The Impacts and Changes Related to the Cancer Drug Resistance Mechanism.

BACKGROUND: Cancer drug resistance remains a difficult barrier to effective treatment, necessitating a thorough understanding of its multi-layered mechanism. OBJECTIVE: This study aims to comprehensively explore the diverse mechanisms of cancer drug resistance, assess the evolution of resistance detection methods, and identify strategies for overcoming this challenge. The evolution of resistance detection methods and identification strategies for overcoming the challenge. METHODS: A comprehensive literature review was conducted to analyze intrinsic and acquired drug resistance mechanisms, including altered drug efflux, reduced uptake, inactivation, target mutations, signaling pathway changes, apoptotic defects, and cellular plasticity. The evolution of mutation detection techniques, encompassing clinical predictions, experimental approaches, and computational methods, was investigated. Strategies to enhance drug efficacy, modify pharmacokinetics, optimizoptimizee binding modes, and explore alternate protein folding states were examined. RESULTS: The study comprehensively overviews the intricate mechanisms contributing to cancer drug resistance. It outlines the progression of mutation detection methods and underscores the importance of interdisciplinary approaches. Strategies to overcome drug resistance challenges, such as modulating ATP-binding cassette transporters and developing multidrug resistance inhibitors, are discussed. The study underscores the critical need for continued research to enhance cancer treatment efficacy. CONCLUSION: This study provides valuable insights into the complexity of cancer drug resistance mechanisms, highlights evolving detection methods, and offers potential strategies to enhance treatment outcomes.

Health profile of people living in the Gare Palma mining area of Tamnar block, Raigarh, Chhattisgarh, India.

Introduction: A community-based health survey was conducted in Tamnar block, Raigarh district of Chhattisgarh, India. Methodology: A total of 909 individuals (adults) were selected from 909 households from 33 sampled villages from March 2019 to February 2020. All individuals were clinically examined, and observations were recorded. Results: Among adults older than 18 years, hypertension was observed in 21.7%. Type II diabetes was observed in only 4.0% of individuals. Tuberculosis was seen in 23 (2.5%) individuals. Discussion: Common morbidities were similar in tribal and non-tribal communities living in the same area. For communicable diseases, being male, having nutritional deficiencies, and smoking were independent risk factors. For non-communicable diseases, the independent significant risk factors identified were being male, an altered body mass index, disturbed sleep, smoking, and nutritional deficiencies.

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab.

PURPOSE: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. PATIENTS AND METHODS: Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. RESULTS: Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. CONCLUSION: Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Achondroplasia: Clinical, Radiological and Molecular Profile from Rare Disease Centre, India.

Achondroplasia is the most common autosomal dominant form of skeletal dysplasia and is caused by heterozygous mutations of the fibroblast growth factor receptor 3 ( FGFR3 ) gene at region 4p16.3. This study highlights the data of achondroplasia cases, clinical spectrum, and their outcome from small cities and the region around Rajasthan. The data for analysis were collected retrospectively from genetic records of rare disease clinic in Rajasthan. Clinical profile, radiographic features, molecular test results, and outcome were collected. There were 15 cases, including eight males and seven females, in this cohort. All had facial hypoplasia, depressed nasal bridge, prominent forehead, and characteristic radiographic features. A total of 14 cases were sporadic and one case was inherited from the mother. Mutation analysis showed 13 out of 15 cases with the p.Gly380Arg mutation in the FGFR3 gene. Hydrocephalus was developed in three cases, required shunting in two cases.

Neutrophil Lymphocyte Ratio: A Predictor of Disease Severity in Nasal Polyposis and Allergic Fungal Rhinosinusitis.

To evaluate Neutrophil Lymphocyte ratio (NLR) as a predictor of disease severity in Nasal Polyposis and Allergic Fungal Rhinosinusitis (AFRS). This was a prospective non-randomized interventional study. Disease severity was graded based on endoscopic and CT scoring. Patients were given pre-operative oral steroids for two weeks and taken up for surgery. The pre-treatment neutrophil lymphocyte ratios were calculated from the differential leucocyte counts and compared with the disease severity and post-operative values. In the interventional arms, the disease severity correlated with the NLR. The mean pre-treatment NLR showed a statistically significant change after the intervention at eight weeks. The NLR normalized in patients with nasal polyposis and continued to be higher in patients with AFRS. NLR correlated to the disease severity and showed a linear correlation with the extent of the disease. NLR could be a potential cost-effective marker for disease severity and prognostication. Level of Evidence: Individual Cohort Study (2b).

