cabozantinib while receiving radiotherapy, and few patients developed serious side effects. The combined use of radiotherapy and cabozantinib requires a careful risk-benefit assessment to achieve optimal treatment outcomes.

Recent studies have shown various neurological adverse events associated with COVID-19 vaccine.We aimed to retrospectively review and report the neurological diseases temporally associated with COVID-19 vaccine.We performed a retrospective chart review of admitted patients from 1st February 2021 to 30th June 2022. A total of 4672 medical records were reviewed of which 51 cases were identified to have neurological illness temporally associated with COVID-19 vaccination.Out of 51 cases, 48 had probable association with COVID-19 vaccination while three had possible association. Neurological spectrum included CNS demyelination (n = 39, 76.5 %), Guillain-Barré-syndrome (n = 3, 5.9 %), stroke (n = 6, 11.8 %), encephalitis (n = 2, 3.9 %) and myositis (n = 1, 2.0 %). Female gender had a greater predisposition (F:M, 1.13:1). Neurological events were more commonly encountered after the first-dose (n = 37, 72.5%). The mean latency to onset of symptoms was 13.2 ± 10.7 days after the last dose of vaccination. COVIShield (ChAdOx1) was the most commonly administered vaccine (n = 43, 84.3 %). Majority of the cases with demyelination were seronegative (n = 23, 59.0 %) which was followed by anti-Myelin oligodendrocyte-glycoprotein associated demyelination (MOGAD) (n = 11, 28.2 %) and Neuromyelitis optica (NMOSD) (n = 5, 12.8 %). Out of 6 Stroke cases, 2 cases (33.3 %) had thrombocytopenia and coagulopathy. At discharge, 25/51 (49.0 %) of the cases had favourable outcome (mRS 0 to 1). Among six patients of stroke, only one of them had favourable outcome.In this series, we describe the wide variety of neurological syndromes temporally associated with COVID-19 vaccination. Further studies with larger sample size and longer duration of follow-up are needed to prove or disprove causality association of these syndromes with COVID-19 vaccination.

PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

Collecting duct carcinoma of the kidney is a rare and aggressive subtype of renal cell carcinoma (RCC) arising from the distal convoluted tubules. At the time of diagnosis, patients are more frequently symptomatic, with advanced locoregional stage, and have metastatic disease. The 2016 WHO Classification of Tumours of the Urinary System defined diagnostic criteria for this entity. However, the diagnostic features continue to evolve, with typical, but not entirely specific, histologic and immunophenotypic characteristics. In addition, the lack of consistent molecular alterations makes collecting duct carcinoma a diagnosis of exclusion, with historical cases being re-classified as fumarate hydratase deficient RCC, ALK rearranged RCC, renal medullary carcinoma or high-grade urothelial carcinoma. The rarity and poor prognosis of the tumor makes it difficult to reach consensus guidelines to guide therapy. In this manuscript we review the clinicopathologic features of collecting duct carcinoma including pathologic diagnostic criteria, molecular characteristics and differential diagnosis, and their possible implications for management.

Quinidine has been proposed as a repurposed licensed drug for the treatment of seizures in KCNT1 gain-of-function associated Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). Sparse evidence from case reports suggests limited effectiveness and tolerability. Here we report the adaptation of a n-of-1 trial protocol and results of adjunctive quinidine intervention. We adapted a n-of-1 trial protocol from two unpublished protocols and with expert advice including input from pediatric neurology, cardiology and pharmacy colleagues. We tailored this protocol to a severely disabled patient with EIMFS and a de novo c.1420CT p.Arg474Lys missense variant. We discussed outcome measures with the family of the patient and initiated adjunctive inpatient quinidine treatment with appropriate safety measures. The trial was terminated as a result of intolerable gastrointestinal adverse effects following the initiation dose. Subsequent reports suggest that quinidine may not be effective for this genotype. Quinidine is poorly tolerated across cardiological and neurological indications. Current pooled evidence suggests limited effectiveness for KCNT1 associated epilepsies at doses ≤40mg/kg/d. It is important to report all clinical evidence in precision medicine trials, whether positive or negative, to counter publication bias. This study highlights universal issues around outcome measurement and the evaluation of evidence in rare disease interventions.

