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River pollution can harm human health through direct contact, drinking water, and the consumption of contaminated fish and irrigated agricultural products. Surface water and Nile tilapia (Oreochromis niloticus) samples were collected monthly from July 2022 to June 2023 at three sites (El-Rahawy, Sabal, and Tala) along the Rosetta Nile branch in Egypt to monitor the presence of eight trace elements. The potential human health risks from consuming contaminated fish were also assessed. Iron and manganese were consistently detected in all water samples across most seasons and locations, with concentrations generally below the WHO permissible levels. All 72 analyzed fish muscle samples were found to contain trace elements. The mean concentrations of metals in the fish muscle samples, in descending order, were: iron > zinc > copper > manganese > tin > antimony > lead > mercury. Significant spatial and seasonal variations were observed in both water and fish samples. El-Rahawy was identified as the most contaminated site, with summer exhibiting the highest contamination rate compared to other seasons. Fish samples collected from El-Rahawy demonstrated the highest bioconcentration factor (BCF) values for most elements, particularly mercury, lead, iron, manganese, and antimony. Target hazard quotient (THQ) calculations for the trace elements in Nile tilapia muscles revealed that all trace elements, except antimony, had THQ values below 1, suggesting that consuming Nile tilapia from these sites is unlikely to cause adverse health effects. However, THQ values for antimony exceeded the threshold of 1, indicating a potential health risk for consumers. Although the detected trace elements in the fish were below the permissible toxicity limits, some could pose a future threat to human health, necessitating further studies, ongoing monitoring, and preventive measures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Safety data on MET inhibitors in patients with advanced NSCLC harboring MET exon 14 mutation and treated with frontline immune checkpoint inhibitors (ICIs) are still limited. Here, we describe clinical characteristics, liver biopsy features, and management of liver injury of two patients with a diagnosis of MET exon 14-mutant NSCLC receiving capmatinib after ICI failure. On the basis of histologic findings and exclusion of other potential causes, a diagnosis of drug-induced liver injury (DILI) associated with portal fibrosis was made in both cases. The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization. To provide a global safety perspective, we queried the Food and Drug Administration Adverse Event Reporting System and detected a robust disproportionality signal. Out of the 918 total reports with capmatinib from the Food and Drug Administration Adverse Event Reporting System database, DILI was recorded in 43 cases (4.7%), mostly serious (93.0%) with hospitalization and death recorded in 25.6% and 16.3% of the cases, respectively. The median time to onset was 42 days, with discontinuation and positive dechallenge documented in 41.9% and 39.5% of the cases, respectively. Anti-programmed cell death protein-1 agents were coreported in 11 DILI cases. Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted., (© 2023 The Authors.)

In recent years, immunotherapy has significantly changed the treatment of locally advanced/metastatic non-small-cell lung cancer (NSCLC). Conversely, the role of immunotherapy in NSCLC with uncommon histologies remains unclear, while in other rare thoracic malignancies, such as malignant pleural mesothelioma and thymic epithelial tumors, the use of immune checkpoint inhibitors is modifying therapeutic strategies with solid hopes for the future. However, larger prospective studies are urgently needed to define the best treatment strategies and the role of immunotherapy in these orphan tumors. This review provides a comprehensive overview of the emerging role of immunotherapy in the treatment of patients affected by these rare thoracic malignancies.

This study aimed to (1) monitor the occurrence and spatiotemporal variations of 100 pesticides in sediments collected monthly from July 2018 to June 2019 from sampling sites in El-Rahawy, Sabal, and Tala, along the Rosetta branch of the Nile River, Egypt, and (2) perform an ecological risk assessment for aquatic organisms upon exposure to the detected sediment pesticides based on the risk quotient (RQ) method. Out of the 100 pesticides monitored, 16 pesticides belonging to seven chemical families were detected, and 55% of the sediment samples were contaminated with one or more pesticide residues. The mean concentration (mg/kg dry weight (dw)) and detection frequency (%) of the four most frequently detected pesticides in the sediment samples were as follows: chlorpyrifos (0.18 mg/kg dw and 34%), p,p'-DDE (0.018 mg/kg dw and 30%), cypermethrin (0.03 mg/kg dw and 14%), and deltamethrin (0.026 mg/kg dw and 13%). The spatial distribution exhibited that El-Rahawy had the highest pesticide load (2.86 mg/kg dw) among the studied sites, whereas the temporal variations revealed that the highest total pesticide concentrations were detected in winter season (1.73 mg/kg dw). Meanwhile, 12 pesticides showed high RQs (>1), posing a potential ecological risk to aquatic species that live and feed on such sediments., (Copyright © 2021. Published by Elsevier B.V.)

Background: The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting., Objective: We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC., Patients and Methods: We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO-UMC system, a standardized probabilistic algorithm., Results: Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizotinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as highly probable and 69.5% as probable. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%)., Conclusion: Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs., (© 2022. The Author(s).)