Surgical Field Quality in Trans-Nasal Endoscopic Surgeries Using Lignocaine Infusion and Dexmedetomidine Infusion. A Prospective Randomized Control Study.

Trans-nasal endoscopic surgery (TNES) is a helpful diagnostic and therapeutic modality in otorhinolaryngology surgeries and requires controlled hypotension for better visualization of the surgical field. Recent literature shows evidence of intravenous Lignocaine infusion to produce the controlled hypotension. The study aims to assess and compare the effects of Lignocaine (LIG) and Dexmedetomidine (DEX) infusion with respect to surgical field quality. 101 Consenting adult patients undergoing elective TNES were double-blinded, randomly allocated in one of the two groups and received either DEX infusion of 0.5ug/kg/hr (n = 51) or LIG infusion of 1.5 mg/kg/h (n = 50) after a loading dose. Surgical field score (SVF) as the primary outcome and secondary outcomes such as variations in hemodynamic parameters, the requirement for rescue agents and total blood loss were recorded. Both the groups were comparable with respect to patient demographics, total duration of anesthesia and surgery. SVF scores were significantly better in the LIG group during the first 105 min of the surgery (p < 0.05). In response to intubation, hemodynamic parameters were lower in LIG group. The requirement of other adjuvant drugs, total blood loss (166.40 ml vs. 251.17 ml) and extubation time were also significantly lower in the LIG group. The study concludes that intravenous Lignocaine gives a better surgical field in the first 105 min of surgery, comparable hemodynamics and decreased blood loss in patients undergoing TNES as compared to Dexmedetomidine infusion. Hence its role as an agent for controlled hypotension during TNES surgery is promising.

Idiopathic Intracranial Hypertension and Endoscopic Optic Nerve Sheath Fenestration.

Idiopathic intracranial hypertension (IIH), also called as benign intracranial hypertension is a disorder, which is  considered benign in its course except its' ill effects on vision. Ocular findings in IIH such as papilledema, macular changes, retinal micro haemorrhages, cotton wool spots and tortuosity of vessels are the prominent features in funduscopy examination in these patients. Papilledema is a hallmark feature for evaluation of response to treatment. Ophthalmological rescue is a primary goal of management of idiopathic intracranial hypertension. Among the treatment options described in literature, optic nerve sheath fenestration is a minimally invasive endoscopic technique for the rescue of vision. We present this case-report, which will help ophthalmologists and the surgeons to determine the significance of the funduscopy changes after optic nerve sheath fenestration and help in decision making.

Bioavailability of acalabrutinib suspension delivered via nasogastric tube in the presence or absence of a proton pump inhibitor in healthy subjects.

AIMS: Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, is approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Many critically ill patients are unable to swallow and need oral medications to be delivered via a nasogastric (NG) tube. Furthermore, critically ill patients are typically administered proton-pump inhibitors (PPIs) to prevent stress ulcers. Concomitant administration with PPIs reduces acalabrutinib exposure and is not currently recommended. To evaluate acalabrutinib in subjects co-administered with PPIs who require NG delivery, a phase 1, open-label, randomized, crossover, single-dose study was conducted in healthy subjects. METHODS: The study assessed the relative bioavailability of an acalabrutinib suspension-in regular, degassed Coca-Cola-administered via NG tube (Acala-NG) versus the pharmacokinetics (PK) of an acalabrutinib capsule administered orally with water. In addition, the PPI effect was evaluated by comparing the PK following Acala-NG in the presence or absence of rabeprazole. RESULTS: Exposure of acalabrutinib and its active metabolite (ACP-5862) were comparable following administration of Acala-NG versus the oral capsule (Geo mean ratio, % ref [90% confidence interval, CI]: acalabrutinib AUCinf : 103 [93-113]; Cmax : 144 [120-173]). In addition, exposure was similar following administration of Acala-NG with and without a PPI (Geo mean ratio, % ref [90% CI]: acalabrutinib AUCinf : 105 [79-138]; Cmax : 95 [66-137]). No safety or tolerability concerns were observed, and all adverse events were mild and resolved without treatment. CONCLUSIONS: Acala-NG with or without a PPI is safe and well-tolerated without impeding bioavailability.

Pretreatment with systemic corticosteroid can mask early symptoms of hypersensitivity reaction to hyaluronidase following peribulbar block.

