Treatment Of Solid Cancers Research Articles

Dysthyroidism during immune checkpoint inhibitors is associated with improved overall survival in solid tumors: Data-mining of 1,382 electronic patient records.

2659 Background: Medical treatment of solid tumors cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune-related adverse events (irAE) are challenging in routine practice. Dysthyroidism is the most common endocrine irAE and small series suggest that dysthyroidism might be associated with ICI efficacy. This led us to explore the association between ICI-induced dysthyroidism and overall survival (OS) in a large cohort of solid tumor patients (pts) using data mining of electronic patient records (EPR). Methods: ConSoRe is a new generation data analytics solution using natural language processing to search aggregated data and perform advanced data mining. It was used for data extraction from EPR of pts treated with ICI for solid tumors in Institut Paoli-Calmettes (Marseille Cancer Center, France), with validation using manual screening of 28.8% EPR. All dysthyroidism were verified and only dysthyroidism ICI-induced were retained. Survival analyses were performed by Kaplan-Meier method and compared using the log-rank test (survminer R package). In the uni/multivariate analysis, the Cox proportional-hazards model was used to estimate the variables associated with OS, using hazard ratio (HR) and its associated 95% confidence interval. Results: Data extraction identified 1,385 pts treated with ICI in 2011-2021. Dysthyroidism was observed in 90 pts (6.5%), including 22 hyperthyroidism (24%), 36 hypothyroidism (40%) and 32 hyperthyroidism and hypothyroidism (36%). In this cohort, 81 % of the dysthyroidism were related to PD(L)-1 inhibitors and 19 % to CTLA-4/PD(L)-1 inhibitors combination. No statistical difference was observed in term of tumor location between patients with or without dysthyroidism. Dysthyroidism was associated with improved OS (HR=0.46, 95%CI 0.29-0.70, p=0.0005) with a median OS of 65 months (mo) vs. 30 mo in patients without dysthyroidism. Survival impact of dysthyroidism was consistent using a 2-mo landmark analysis, fixed on median time to dysthyroidism. In multivariate analysis including sex, age, tumor localization, line numbers and type of ICI, dysthyroidism was independently associated with an improved OS (HR=0.49, 95%CI 0.32-0.75, p=0.001), as presented in the Table. Conclusions: Data mining identified a large number ICI-induced dysthyroidism, associated with an improved OS. The onset of dysthyroidism might help oncologist detecting patients more likely to benefit from ICI. [Table: see text]

Booster third dose of SARS-CoV-2 vaccine effectively lifts the waning immune response of solid cancer patients.

e18791 Background: Since cancer patients (pts) are at increased risk of severe morbidity and mortality due to COVID-19, SARS-CoV-2 vaccination is crucial to prevent severe disease course. The efficacy and longevity of vaccine protection, however, is still in question. Methods: In this prospective observational study we assessed immunogenicity of cancers patients on active treatment for solid cancers in two Slovenian Oncology Centres receiving SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum; before, after first and second dose, 3 and 6 months (mo) after complete primary course of vaccination and 1 mo after the 3rd booster dose. Samples with ≥ 175 ng/ml were considered positive. Results: There were 125 pts included in the study, 112 completed the primary course of vaccination with 2 vaccine doses and 34 received the booster 3rd dose. Out of 34 pts receiving booster 3rd dose, the majority received mRNA based vaccines (88%) for the primary course of vaccination and all patients received mRNA based vaccines for the booster 3rd dose. Median time from 2nd to booster 3rd dose of vaccine was 6.75 mo, median age of pts was 66 yrs and 59% were male. Patients were receiving chemotherapy (ChT), immune checkpoint inhibitors (IO) or targeted therapy (TT) in 9%, 56% and 35%, respectively. They achieved seroconversion in 94% after the 2nd and in 97% after the 3rd booster dose. Overall, the median anti-SARS-CoV-2 S1 IgG titer was 11,191 ng/ml (mean 25,394; range 0 – 100,000) after complete primary course of vaccination and 1892 ng/ml (mean 6413; range 0 – 72,000) 6 mo after, P < 0.0001. However anti-SARS-CoV-2 S1 IgG antibodies increased significantly after the 3rd booster dose with median antibody value 51,310 ng/ml (mean 51,787; range 0 – 100,000), P < 0.001. Only one pt in this group got infected with SARS-CoV-2 and had a mild disease course. Conclusions: Cancer pts treated for solid malignancies achieve a high rate of seroconversion through the primary course of vaccination. However, significant waning of immunity against SARS-CoV-2 is observed 6 months thereafter, which can be potentiated with additional 3rd booster dose of vaccine.

Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib.

The anti-diabetic drug metformin is currently tested for the treatment of hematological and solid cancers. Proteasome inhibitors, e.g., Bortezomib, are approved for the treatment of multiple myeloma and mantle cell lymphoma but are also studied for lung cancer therapy. We here analyzed the interaction of the two drugs in two cell lines, namely the mantle cell lymphoma Jeko-1 and the non-small-cell lung cancer (NSCLC) H1299 cells, using proliferation and survival assays, native-gel analysis for proteasome activity and assembly, and expression analysis of proteasome assembly factors. Our results demonstrate that metformin treatment induces resistance of cancer cells to the proteasome inhibitor Bortezomib by impairing the activity and assembly of the 26S proteasome complexes. These effects of metformin on proteasome inhibitor sensitivity in cancer cells are of potential relevance for patients that receive proteasome inhibitor therapy.

Specificity of Binding and Antitumor Efficacy of a Covalent Microtubule Stabilizer

Microtubule stabilizers, including the taxanes paclitaxel and docetaxel, are a mainstay in the treatment of solid tumors, including breast and ovarian cancers. Although these agents are often effective as first‐line therapy, they are susceptible to common drug resistance mechanisms, including the upregulation of drug efflux pumps. Therefore, there is a critical need to develop novel classes of microtubule targeted agents that retain activity in taxane‐resistant settings. The C22,23‐epoxy taccalonolides are a class of plant‐derived microtubule stabilizers that covalently and irreversibly bind microtubules, allowing them to retain efficacy in a variety of taxane‐resistant cancer models. We employed cellular‐based binding studies to fully map the taccalonolide pharmacophore and confirm the target specificity of this covalent compound. The identification of β‐tubulin residues that are critical for taccalonolide binding in a cellular context has provided the opportunity to generate functional taccalonolide mimetics through a synthetically tractable approach.Herein, we demonstrate that taccalonolide AF is less susceptible to p‐glycoprotein‐mediated drug efflux than paclitaxel in two separate ovarian cancer models and that it has superior cellular persistence after drug washout, likely due to irreversible target engagement. While taccalonolide AF demonstrated potent and persistent in vivo antitumor efficacy against the taxane‐resistant NCI/ADR‐RES ovarian cancer model as a flank xenograft when administered systemically, it was associated with a narrow therapeutic window. Additional studies showing that intratumoral injection of the taccalonolides into flank tumors provided long‐term antitumor efficacy months after the final dose prompted a study of their utility in the targeted delivery to a disseminated orthotopic ovarian cancer model representing localized metastasis. Indeed, we found that taccalonolide‐treated animals showed a significant decrease in micrometastasis of taxane‐resistant ovarian cancer cells to the spleen, as detected by quantitative RT‐PCR, without any evidence of systemic toxicity. We propose that the irreversible mechanism of microtubule stabilization elicited by the taccalonolides has the unique potential for intraperitoneal treatment of locally disseminated taxane‐resistant disease, which represents a significant unmet clinical need in the treatment of ovarian cancer patients.

Emerging Role for 7T MRI and Metabolic Imaging for Pancreatic and Liver Cancer.

Advances in magnet technologies have led to next generation 7T magnetic resonance scanners which can fit in the footprint and price point of conventional hospital scanners (1.5–3T). It is therefore worth asking if there is a role for 7T magnetic resonance imaging and spectroscopy for the treatment of solid tumor cancers. Herein, we survey the medical literature to evaluate the unmet clinical needs for patients with pancreatic and hepatic cancer, and the potential of ultra-high field proton imaging and phosphorus spectroscopy to fulfil those needs. We draw on clinical literature, preclinical data, nuclear magnetic resonance spectroscopic data of human derived samples, and the efforts to date with 7T imaging and phosphorus spectroscopy. At 7T, the imaging capabilities approach histological resolution. The spectral and spatial resolution enhancements at high field for phospholipid spectroscopy have the potential to reduce the number of exploratory surgeries due to tumor boundaries undefined at conventional field strengths. Phosphorus metabolic imaging at 7T magnetic field strength, is already a mainstay in preclinical models for molecular phenotyping, energetic status evaluation, dosimetry, and assessing treatment response for both pancreatic and liver cancers. Metabolic imaging of primary tumors and lymph nodes may provide powerful metrics to aid staging and treatment response. As tumor tissues contain extreme levels of phospholipid metabolites compared to the background signal, even spectroscopic volumes containing less than 50% tumor can be detected and/or monitored. Phosphorus spectroscopy allows non-invasive pH measurements, indicating hypoxia, as a predictor of patients likely to recur. We conclude that 7T multiparametric approaches that include metabolic imaging with phosphorus spectroscopy have the potential to meet the unmet needs of non-invasive location-specific treatment monitoring, lymph node staging, and the reduction in unnecessary surgeries for patients undergoing resections for pancreatic cancer. There is also potential for the use of 7T phosphorous spectra for the phenotyping of tumor subtypes and even early diagnosis (<2 mL). Whether or not 7T can be used for all patients within the next decade, the technology is likely to speed up the translation of new therapeutics.

