Association between Patient-Reported Outcomes and Survival in Patients with Advanced Urothelial Carcinoma Treated with Atezolizumab

BACKGROUND: Atezolizumab is an immune checkpoint inhibitor (ICI) and a frontline treatment of patients with cisplatin-ineligible advanced urothelial carcinoma (UC). There is limited evidence on the prognostic value of patient reported outcomes (PROs) in advanced UC treatment, particularly in the context of ICI therapy. OBJECTIVE: To investigate the prognostic association of PROs with survival in patients with advanced UC treated with atezolizumab. METHODS: This study used data from 467 patients with advanced UC initiating atezolizumab in the IMvigor211 trial. Pre-treatment PROs association with overall survival (OS) and progression free survival (PFS) was assessed using Cox proportional hazard analysis. PROs were recorded via the European Organisation for Research and Treatment of Cancer QLQ-C30. Discrimination performance was assessed via the C-statistic (c). RESULTS: Patient reported physical function, pain, appetite loss, global health, fatigue, role function, constipation, nausea and vomiting, dyspnoea, and insomnia were significantly associated with OS and PFS on univariable and adjusted analysis (P < 0.05). Physical function (c = 0.63), pain (c = 0.63), appetite loss (c = 0.62), global health status (c = 0.62), and fatigue (c = 0.62), were the most prognostic factors of OS. The OS discrimination performance of physical function (c = 0.61) was superior to ECOG PS (c = 0.58). Of patients assessed by investigators as having no performance restrictions (ECOG PS of 0), 38 (18%) and 91 (42%) self-reported low and intermediate physical function scores, respectively. CONCLUSION: Pre-treatment PROs were identified as independent prognostic factors of OS and PFS. Patient-reported physical function was more prognostic of OS than ECOG PS. This highlights a potential for PROs to enable improved patient stratification in ICI trials.

In silico discovery of GPCRSs and GnRHRs as Novel SARS-CoV-2 binding receptors, the Scientific Breakthrough that could explain the observed High cortisol, Appetite loss, Ansomnia and Hypogonadism, as well as Hypothyroidism, Retinol deficiency and menstrual disturbances among SARS-COV-2 patients.