Hyaluronidase is a hydrolytic enzyme that helps in breaking down hyaluronic acid, a component of the extracellular tissue matrix, thereby facilitating the dispersion of local anaesthetic drugs through tissue planes. It is a key component in peribulbar anaesthesia for ocular surgeries. Allergic response to hyaluronidase is relatively rare but a potentially vision-threatening complication. A preoperative intradermal hypersensitivity test is useful to detect such cases and avoid potential complications. Here we report a case of hypersensitivity reaction to hyaluronidase after peribulbar anaesthesia for cataract surgery where an intradermal hypersensitivity test was falsely negative, and presentation was delayed due to the use of preoperative systemic corticosteroids. However, correct, and timely diagnosis and treatment saved the eye from permanent vision loss.

Modeling defluoridation of real-life groundwater by a green adsorbent aluminum/olivine composite: Isotherm, kinetics, thermodynamics and novel framework based on artificial neural network and support vector machine.

The kinetic, isotherm, and thermodynamics of adsorptive removal of fluoride from the real-life groundwater was evaluated to assess the applicability of a green adsorbent, aluminum/olivine composite (AOC). The isotherm and kinetics were demonstrated by the Freundlich and Elovich model indicating significant surface heterogeneity of AOC in favouring the fluoride sorption. The fluoride removal efficiency of AOC was achieved as 87.5% after 240 min of contact time. The diffusion kinetic model exhibited that both the intra-particle and film diffusion together control the rate-limiting step of fluoride adsorption. A negative value of ΔG0 (-19.919 kJ/mol) at 303 K confirmed the spontaneous adsorption reaction of fluoride, and its endothermic nature was supported by the negative value of ΔH0 (39.504 kJ/mol). A novel framework for a predictive model by artificial neural network (ANN), and support vector machine (SVM) considering the real and synthetic fluoride-containing water was developed to assess the efficiency of adsorbent under different scenarios. ANN model was observed to be statistically significant (RMSE: 1.0955 and R2: 0.9982) and the proposed method may be instrumental in a similar area for benchmarking the synthetic and real-life samples. The low desorption potential of the spent adsorbent exhibited safe disposal of sludge and the secondary-pollutant-free treated water by the efficient and green adsorbent AOC enhanced the field-scale applicability of the green technology.

Resistance to Durvalumab and Durvalumab plus Tremelimumab Is Associated with Functional STK11 Mutations in Patients with Non-Small Cell Lung Cancer and Is Reversed by STAT3 Knockdown.

Mutations in the STK11 (LKB1) gene regulate resistance to PD-1/PD-L1 blockade. This study evaluated this association in patients with nonsquamous non-small cell lung cancer (NSCLC) enrolled in three phase I/II trials. STK11 mutations were associated with resistance to the anti-PD-L1 antibody durvalumab (alone/with the anti-CTLA4 antibody tremelimumab) independently of KRAS mutational status, highlighting STK11 as a potential driver of resistance to checkpoint blockade. Retrospective assessments of tumor tissue, whole blood, and serum revealed a unique immune phenotype in patients with STK11 mutations, with increased expression of markers associated with neutrophils (i.e., CXCL2, IL6), Th17 contexture (i.e., IL17A), and immune checkpoints. Associated changes were observed in the periphery. Reduction of STAT3 in the tumor microenvironment using an antisense oligonucleotide reversed immunotherapy resistance in preclinical STK11 knockout models. These results suggest that STK11 mutations may hinder response to checkpoint blockade through mechanisms including suppressive myeloid cell biology, which could be reversed by STAT3-targeted therapy. SIGNIFICANCE: Patients with nonsquamous STK11-mutant (STK11mut) NSCLC are less likely than STK11 wild-type (STK11wt) patients to respond to anti-PD-L1 ± anti-CTLA4 immunotherapies, and their tumors show increased expression of genes and cytokines that activate STAT3 signaling. Preclinically, STAT3 modulation reverses this resistance, suggesting STAT3-targeted agents as potential combination partners for immunotherapies in STK11mut NSCLC.This article is highlighted in the In This Issue feature, p. 2659.

Curative-Intent Treatment with Durvalumab in Early-Stage Cancers.