Synthesis of gold nanoparticles using extract of Carica papaya fruit: Evaluation of its antioxidant properties and effect on colorectal and breast cancer cells

Green synthesis of gold nanoparticles (AuNPs) is a fast-growing and eco-friendly approach in the field of biomedical research. The present study reports the synthesis of AuNPs using unripe Carica papaya fruit (CPf) extract and its possible antioxidant and anti-cancer activities. Parameters such as plant extract concentration, reaction pH, temperature, size and morphology of the AuNPs were examined using UV–Vis absorption spectroscopy, dynamic light scattering (DLS) and high resolution transmission electron microscope (HRTEM). The in vitro antioxidant activities were estimated using total antioxidant capacity assay and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The anti-proliferative activity of CPf and CPf-AuNPs were assessed against different cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction assay. The CPf-AuNPs showed a characteristic absorption peak at 529 nm, while the HRTEM analysis revealed spherically-shaped AuNPs with an average size of 12 ± 2.31 nm. The antioxidant activities of CPf-AuNPs were in a concentration dependent manner. The CPf-AuNPs showed cytotoxic effects against different cancer cells (HT-29 and MDA-MB-231) and non-cytotoxic to normal human fibroblast cells (KMST-6), at various concentrations. It can be concluded based on the results of this study that CPf-AuNPs demonstrated antioxidant and anti-cancer properties, which give an insight to the development of potential drug molecules for the treatment of various solid cancers.

Price changes and within-class competition of cancer drugs in the USA and Europe: a comparative analysis.

Cancer drugs are a major component of pharmaceutical spending in the USA and Europe. The number of approved cancer drugs continues to increase. More new drugs with overlapping mechanisms of action and similar approved indications might be expected to decrease prices within drug classes. We compared patterns of price changes for cancer drugs within the same class in the USA and in two European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. For this comparative analysis, we identified cancer drugs approved for the treatment of solid cancers in the USA and Europe (Germany and Switzerland) between Jan 1, 2009, and Dec 31, 2020, using the US Food and Drug Administration's Drugs@FDA database and the European Medicines Agency's publicly available database. We considered cancer drugs as within-class competitors if they were approved for the same indication and had the same biological mechanism. We calculated monthly treatment prices for each drug, median price changes at launch and over time, and differences within and across drug classes. European price data were converted to US dollars by applying the exchange rates on Dec 1, 2020, and prices were adjusted for inflation. Median changes in the drugs' monthly treatment prices at 2 and 4 years after market entry across and within drug classes were also assessed. For the USA, correlations in relative price changes between all pairs of drugs within and across drug classes were calculated with Spearman's rank correlation. Our study cohort comprised 12 drug classes covering nine indications. With the exception of one drug, increasing prices were observed within and across all drug classes in the USA (median 6·07% [range -3·60 to 33·83] 2 years after market entry, and 15·31% [-4·15 to 54·64] 4 years after market entry). By contrast, in Europe, prices generally decreased over time or did not increase more than inflation (2 years after market entry: -21·01% [range -50·72 to 12·71] in Germany and -1·48% [-26·81 to 1·69] in Switzerland; 4 years after market entry: -25·54% [-51·81 to 11·63] in Germany and -13·02% [-43·83 to 18·31] in Switzerland). In the USA, most prices changes within and across drug classes occurred at the end and beginning of the year (ie, from Dec 1 to Jan 31). In the USA, correlation for price changes was r=0·29 (SD 0·36) for within-class drugs and r=0·28 (0·36) for drugs across drug classes. Competition within classes of cancer drugs generally did not constrain rising prices in the USA. Price negotiations, as practised in Germany or Switzerland, could help address the high prices of cancer drugs in the USA. Swiss Cancer Research Foundation (Krebsforschung Schweiz), Swiss National Science Foundation, and Arnold Ventures.