Tivozanib, vascular endothelial growth factor receptor inhibitor, met the primary endpoint of improved progression free survival compared to sorafenib in the phase 3 TIVO-3 study in patients with previously treated metastatic renal cell carcinoma. In this study we sought to understand the temporal characteristics of treatment related adverse events (TRAEs) and frequency and timing of the dose modifications.In this open label, randomized, phase 3 TIVO-3 study, previously treated patients with a diagnosis of metastatic renal cell carcinoma and with measurable disease were included. Patients were randomized to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Based on updated safety analysis data (cutoff date of August 15, 2019), time to onset of the most commonly reported TRAEs, duration of toxicity, rate of dose modifications was calculated for each treatment arm.Overall, 350 patients were randomly assigned to receive tivozanib or sorafenib;173 patients from the tivozanib arm and 170 patients from the sorafenib arm were included in this analysis. Patients received a median of 11.9 cycles (336 days) and 6.7 cycles (192 days) of tivozanib and sorafenib, respectively. Dose reductions, interruptions and treatment discontinuations were 25%, 50%, and 21%, and 39%, 50%, and 30% in the tivozanib and sorafenib arms, respectively, with a longer time to onset of TRAEs in the tivozanib arm.Tivozanib was associated with less TRAEs, fewer dose modifications, a longer time to onset and a shorter duration of TRAEs compared to sorafenib.

Relative humidity (RH), an important climatic element influencing tree growth, is also crucial in assessing the General Circulation Models (GCMs) on global warming. However, in the absence of a relatively long record of RH in the Himalayan region, precise modelling of the climate change related processes and their impacts on this region are not well established. Here we present a new RH reconstruction for the pre-monsoon months (February–May) starting from 1800 C.E. using the tree-ring width data of subtropical Pinus roxburghii (chir-pine) from Pithoragarh, Western Himalaya, India. We found significant positive correlation between tree growth and pre-monsoon RH (n = 67, r = +0.569, p

Plant lectins, a natural source of glycans with a therapeutic potential may lead to the discovery of new targeted therapies. Glycans extracted from plant lectins are known to act as ligands for C-type lectin receptors (CLRs) that are primarily present on immune cells. Plant-derived glycosylated lectins offer diversity in their N-linked oligosaccharide structures that can serve as a unique source of homogenous and heterogenous glycans. Among the plant lectins-derived glycan motifs, Man9GlcNAc2Asn exhibits high-affinity interactions with CLRs that may resemble glycan motifs of pathogens. Thus, such glycan domains when presented along with antigens complexed with a nanocarrier of choice may bewilder the immune cells and direct antigen cross-presentation - a cytotoxic T lymphocyte immune response mediated by CD8+ T cells. Glycan structure analysis has attracted considerable interest as glycans are looked upon as better therapeutic alternatives than monoclonal antibodies due to their cost-effectiveness, reduced toxicity and side effects, and high specificity. Furthermore, this approach will be useful to understand whether the multivalent glycan presentation on the surface of nanocarriers can overcome the low-affinity lectin-ligand interaction and thereby modulation of CLR-dependent immune response. Besides this, understanding how the heterogeneity of glycan structure impacts the antigen cross-presentation is pivotal to develop alternative targeted therapies. In the present review, we discuss the findings on structural analysis of glycans from natural lectins performed using GlycanBuilder2 - a software tool based on a thorough literature review of natural lectins. Additionally, we discuss how multiple parameters like the orientation of glycan ligands, ligand density, simultaneous targeting of multiple CLRs and design of antigen delivery nanocarriers may influence the CLR targeting efficacy. Integrating this information will eventually set the ground for new generation immunotherapeutic vaccine design for the treatment of various human malignancies.

Introduction To describe the efficacy of infigratinib, a potent, selective fibroblast growth factor receptor (FGFR) 1-3 tyrosine kinase inhibitor, across lines of therapy (LOT) in patients with metastatic urothelial cancer (mUC). Patients and Methods Eligible patients had mUC and prior platinum-based chemotherapy, unless contraindicated, and activating FGFR3 mutation/fusion. Patients received infigratinib 125 mg orally daily (3 weeks on/1 week off) in a single-arm, open-label study. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), best overall response (BOR) that included unconfirmed responses, and overall survival (OS) were also assessed. Subgroup analysis of efficacy and safety outcomes by LOT was performed. Results Sixty-seven patients were enrolled; 13 (19.4%) received infigratinib as early-line therapy for mUC due to ineligibility to receive platinum-based chemotherapy. Overall, ORR was 25.4% (95% CI 15.5-37.5) and DCR was 64.2% (95% CI 51.5-75.5). ORR was 30.8% (95% CI 9.1-61.4) with early-line infigratinib and 24.1% (95% CI 13.5-37.6) for ≥2 LOT. DCR was 46.2% (95% CI 19.2-74.9) for early-line and 68.5% (95% CI 54.4-80.5) for ≥2 LOT. PFS and OS appeared similar in both groups. Thirteen of 59 patients with a bladder primary tumor received early-line treatment with an ORR of 30.5% (95% CI 9.1-61.4), and 46 received ≥2 LOT with an ORR of 20.3% (95% CI 9.4-33.9); BOR was 38.5% (95% CI: 13.9-68.4%) and 42.6% (95% CI: 29.2-56.8%) in the early-line and salvage settings, respectively. Eight patients with upper tract urothelial carcinoma received salvage therapy (ORR, 50.0%; DCR, 100.0%). No significant differences in toxicities between LOT were observed. Conclusion Infigratinib has notable activity in patients with mUC regardless of LOT. The findings support the evaluation of infigratinib across different settings in mUC.