The introduction of immunotherapy has fundamentally transformed the treatment landscape in cancer, providing long-term survival benefit for patients with advanced disease across multiple tumor types, including non-small cell lung cancer (NSCLC). In the placebo-controlled phase 3 PACIFIC trial, the PD-L1 inhibitor durvalumab demonstrated significant improvements in progression-free survival and overall survival in patients with unresectable, stage III NSCLC who had not progressed after platinum-based chemoradiotherapy (CRT). These findings have led to the widespread acceptance of the 'PACIFIC regimen' (durvalumab after CRT) as the standard of care in this setting. Moreover, the PACIFIC trial is the first study to demonstrate a proven survival advantage with an immunotherapy in a curative-intent setting, thereby providing a strong rationale for further investigation of durvalumab in early-stage cancers. Herein, we describe the extensive clinical development program for durvalumab across multiple tumor types in curative-intent settings, outlining the scientific rationale(s) for its use and highlighting the innovative research (e.g., personalized cancer monitoring) advanced by these trials.

Clinicopathological Correlation of Glioma Patients with respect to Immunohistochemistry Markers: A Prospective Study of 115 Patients in a Tertiary Care Hospital in North India.

BACKGROUND: With the incorporation of molecular subtyping in glioma patients in 2016 WHO classification, there is a need to understand the immunohistochemistry (IHC) marker expression in various glioma patients and to clinically correlate with various subgroups. OBJECTIVE: Aim of the study was to assess IHC marker expression profile in glioma patients and to clinically correlate them in various subgroups. MATERIALS AND METHODS: The prospective study included 115 glioma patients. IHC markers (isocitrate dehydrogenase [IDH] 1, ATRX, P53, Ki-67 antibody) were done in all patients. Patients received treatment as per the grade of tumor. The patients were followed in 3 monthly intervals, for a period of 12 months. SPSS software version 20.0 was used for statistical analysis. Tables were prepared in Microsoft Excel sheet. Kaplan-Meier method was used for survival analysis. RESULTS: There were 11 Grade 1, 33 Grade 2, 26 Grade 3, and 45 glioblastoma multiforme (GBM) patients out of which 10 patients were secondary GBM cases. IDH1 mutation is frequent in Grade 2 and Grade 3 tumors of both astrocytic and oligodendroglia tumors. Its mutation is also common in secondary GBM patients. ATRX mutation is specific to astrocytic lineage, Grade 2, Grade 3, and secondary GBM patients. CONCLUSION: Molecular nature of DA and AA cases can be accurately confirmed by combined IDH1 and ATRX IHC thereby avoiding costly investigations such as fluorescence in situ hybridization. In astrocytic tumors, p53 can act as a surrogate marker. IDH-mutant glioma patients have better prognoses than IDH wild gliomas.

Duchenne Muscular Dystrophy: Genetic and Clinical Profile in the Population of Rajasthan, India.

Background: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscular dystrophy that affects young boys and is caused by mutation of the dystrophin gene located over X chromosome. Materials and Methods: In this prospective study, 120 clinically diagnosed DMD patients were tested for exon deletions, duplication or point mutation. Results: Of the 120 clinically suspected DMD patients, the diagnosis of DMD was confirmed by the genetic study or muscle biopsy in 116 patients. The mean age of onset was 3.2 years and the mean age at presentation was 7.2 years. 110/120 cases were confirmed by genetic testing and six were by absence of staining for dystrophin on muscle biopsy. DMD gene deletion was present in 78.5%, duplication in 5.3% and point mutation in 11.2% cases. 70.3% of patients had deletion located at a distal hot spot region. Single exon deletion was found in 16.5%. Distal hotspot exons 47, 48 and 50 were the commonly deleted exons. Conclusions: In our study, 94.8% cases showed genetic change in the DMD gene. Muscle biopsy was the choice of investigation in earlier days. Detection of DMD by DNA based method eliminates the need to do an invasive procedure for diagnosis. Hence the genetic testing should be the investigation of choice in suspected cases of DMD. The pattern of deletion, obtained in the population of Rajasthan was similar when compared with other ethnic groups of the Indian population. It would be helpful for researchers to develop drugs specific to exons or for ongoing mutation-specific therapies.

Efficacy and Comparison of Vestibular Rehabilitation Exercises on Quality of Life in Patients with Vestibular Disorders.