Background COVID-19 is known to cause chemosensory dysfunction. A common symptoms of COVID-19 is a disorder in hormonal balance and olfactory function which may persist after recovery including COVID-19-related anosmia and hypogonadism. Hormonal problems such as Hypogonadism and Hypothyrodism are being observed in patients with Covid-19. Rise in cases of hormonal imbalance post COVID recovery is a cause for concern. Moreover, anosmia is a well-tolerated symptom of COVID-19, but their aetiology isn't understood. The studies demonstrated that the new coronavirus could affect the central nervous system through the olfactory bulb or blood circulation. Furthermore, in addition to anosmia or hyposmia induction, as well as taste disorders, the virus may cause Appetite loss, High cortisol, Anxiety ,Retinol deficiency, Eye-ache, earache, Dizziness, Memory, Minstrual disturbances and hallucination. G-protein coupled receptors (GPCRSs) are well known to be expressed throughout the body, and they represent the genome's largest superfamily of signaling. It was showed that G-protein coupled receptors (GPCRS) and Gonadotropin-releasing hormone receptors (GnRHRs, a subtype of GPCRS), were expressed sufficiently in olfactory region and hypothalamus as well as thyroid gland and the human lung. It was found that GPCRs are responsible for diverse biological functions such as Appetite, Cortisol level, Smelling and Tasting regulation as well as Retinol transport and act as receptors of Thyroxin. Herein by using molecular docking and stimulation analysis , we succeeded to elucidate the direct neuroinvasive route of COVID-19 into the nasal epithelium and human brain cells which may lead to anosmia and hormonal imbalance mainly through the olfactory route by direct binding to G-protein coupled receptors (GPCRS). Furthermore, we strongly suspect that binding of COVID-19 to the expressed GPCRS in the lung is a main cause of ion changing disruption leading to pulmonary edema and failure . Moreover, we confirmed our results by investigating Gonadotropin-releasing hormone receptors (GnRHRs) as a novel binding receptor of COVID-19.MethodologyIn the current study, we used PatchDock server to conduct a docking study of the SARS-CoV-2 Spike protein with both of GnRHRs and GPCRSs protein. The structure of the crystal structure of the proteins were retrieved from RSCP (https://www.rcsb.org/ ) with accessions numbers (PDB ID 7BR3 and 6P9X respectively. we obtained the crystal structure of spike with accession number (PDB ID: 6VYB). The proteins are downloaded in the pdb format. The spike - receptor protein was investigated to determine the conservative residues of binding of Spike protein with the GnRHRs and GPCRS proteins in order to discover the ability of Spike to interact with GnRHR and GPCR receptors. We performed Molecular Dynamics (MD) Simulation to investigate the positional and conformational changes of the included proteins in relation to the binding site that provides insight into the binding stability. MD simulation of the complex was carried out with the GROMACS 4.5.4 package using the GROMOS96 43a1 force field.ResultsThis analysis of simulations molecular dynamics and molecular docking showed a high affinity between Spike protein and both of GnRHRs and GPCRSs . Results indicated that the spike binds to GNRHRS with binding energy (-1424.7 k.cal/mol) and to GPCRS with binding energy (-1451.8 k.cal/mol). The obtained results confirmed that the native model binds to GPCRS with the highest docking score of ( -1451.8) when compared to the other GNRHRS complexes, which have the lowest binding affinity, as evidenced by the docking score of (-1424.9). These results signifies better conjugation of GNRHRS to the binding pocket of the spike receptor in the RDB of the spike protein . Comparing the binding free energy of GPCRS to GNRHRS showed that the GNRHRS protein was found to bind to the vital residues in the RBD of the spike protein. But GPCRSs protein were found to bind to new RDB in other place in chain B of the spike. The molecular dynamics (MD) simulations study revealed significant stability of s pike protein with the GnRHRs and GPCRS separately up to 50 ns.CONCLUSIONSThe COVID-19 entry receptor, angiotensin-converting enzyme 2 (ACE2), is not expressed in the receptor of olfactory neurons, or its generation is limited to a minor fraction of these neurons. A change or disorder in hormonal balance and olfactory function is a common symptom of COVID-19 as well as Appetite loss and retinol deficiency , but its aetiology is unknown. SARS-CoV-2 was found to bind strongly and directly to both GPCRS and GnRHRs which expressed sufficiently in olfactory neurons. As a result, we confirm that COVID-19 could use these receptors especially GNRHRS as a direct neuroinvasive route into human brain cells, potentially leading to long-term neurological complications and hormonal imbalance in addition to Appetite loss and retinol deficiency via the olfactory route. Our findings may also shed a new light on the mechanism of pulmonary edema in COVID-19 patients. Therefore ,we propose that GPCRS and is involved in COVID-19 pathophysiology and can be exploited as a potential therapeutic target for COVID-19.

Broadening symptom criteria improves early case identification in SARS-CoV-2 contacts

IntroductionThe success of case isolation and contact tracing for the control of SARS-CoV-2 transmission depends on the accuracy and speed of case identification. We assessed whether inclusion of additional symptoms alongside three canonical symptoms (CS) - fever; cough; loss or change in smell or taste – could improve case definitions and accelerate case identification in SARS-CoV-2 contacts.MethodsTwo prospective longitudinal London-based cohorts of community SARS-CoV-2 contacts, recruited within 5 days of exposure, provided independent training and test datasets. Infected and uninfected contacts completed daily symptom diaries from the earliest possible time-points. Diagnostic information gained by adding symptoms to the CS was quantified using likelihood ratios and AUC-ROC. Improvements in sensitivity and time-to-detection were compared to penalties in terms of specificity and number-needed-to-test.ResultsOf 529 contacts within two cohorts, 164 (31%) developed PCR-confirmed infection and 365 (69%) remained uninfected. In the training dataset (n=168), 29% of infected contacts did not report the CS. Four symptoms (sore throat, muscle aches, headache and appetite loss) were identified as early-predictors (EP) which added diagnostic value to the CS. The broadened symptom criterion “≥1 of the CS, or ≥2 of the EP” identified PCR-positive contacts in the test dataset on average 2 days earlier after exposure (p=0.07) than “≥1 of the CS”, with only modest reduction in specificity (5.7%).ConclusionsBroadening symptom criteria to include individuals with at least 2 of muscle aches, headache, appetite loss and sore throat identifies more infections and reduces time-to-detection, providing greater opportunities to prevent SARS-CoV-2 transmission.