Platinum-Based Chemotherapy ‘Rechallenge’ in Advanced Non-ovarian Solid Malignancies

Platinum-based chemotherapy forms the backbone of treatment for many solid cancers. However, resistance inevitably develops in those with advanced disease. Platinum rechallenge is a well-established concept in the management of ovarian cancer, small cell lung cancer and germ cell tumours. In other solid malignancies there is a lack of quality evidence to support platinum rechallenge, yet it is a widely adopted strategy. Often, patients are within the last year of life, making questions of efficacy, treatment-related toxicity and quality of life critical factors for treatment recommendations. In this overview we appraise the available evidence for platinum rechallenge and strategies being developed to attempt resensitisation of tumours to platinum-based chemotherapy.

Evaluation of PD-L1 Expression in Undifferentiated Pleomorphic Sarcomas, Liposarcomas and Chondrosarcomas.

Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan–Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.

Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis.

These findings demonstrate a novel role for G9a and EZH2 histone methyltransferases in suppressing apoptosis, which can be targeted with small molecule inhibitors as a potential approach to improve solid cancer treatment.

Neutral ceramidase deficiency protects against cisplatin-induced acute kidney injury

Cisplatin is a commonly used chemotherapeutic for the treatment of many solid organ cancers; however, its effectiveness is limited by the development of acute kidney injury (AKI) in 30% of patients. AKI is driven by proximal tubule cell death, leading to rapid decline in renal function. It has previously been shown that sphingolipid metabolism plays a role in regulating many of the biological processes involved in cisplatin-induced AKI. For example, neutral ceramidase (nCDase) is an enzyme responsible for converting ceramide into sphingosine, which is then phosphorylated to become sphingosine-1-phosphate, and our lab previously demonstrated that nCDase knockout (nCDase−/−) in mouse embryonic fibroblasts led to resistance to nutrient and energy deprivation–induced cell death via upregulation of autophagic flux. In this study, we further characterized the role of nCDase in AKI by demonstrating that nCDase−/− mice are resistant to cisplatin-induced AKI. nCDase−/− mice display improved kidney function, reduced injury and structural damage, lower rates of apoptosis, and less ER stress compared to wild-type mice following cisplatin treatment. Although the mechanism of protection is still unknown, we propose that it could be mediated by increased autophagy, as chloroquine treatment resensitized nCDase−/− mice to AKI development. Taken together, we conclude that nCDase may represent a novel target to prevent cisplatin-induced nephrotoxicity.

Radiotherapy resistance: identifying universal biomarkers for various human cancers.

Radiotherapy (RT) is considered as a standard in the treatment of most solid cancers, including glioblastoma, lung, breast, rectal, prostate, colorectal, cervical, esophageal, and head and neck cancers. The main challenge in RT is tumor cell radioresistance associated with a high risk of locoregional relapse and distant metastasis. Despite significant progress in understanding mechanisms of radioresistance, its prediction and overcoming remain unresolved. This review presents the state-of-the-art for the potential universal biomarkers correlated to the radioresistance and poor outcome in different cancers. We describe radioresistance biomarkers functionally attributed to DNA repair, signal transduction, hypoxia, and angiogenesis. We also focus on high throughput genetic and proteomic studies, which revealed a set of molecular biomarkers related to radioresistance. In conclusion, we discuss biomarkers which are overlapped in most several cancers.