Traditional encryption is based on secrecy provided by secret-key. But this leads to generation of same cipher text when the encryption scheme is applied to same plaintext with same key. Thus, replay of messages can be effortlessly identified by an adversary which can be a weak link in any communication. Probabilistic encryption is an approach to overcome this weakness where different cipher texts are generated each time same plaintext is encrypted using the same key. Extending the probabilistic approach, which is generally employed in asymmetric encryption, this paper proposes a new chaos-based probabilistic symmetric encryption scheme with customizable block-size suitable for image encryption. It employs a Random Bits Insertion phase followed by four rounds of two-staged diffusion involving simple XOR (exclusive-OR) operation making it computationally efficient. Random Bits Insertion makes the scheme probabilistic. This phase also helps in increasing entropy and making intensity distribution more uniform in cipher. The generated cipher text is twice the size of plain text. An increase in cipher text space is inevitable for probabilistic encryption and it provides an advantage as the apparent message space for the attacker is increased. The observations show that the scheme offers high strength to resist statistical and cryptanalytic attacks.

Stereotactic body radiation therapy (SBRT) has been shown to be safe and effective for delaying systemic treatment change among patients with metastatic renal cell carcinoma (mRCC). In this study, we sought to assess the genomic signatures of patients with mRCC who underwent SBRT for oligoprogression. A total of 30 patients with oligoprogressive disease were identified, the majority of whom had clear cell renal cell carcinoma (83.3%) and were receiving first-line treatment (53.3%). Genomic and transcriptomic sequencing were available in 20 and 16 patients, respectively. Duration of systemic treatment (DOT) was categorized as that prior (DOT[P]) and subsequent (DOT[S]) to radiation treatment. The median DOT(P) and DOT(S) were 15.1 and 18.3 mo, respectively, with a median DOT(S)/DOT(P) ratio of 1.4. Patients who had a DOT(S)/DOT(P) ratio of ≥1 had increased expression in pathways related to cell proliferation and development. In contrast, among patients with a ratio of ≤1, the reactive oxygen species pathway was enriched. This study highlights the potential role of genomics and transcriptomics to refine radiation treatment selection in patients with mRCC. PATIENT SUMMARY: In this study, we looked at mutations and genomic expressions among kidney cancer patients who responded better to stereotactic body radiotherapy. We found that enriched expression of certain pathways might play a role in response to radiotherapy.

The association between tobacco use and urothelial cancer of the bladder is well known. Given the worsening tobacco epidemic, here we make the case for systematic targeted points of intervention for urologists and other professionals to intervene against bladder cancer. Awareness of contemporary checkpoints where we can intervene for counseling patients may help medical education in a tobacco-pandemic difficult setting.