In Egypt, the shortage of freshwater resources and their pollution constitutes a growing concern. Therefore, the objectives of this study were to (i) monitor the occurrence and spatiotemporal variations of 100 pesticides in surface water samples collected monthly (from July 2018 to June 2019) from El-Rahawy, Sabal, and Tala sampling sites along the Rosetta branch of the River Nile in Egypt, (ii) identify potential non-carcinogenic health risks for the local people through the lifetime consumption of contaminated drinking water, and (iii) perform an ecological risk assessment of aquatic organisms upon exposure to pesticides detected in surface waters based on the risk quotients (RQs) method. Of the 100 pesticides analyzed, 22 belonging to 11 chemical families were detected, and 75.5% of surface water samples were contaminated with one or more pesticide residues. The most frequently detected pesticide was malathion (57%), followed by chlorpyrifos (54%), atrazine (23%), and carbendazim (20%). Spatial distribution showed that the El-Rahawy site had the highest pesticide load (38.47 μg/L), and Sabal had the lowest (16.29 μg/L). Temporal variations revealed that the highest total pesticide concentrations were detected in summer (27.98 μg/L) compared to spring (23.16 μg/L), winter (19.18 μg/L), and autumn (11.85 μg/L). For non-carcinogenic risks of pesticides detected in surface water, the target hazard quotient (THQ) values were less than one. This implies that there is no potential human risk from exposure to drinking water at the sites under study. However, 13 pesticides presented high-risk quotients (RQ > 1), posing potential ecological risks to aquatic organisms., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Until recently, platinum-based chemotherapy has represented the benchmark for the treatment of extensive disease small-cell lung cancer (ED-SCLC). ED-SCLC patients are often diagnosed with poor performance status (PS ≥2) and/or compromised organ functions. In fact, up to 63% of ED-SCLC has extensive liver involvement at diagnosis, which correlates with a poor prognosis. Whether to treat patients with tumor-related organ failure is still debated and the selection of those who could benefit from chemotherapy is crucial. Moreover, severe liver impairment contraindicates the administration of etoposide. Among 74 consecutive ED-SCLC patients followed at our institution from January 2017 to November 2019, three patients received single-agent carboplatin as a first-line treatment due to liver failure. We provide a brief description of a former heavy smoker 70-year-old man who was diagnosed with ED-SCLC and severe liver involvement leading to liver failure. The patient received a first-line treatment with single-agent carboplatin, obtaining a partial response, clinical benefit and the normalization of laboratory test, which documented the complete recovery of liver function. The intent of our work is to highlight the feasibility of single-agent carboplatin in ED-SCLC patients with tumor-related hepatic failure but preserved Eastern Cooperative Oncology Group PS, suggesting that this therapeutic option should not be discouraged a priori. Indeed, the identification of specific tools guiding physicians in the selection of patients who might benefit from the treatment is remarkably needed; meanwhile, the use of available prognostic score (e.g. Manchester score) might be of great value and should be considered in clinical practice., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Novel treatment strategies incorporating PD-1/PD-L1 inhibitors in the first-line setting of advanced non-small-cell lung cancer (NSCLC) provided relevant improvements in survival outcomes. Among NSCLC patients with PD-L1 tumor proportion score ≥50%, identifying the ones to be addressed to pembrolizumab monotherapy or chemo-immunotherapy combinations is a matter of debate, taking into account the risks of overtreatment and toxicity. Here we report the clinical stories of four NSCLC patients with PD-L1 tumor proportion score ≥50% and good performance status, sharing high tumor burden including serosal involvement. After having rapidly progressed on first-line PD-1/PD-L1 inhibitors, they achieved major clinical and radiological response to pembrolizumab-chemotherapy combination. These cases prove the feasibility and effectiveness of salvage chemo-immunotherapy in pembrolizumab-refractory NSCLC patients.

Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabine-induced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 μmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 μmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidines-based chemotherapy, especially combined with platinum-derivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels.

Treatment with inhibition of programmed cell death 1 (PD-1) or its ligand (PD-L1) improves survival in advanced non-small-cell lung cancer (NSCLC). Nevertheless, only a subset of patients benefit from treatment and biomarkers of response to immunotherapy are lacking. Expression of PD-L1 on tumor cells is the primary clinically-available predictive factor of response to immune checkpoint inhibitors, and its relevance in cancer immunotherapy has fostered several studies to better characterize the mechanisms that regulate PD-L1 expression. However, the factors associated with PD-L1 expression are still not well understood. Genomic alterations that activate KRAS , EGFR , and ALK , as well as the loss of PTEN , have been associated with increased PD-L1 expression. In addition, PD-L1 expression is reported to be increased by amplification of CD274 , and decreased by STK11 deficiency. Furthermore, PD-L1 expression can be modulated by either tumor extrinsic or intrinsic factors. Among extrinsic factors, the most prominent one is interferon-γ release by immune cells, while there are several tumor intrinsic factors such as activation of the mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Myc pathways that can increase PD-L1 expression. A deeper understanding of PD-L1 expression regulation is crucial for improving strategies that exploit inhibition of this immune checkpoint in the clinic, especially in NSCLC where it is central in the therapeutic algorithm. We reviewed current preclinical and clinical data about PD-L1 expression regulation in NSCLC.