Patient-reported outcomes during repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for isolated unresectable colorectal peritoneal metastases in a multicenter, single-arm, phase 2 trial (CRC-PIPAC)

Background CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment. Methods In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m2). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen’s D ≥ 0.50) of statistically significant differences. Results Twenty patients underwent 59 procedures (median 3 [range 1–6]). Several PROs solely worsened 1 week after the first procedure (index value − 0.10, p < 0.001; physical functioning − 20, p < 0.001; role functioning − 27, p < 0.001; social functioning − 18, p < 0.001; C30 summary score − 16, p < 0.001; appetite loss + 15, p = 0.007; diarrhea + 15, p = 0.002; urinary frequency + 13, p = 0.004; flatulence + 13, p = 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23, p < 0.001; pain + 29, p < 0.001; abdominal pain + 32, p < 0.001), second procedure (fatigue + 20, p < 0.001; pain + 21, p < 0.001; abdominal pain + 20, p = 0.002), and third procedure (pain + 22, p < 0.001; abdominal pain + 22, p = 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure. Conclusions Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure. Trial registration Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426.

A phase I study of the tyrosine kinase inhibitor anlotinib combined with platinum/pemetrexed-based chemotherapy in untreated nonsquamous non-small-cell lung cancer

SummaryBackground. Anlotinib hydrochloride is an oral small molecule inhibitor of multiple tyrosine kinases, and it has been approved as a third-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) in China. This dose-exploration study was designed to investigate the feasibility of anlotinib in combination with other chemotherapy regimens in patients with nonsquamous NSCLC. Methods. This phase I study followed a 3 + 3 dose reduction design with three doses of anlotinib (12 mg, 10 mg, and 8 mg). Anlotinib was given at an initial dose of 12 mg with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC = 5) on 21-day cycles for 4 cycles. The primary goal of the study was to identify the maximum tolerated dose (MTD), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results. A total of eight participants were enrolled. Dose-limiting toxicities (DLTs) were observed in two patients (pts) at anlotinib 12 mg (grade 3 hand-foot syndrome and grade 3 appetite loss). No DLTs occurred with 10 mg anlotinib, and the MTD was 10 mg. Among seven evaluable pts, four achieved a confirmed partial response (PR), and three had stable disease (SD). With a median follow-up of 10.05 months, the median PFS was 7.00 months (95% CI: 2.76 to NE). Grade 3 treatment-related adverse events (TRAEs) included appetite loss (n = 2), hypertension (n = 2), thrombocytopenia (n = 1), diarrhea (n = 1) and hand-foot syndrome (n = 1). No grade 4 or grade 5 TRAEs were observed during the treatment. Conclusion. The feasible dose of anlotinib in combination with platinum/pemetrexed-based chemotherapy as a first-line regimen was 10 mg, which was well tolerated and showed promising antitumor activity in advanced nonsquamous NSCLC.

Brain MRI detection of early Wernicke's encephalopathy in a hemodialysis patient

Wernicke’s encephalopathy should be suspected in hemodialysis patients with appetite loss alone, with careful brain MRI analysis for detecting possible Wernicke’s encephalopathy at an early stage.

Synthesis and Evaluation of Mycophenolic Acid Derivatives as Potential Anti-Toxoplasma Gondii Agents

Nineteen mycophenolic acid (MPA) derivatives were designed and synthesized, and their anti-Toxoplasma activity evaluated for the first time. Among them, N-propylimidazole-modified compound E5 demonstrated the strongest activity, and the IC50 against HFF-1 (Human Foreskin Fibroblasts-1) cells following infection with T. gondii is 80.9 μM (MPA-211.5 μM) and its selectivity value is 2.2 (MPA-1.2). In vivo experiments, E5 significantly inhibited the proliferation of tachyzoites in the abdominal cavity of mice acutely infected with T. gondii (inhibition rates 46.7%), and this inhibitory effect was greater than that of spiramycin (inhibition rates 31.3%) and MPA (inhibition rates 15.9%), this indicated that E5 had significant protective effects on the host during acute Toxoplasma infection. In addition E5 significantly reduced the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of infected mice, significantly increased the level of glutathione (GSH) in the liver, and significantly reduced the level of malondialdehyde (MDA), indicating that it has a significant hepatoprotective effect against T. gondii infection. Similarly, E5 can relieve hepatomegaly and splenomegaly induced by acute Toxoplasma infection. Spiramycin aggravated appetite loss in infected mice, while E5 did not. In summary, the results indicated that E5 has potential as a candidate anti-T. gondii drug.