Context Bladder and kidney cancers require invasive procedures for definitive diagnosis, and bladder cancer requires repeated procedures to monitor for disease recurrence. Given the recent work to identify molecular alterations in liquid biopsies to diagnose and monitor these diseases, a synthesis of the growing body of evidence is merited. Objective To review current data on cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) and to synthesize their roles in the diagnosis, monitoring, and prognostication of bladder and kidney cancer. Evidence acquisition A literature review was conducted through August 15, 2020 including prospective and retrospective studies. Keywords included “cell-free DNA”, “circulating tumor DNA”, “kidney cancer”, “renal cell carcinoma”, “bladder cancer”, “upper tract urothelial carcinoma”, and “urothelial carcinoma”. Evidence synthesis Urine tumor DNA (utDNA) has sensitivity of 91% and specificity of 96% for detecting bladder cancer, outperforming cystoscopy and cytology. Increased utDNA and ctDNA are associated with progression from non–muscle-invasive to muscle-invasive disease. In patients undergoing cystectomy, ctDNA detection is associated with worse overall survival and disease recurrence, and with persistent tumor on surgical pathology in those who received neoadjuvant chemotherapy. cfDNA is significantly higher in patients with kidney cancer than in healthy controls or in those with benign lesions, and detectable ctDNA and increased cfDNA are associated with decreased survival. Conclusions Combined data from small studies provide evidence that cfDNA and ctDNA may have the ability to detect, monitor, and prognosticate in patients with bladder, upper tract urothelial, and kidney cancers. Patient summary In this review, we looked at the work that has been published so far on cell-free and circulating tumor DNA in bladder and kidney cancers. We found that while many of the studies were small, there is evidence that cell-free tumor DNA can emerge as a tool for the diagnosis and monitoring of treatment response for patients with these cancers.

Dissimilar material joining between magnesium (AZ31B) alloy and dual-phase steel (DP600) was achieved using the friction stir welding (FSW) process. The present work aimed at studying the effect of tool rotational speed and welding speed on the microstructure and mechanical properties of the dissimilar joints. The joints were fabricated at tool rotational speeds of 800 and 1600 rpm with weld speeds of 50, 100, and 150 mm/min, respectively. The plunge depth of 0.2 mm and tool tilt angle of 2° was kept constant during the welding. Temperature rise and variation of torque during the welding process were recorded. Optical microscopy, scanning electron microscopy equipped with energy dispersive spectroscopy (EDS), and X-ray diffraction studies were carried out to understand the microstructural changes, the interface of the weld joints, fracture morphology, and formation of intermetallic compounds during FSW. Maximum joint efficiency of 76.4% was achieved with respect to AZ31B. The microstructural observation revealed the formation of finer grains at the stir zone for all weld parameters because of the dynamic recrystallization. The metallurgical bonding between the dissimilar materials was observed due to the formation of intermetallic compounds. The formation of the sawtooth profile at the joint interface indicated mechanical interlocking between AZ31B Mg alloy and DP600 steel. Though the AZ31B Mg–DP600 steel combination is highly immiscible, the present attempts have successfully created the joining, where one of the substrates provides lightweight while the other provides strength.

Friction processing was used to fabricate solid sintered, open-cell, copper foam parts of different shapes and sizes. Sintering and dissolution with NaCl spacers were used to obtain the foam parts. Pressure and temperature needed for sintering were obtained by plunging a rotating tool into a top sheet in the setup. Setups and tool paths were chosen to get the desired shape and size of sintered parts. The presented method is an attractive alternative to conventional sintering methods, particularly for fabricating solid sintered metal parts with a large specific surface area and high strength to weight ratio.

In less than 5years immune checkpoint inhibitors (ICI) went from first FDA approval to become first-line options in advanced renal cell carcinoma. Despite that many patients have benefited from ICI, a significant fraction of individuals are refractory to these new immunological treatments. In this review, we discussed using intratumoral (i.t.) route of drug administration as an alternative to systemic therapy to increase the response rates and to circumvent potential drug-induced systemic adverse events. We provided a historic account of i.t. drug treatments in cancer and reviewed the contemporary experience in local drug delivery. We discussed the potential for enhancing the therapeutic impact of ICI by leveraging hydrogels as drug delivery vehicles and presented an outlook for implementing i.t. in renal cell carcinoma.

5068 Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P < 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p < 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p < 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.

Background The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. Objective To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participants IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. Intervention Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysis The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitations Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. Conclusions The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summary Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

Context Bladder urothelial carcinoma (BUC) and upper tract urothelial carcinoma (UTUC) have genetic differences, which may influence therapy. Objective The aim of the current review was to summarize the current genetic understanding of upper tract and BUC. Evidence acquisition PubMed, Cochrane, and Web of Science online databases were searched systematically up to February 2020, using the following keywords: urothelial carcinomas, upper urinary tract, renal pelvis, ureter, bladder cancer, and genetics. Evidence synthesis UTUC and BUC share mutations in similar genes, such as FGFR3, TP53, and HRAS, and epigenetic genes, such as KDM6A and KMT2A-C, but at varying frequencies. Furthermore, subtyping of UTUC and BUC has identified similar expression subtypes, but UTUC is more often luminal with more T-cell depletion. Clonal studies indicate that BUC after UTUC is also likely luminal, while UTUC after BUC is often basal. Conclusions UTUC and BUC share many genomic alterations, but at different frequencies, which recapitulate with their metachronous recurrences. These differences likely contribute to the behavior of these two cancers and imply that they and their metachronous recurrences should be treated as two related yet distinct entities. Patient summary Urothelial carcinoma of the bladder has distinct genomic features, which are different from distinct genomic features of urothelial carcinoma of the renal pelvis and/or ureter. These features can be used for tailored treatment options specific to tumors of different locations.