DNA damage response and repair ( DDR ) genes play a central role in the life of actively replicating cells, cooperating to maintenance of genomic integrity. However, exogenous or endogenous factors, including deficiency in DDR genes, can cause different degrees of DNA damage that profoundly impacts the tumor immunogenicity and enhance antitumor immune response through neoantigen-dependent and neoantigen-independent mechanisms. Inhibition of DDRs is already an effective therapeutic strategy in different cancer types. In addition, because DDR inhibition can also induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses, combining DDR inhibitors with immune checkpoint inhibitors represent an attractive therapeutic strategy to potentially improve the clinical outcomes of patients with metastatic cancer. In this review, we provide an overview of the rational and potential of combining DDR and immune checkpoint inhibition to exploit the enhanced antitumor immune response induced by DNA damage.

Nile tilapia ( Oreochromis niloticus ) samples were collected at monthly intervals between July 2018 and June 2019 from 3 sampling sites (El-Rahawy, Sabal and Tala) situated along the Rosetta branch of the Nile, Egypt, to monitor the presence of 100 pesticides and 5 antibiotics using different extraction procedures followed by GC-MS/MS and LC-MS/MS. Potential human health risks via the consumption of contaminated fish was also assessed. Of the 72 analyzed fish muscle samples; 86% and 21% were contaminated with pesticides and antibiotics, respectively. Chlorpyrifos (ranging from < LOQ to 0.08 mg/kg) was the most frequently detected pesticide followed by p,p'- DDE (ranging from < LOQ to 0.04 mg/kg) in 83 and 45% of the fish muscle samples, respectively. Nitrofurazone (ranging from 8.6 to 52 μg/kg) was the most frequently detected antibiotic, followed by nitrofurantoin (ranging from 1.1 to 2 μg/kg) and chloramphenicol (ranging from < LOQ to 0.17 μg/kg). These antibiotics were found in 12, 6 and 5% of the fish muscle samples, respectively. The spatial distribution of the detected pesticides and antibiotics in fish samples along the Rosetta branch showed that the highest mean concentrations were found in the Sabal area, followed by samples from Tala and El-Rahawy. An investigation into seasonal variations revealed that the highest mean concentrations of pesticides and antibiotics in fish samples were detected in winter and spring, respectively. According to target hazard quotient (THQ) calculations for the detected pollutants in Nile tilapia muscle, all pollutants gave THQ values lower than 1, indicating that the consumption of this fish from the study sites is unlikely to cause any detrimental effects to consumers., Competing Interests: The authors report no declarations of interest., (© 2020 The Authors.)

Background: As important players of the innate immune system, Toll-like receptors (TLRs) and their role for tumorigenesis have been in the focus of research. In particular TLR7 is an interesting candidate, as TLR7 agonists are broadly used for the treatment of cutaneous tumors. However, data addressing the baseline expression of TLR7 in both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) on the protein level are lacking, while on the genomic level significantly elevated expression of TLR7 in SCC but not in BCC has been demonstrated., Aim: Our aim was to characterize the immunohistochemical staining pattern of TLR7 in SCC and BCC. Besides, we aimed to clarify if, in case of different TLR7 expression between SCC and BCC, TLR7 expression would help to define basosquamous carcinoma (BSC), a tumor entity sharing characteristics of both SCC and BCC., Methods: We examined histopathological samples from 23 BCC, 4 BSC, and 24 SCC and characterized the expression of TLR7 by immunohistochemistry and immunofluorescence., Results: We found that TLR7 was not expressed by the tumor tissue of SCC, BCC, and BSC, but by inflammatory cells located within the tumoral and/or peritumoral tissue. Whereas the overall expression of TLR7 did not differ between BCC and SCC (30.4% vs. 45.8%, respectively), we found that within the group of SCC, the well-differentiated SCC showed strong tumoral and/or peritumoral immunocellular TLR7 reactivity in contrast to the poorly differentiated SCC (73.33% vs. 11.1%, respectively). Besides, immunofluorescence double staining revealed the expression of TLR7 in immune cells closely interacting with T cells and natural killer cells., Conclusions: In contrast to genomic data, we did not find a general difference between baseline TLR7 expression of SCC and BCC on the protein level. Nevertheless, the expression of TLR7 by the inflammatory infiltrate associated with SCC may correlate with the degree of differentiation of SCC possibly indicating better outcome.