Vertigo is the sensation of spinning or having one's surroundings spin about them. It represents about 25% of cases of occurrences of dizziness Yardley et al. (Br J Gen Pract 48(429):1131-1135, 1998). About 40% patients have peripheral vestibular dysfunction (Neuhauser in Curr Opin Neurol 20:40-46, 2007). Quality of life (QOL) is significantly impaired by vertigo (Patatas et al. in Braz J Otorhinolaryngol 75:387-394, 2009). To study the effect and compare vestibular exercises on QOL in patients with vestibular disorders. 120 individuals with vestibular disorders like acoustic neuroma, vestibular neuritis, labyrinthitis, Meniere's disease, vestibulopathy, ISSNHL and ototoxicity were included. Four groups adaptation exercises, habituation exercises, substitution exercises, and combined exercises were formed and 30 individuals were selected in each group randomly. Vestibular activities and participation (VAP) was administered before and after exercises to fulfill the aim. VAP Scale results revealed significant difference between pre and post treatment score in all groups, suggestive of positive effect on QOL in patients with vestibular disorders. Improvements in VAP Score between all groups were compared and significant difference was observed. Combined exercises group found to be best out of 4 exercises group.

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. METHODS: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. FINDINGS: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). INTERPRETATION: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. FUNDING: AstraZeneca.

Durvalumab activity in previously treated patients who stopped durvalumab without disease progression.

BACKGROUND: Limited data exist on potential clinical benefit with anti-programmed cell death ligand-1 (PD-L1) retreatment in patients who stop initial therapy for reasons other than disease progression or toxicity and develop disease progression while off treatment. PATIENTS AND METHODS: NCT01693562 was a phase I/II study evaluating durvalumab monotherapy in advanced solid tumors. Patients benefiting from treatment were taken off durvalumab at 1 year per protocol and prospectively followed. At disease progression, they were eligible for durvalumab retreatment. Outcomes evaluated during retreatment included best overall response (BOR2), duration of response (DoR2), disease control rate (DCR2), and progression-free survival (PFS2). RESULTS: Of 980 patients enrolled and treated with durvalumab 10 mg/kg every 2 weeks (Q2W) in the dose-expansion cohorts, 168 completed 1 year of initial durvalumab treatment with confirmed BOR1 of complete response in 20 (11.9%), partial response (PR) in 84 (50%), stable disease (SD) in 52 (31%), and disease progression in 12 (7.1%). All 168 patients stopped treatment and were eligible for retreatment at progression; 70 patients (41.7%) representing 14 primary tumor types were retreated and response evaluable. Confirmed BOR2 was PR in 8 patients (11.4%), SD in 42 (60.0%), disease progression in 16 (22.9%), and unevaluable in 4 (5.7%). Median DoR2 was 16.5 months. DCR2 ≥24 weeks (DCR2 24) was 47.1%. PFS2 rate at 12 months was 34.2%, and median PFS2 was 5.9 months. Median overall survival (OS2) was 23.8 months. Response rates, DCR2 24, and median DoR2 were generally greater in patients with high PD-L1 expression than those with low/negative expression. No new safety signals were observed during retreatment. CONCLUSION: Retreatment restored antitumor activity, resulting in high rates of durable disease control with an acceptable safety profile. This evidence supports retreatment of patients who stop anti-PD-L1 therapy for reasons other than progression or toxicity, and supports further investigation.

A review on treatment of petroleum refinery and petrochemical plant wastewater: A special emphasis on constructed wetlands.

Petroleum refinery and petrochemical plants (PRPP) are one of the major contributors to toxic and recalcitrant organic polluted water, which has become a significant concern in the field of environmental engineering. Several contaminants of PRPP wastewater are genotoxic, phytotoxic, and carcinogenic, thereby imposing detrimental effects on the environment. Many biological processes were able to achieve chemical oxygen demand (COD) removal ranging from 60% to 90%, and their retention time usually ranged from 10 to 100 days. These methods were not efficient in removing the petroleum hydrocarbons present in PRPP wastewater and produced a significant amount of oily sludge. Advanced oxidation processes achieved the same COD removal efficiency in a few hours and were able to break down recalcitrant organic compounds. However, the associated high cost is a significant drawback concerning PRPP wastewater treatment. In this context, constructed wetlands (CWs) could effectively remove the recalcitrant organic fraction of the wastewater because of the various inherent mechanisms involved, such as phytodegradation, rhizofiltration, microbial degradation, sorption, etc. In this review, we found that CWs were efficient in handling large quantities of high strength PRPP wastewater exhibiting average COD removal of around 80%. Horizontal subsurface flow CWs exhibited better performance than the free surface and floating CWs. These systems could also effectively remove heavy oil and recalcitrant organic compounds, with an average removal efficiency exceeding 80% and 90%, respectively. Furthermore, modifications by varying the aeration system, purposeful hybridization, and identifying the suitable substrate led to the enhanced performance of the systems.