Although predominantly urothelial, some bladder cancer and upper tract urothelial cancer (BC/UTUC) harbor histologic variants. Small cell BC (SCBC) variants comprised ˜5% of The Cancer Genome Atlas BC cohort, with a poor prognosis. We describe genomic profiles of BC/UTUC with small cell/neuroendocrine features identified in the Foundation Medicine database from June 2012 to September 2018. Of 3368 BC/UTUC samples, 3.92% (132) harbored small cell/neuroendocrine features by immunohistochemistry. Mutations were noted in: TP53 (92%), RB1 (75%), combined TP53/RB1 (72%), and TERT promoter (68%). Of the samples, 6.5% had TMB ≥ 10 mutations/Mb. RNA expression profiling of 24 pure SCBC and 51 urothelial BC (UBC) muscle-invasive samples evaluated from a separate cohort revealed a large number of differentially expressed genes with suppression of several inflammatory pathways in SCBC compared with UBC. This largest reported SCBC dataset to date confirms enrichment of signatures in SCBC similar to small cell lung cancer and describes unique gene expression compared with UBC. These findings may explain aggressive SCBC phenotype. Patient summary Small cell bladder cancer (SCBC) is an aggressive subtype that microscopically resembles aggressive small cell lung cancer (SCLC). This study confirms that SCBC shares DNA changes similar to SCLC and that SCBC expresses many genes that urothelial bladder cancer does not, possibly explaining aggressive SCBC activity.

This article defines a new methodology for pre-recognition of events with object motion analysis in a video without any prior knowledge. This unsupervised application is named as ‘conceptualization’. This conceptualization technique is also tested with real-time video data in an internet of things (IoT) architecture. The merits of rough sets in the framework of granular computing are explored to execute the task. The proposed method is designed for the video sequences that are acquired by simple static RGB sensors. Here the video sequences are granulated with our newly defined ‘motion granules’ and then those are modeled as rough sets over this granulation for moving object/ background estimation. Video conceptualization is performed afterwards by quantifying the approximation with a new measure, namely, motion entropy. The values obtained by this measure reflect the amount of uncertainty present in the motion of each individual moving object which enables precognition of events. The effectiveness of the proposed method is verified with extensive experiments in identifying the different motion patterns present in a video sequence. The frames with possibilities of events present therein are identified with this analysis. Both offline and real-time sequences are used for this verification. An IoT architecture is formed to test the proposed algorithm with physical devices in identifying the frames containing possible events.

In this paper we report a novel way of processing CsI powder into poly-crystalline transparent plate by vacuum hot pressing technique. The fabricated CsI plate is investigated for its microstructure and phase purity. Further we have measured the luminescence and scintillation characteristics of this plate. These measurements establish that the polycrystalline plate can have application in radiation detection. Further the efficacy of the transparent CsI plate is shown for industrial X-ray radiography applications. Our results show that this kind of CsI plate can be economically fabricated and can replace the use of CsI single crystals and thin films in specific applications like radiation detection and industrial radiography.

Patients with advanced genitourinary cancers face many challenges throughout their disease trajectory, and many will experience clinically relevant psychosocial distress. Certain groups, including female gender, younger age (and older age for suicide), unmarried status, and non–clear cell histology, remain at a higher risk, and evidence suggests that those with kidney and bladder cancers may be at an increased risk of suicide. Routine psychosocial screening, with brief validated tools, has the ability to identify patients’ unmet needs, assist the health care team in addressing such symptoms, and subsequently improve quality of life, adherence, and clinical outcomes. Effective supportive care modalities are available that address common patient needs in the context of incurable disease (eg, emotional and physical symptoms); however, challenges remain in terms of patient acceptance and access through insurance coverage. As a result, remote home-based interventions have emerged with the potential to mitigate emotional symptom burden and improve disease adjustment. In this study, we highlight studies reporting on the prevalence of psychosocial distress and associated risk factors in advanced genitourinary cancers, and review evidence-based interventions for the management of distress, including distress screening and psychosocial interventions. Patient summary This mini-review reports the prevalence of psychosocial distress and associated risk factors among patients with advanced kidney, bladder, or prostate cancer. We found that patients with these types of advanced genitourinary cancers are at a great risk of distress, including suicide, with consequent impairments in quality of life. We recommend that a distress screening program be incorporated as the standard of care and that referrals to appropriate psychosocial interventions be available to assist patients in greatest need.

Preclinical models and early clinical data suggest an interplay between the gut microbiome and response to immunotherapy in solid tumors including metastatic renal cell carcinoma (mRCC). We sought to characterize the stool microbiome of mRCC patients receiving a checkpoint inhibitor (CPI) and to assess treatment-related changes in microbiome composition over the course of CPI therapy. Stool was collected from 31 patients before initiation of nivolumab (77%) or nivolumab plus ipilimumab (23%) therapy, of whom 58% experienced clinical benefit. Greater microbial diversity was associated with clinical benefit from CPI therapy (p = 0.001), and multiple species were associated with clinical benefit or lack thereof. Temporal profiling of the microbiome indicated that the relative abundance of Akkermansia muciniphila increased in patients deriving clinical benefit from CPIs. This study substantiates results from previous CPI-related microbiome profiling studies in mRCC. Temporal changes in microbiome composition suggest potential utility in modulating the microbiome for more successful CPI outcomes. Patient summary We compared the composition and diversity of the gut microbiome in patients receiving immunotherapy for renal cell carcinoma. We found that higher microbial diversity is associated with better treatment outcomes. Treatment response is characterized by changes in microbial species over the course of treatment.

In the present work, a novel cloud-based remote and real time monitoring and control scheme has been developed for a manufacturing process named friction stir welding (FSW) to avoid occurrence of weld defects. This model acquires data from multiple sensors associated with the FSW machine and transmits them to the cloud. The signals are analyzed and processed in the cloud in real time through various signal processing and machine learning techniques. The model provides a feedback to the machine regarding the desired controlled parameters to achieve an improved weld quality. This is an example of Industry 4.0 where a manufacturing process can be controlled in real time from any location.

In an era of several therapeutic options available, optimal treatment sequencing is crucial to providing patients the most effective therapy and promoting quality of life. In clear cell renal cell carcinoma, a combination approach with an immunotherapy backbone, such as nivolumab/ipilimumab or axitinib/pembrolizumab, has a key role in the first-line setting. Safety and activity data support the transition to single-agent targeted therapies in the second-line setting. Nivolumab monotherapy possesses clinical and mechanistic rationale as a second-line therapeutic option for patients treated with targeted therapies in the first-line setting. Gene expression models are being generated from large prospective clinical trial data sets.

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.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.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 P0.0001; 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 P0.0001; 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].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.NCT02684006.

Friction stir lap welding of aluminum and steel structures yields inhomogeneous microstructural changes, hooking defects and non-uniform layer of intermetallic compounds in the weld zones. These metallurgical changes and hooking defect affect the mechanical and metallurgical properties of the welds. In the present study, authors have quantified the mechanical properties of the weld regions, steel hook and inter-metallic which include hardness, elastic modulus, and stiffness by using lap shear tensile test and nano-indentation. Variations in the local mechanical properties at various locations of the welds have been investigated through a qualitative and quantitative study of microstructure size, the fraction of dynamic recrystallization and Inter-metallic compounds. Intermetallic compounds such as Fe2Al5, Fe4Al13, FeAl3Si2, and FeAl2Si have been found at the weld interface which has higher hardness (8.4-11.6 GPa) and elastic modulus (278-301 GPa) than the weld regions. Indentation depths on the IMC layers and the weld regions have also been studied to analyze the deformation behavior during indentation.

Detection of eye closing/opening from alpha-blocking in the EEG of occipital region has been used to build human-machine interfaces. This paper presents an alternative method for detection of eye closing/opening from EOG signals in an online setting. The accuracies for correct detection of eye closing and opening operations with the proposed techniques were found to be 95.6% and 91.9% respectively for 8 healthy subjects. These techniques were then combined with the detection of eye blinks, the accuracy of which turned out to be 96.9%. This was then used to build an interface for robotic arm control for a pick and place task. The same task was also carried out using a haptic device as a master. The speed and accuracy for these two methods were then compared to assess quantitatively the ease of using this interface. It appears that the proposed interface will be very useful for persons with neurodegenerative disorders who can perform eye closing/opening and eye blinks.