Immunotherapy in pancreatic cancer—an emerging role: a narrative review

Immunotherapy is the fastest growing branch in oncology that have already revolutionized the treatment of few solid cancers. The number of immunotherapy trials for pancreatic cancer (PC) is growing but the vast number of different agents used make it difficult to comprehend a possible success trait of a certain type of immunotherapy. The aim of this review is to summarize and critically evaluate the outcome of immunotherapy trials for PC intended to aid the comprehensiveness for the treating physicians. A PubMed search was performed to identify clinical trials in patients with PC, published in English from year 2000 to June 2021 and using combination of the terms immunotherapy, PC, and cross-checked the bibliography of the revised literature as the dublettes have been removed. Studies were divided into three groups depending on what immune components have been applied: passive products (peptides, antibodies, etc.), antigen-presenting cells, and adoptive cell transfer trials. The vast majority of trials, including those from most recent years, used passive products of the immune system-peptide vaccines and antibodies. The administration was often parallel to chemotherapy that was prevalently gemcitabine-based. Although immunological responses have been detected, the clinical efficacy was very limited. Trials with check point inhibitors did not show survival advantage. Dendritic cell (DC) vaccines have been associated with some clinical objective response and prolonged survival in few patients with delayed type hypersensitivity reactions. Trials with adoptive transfer therapy are lacking. The very few trials with lymphokine-activated killer (LAK)/cytokine-induced killer (CIK) cells tested only in Asian population have resulted in some clinical effects with prolonged survival. In none of the trials have the patients been preconditioned before receiving immunotherapy. Although the clinical effectiveness in the majority of the reported trials has been limited, the immunological effects observed in almost all trials show a proof of concept-that immunotherapy can work. Careful re-evaluation of the clinical premises and focus on combination and cell therapy may be the way to achieve improved survival by immunotherapy in PC.

Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors.

Simple SummaryFluoropyrimidines represent the backbone of many combination chemotherapy regimens for the treatment of solid cancers but are still associated with toxicity and mechanisms of resistance. In this review, we focused on the epigenetic modifiers histone deacetylase inhibitors (HDACis) and on their ability to regulate specific genes and proteins involved in the fluoropyrimidine metabolism and resistance mechanisms. We presented emerging preclinical and clinical studies, highlighting the mechanisms by which HDACis can prevent/overcome the resistance and/or enhance the therapeutic efficacy of fluoropyrimidines, potentially reducing their toxicity, and ultimately improving the overall survival of cancer patients.Although fluoropyrimidines were introduced as anticancer agents over 60 years ago, they are still the backbone of many combination chemotherapy regimens for the treatment of solid cancers. Like other chemotherapeutic agents, the therapeutic efficacy of fluoropyrimidines can be affected by drug resistance and severe toxicities; thus, novel therapeutic approaches are required to potentiate their efficacy and overcome drug resistance. In the last 20 years, the deregulation of epigenetic mechanisms has been shown to contribute to cancer hallmarks. Histone modifications play an important role in directing the transcriptional machinery and therefore represent interesting druggable targets. In this review, we focused on histone deacetylase inhibitors (HDACis) that can increase antitumor efficacy and overcome resistance to fluoropyrimidines by targeting specific genes or proteins. Our preclinical data showed a strong synergistic interaction between HDACi and fluoropyrimidines in different cancer models, but the clinical studies did not seem to confirm these observations. Most likely, the introduction of increasingly complex preclinical models, both in vitro and in vivo, cannot recapitulate human complexity; however, our analysis of clinical studies revealed that most of them were designed without a mechanistic approach and, importantly, without careful patient selection.

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The anti-diabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of anti-apoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

Antiproliferative pharmacophore azo-hydrazone analogue BT-1F exerts death signalling pathway targeting STAT3 in solid tumour.

Anomalous activation of intra-cellular signalling cascades confers neoplastic properties on malignant cells. The JAK2/STAT3 proteins play a pivotal role in the pathogenesis of most of the solid malignancies. The over expression of STAT3 in these tumours results in an evasion of apoptosis and thereby pathogenesis. Hence, strategy to target STAT3 to regress tumour development is an emerging new concept. As an approach, anti-neoplastic drug, Azo-hydrozone analogue, BT-1F with potential anti-proliferative effect was evaluated to demonstrate its capacity to counteract STAT3 signal with mechanistic approach. Cell based screening for cytotoxicity was performed through MTT, LDH and Trypan blue. The BT-1F induced anti-clonogenic property by clonogenic assay. The apoptotic capacity was examined by crystal violet staining, flow cytometry, Annexin-FITC, DAPI and TUNEL assay. The altered signalling events were studied using immunoblot. The drug-induced anti-tumour effect was evaluated in an in-vivo solid tumour model and molecular interaction was further validated by in-silico studies. The BT-1F exerts chemo-sensitivity specifically against EAC and A549 cells without altering its normal counterpart. The anti-proliferative/anti-clonogenic effect was due to the induction of apoptosisthrough inhibition of STAT3Tyr705 signal. Eventuallydownstream signalling proteins p53, Bax, Bad and Bcl-xL were significantly altered. Further in-vivo experimental results validated in-vitro findings.Thecomputational approaches assuresthe BT-1F efficiencyin binding with STAT3. Systemic validation of STAT3 target drug, BT-1F in in-vitro, in-silico and in-vivo models has promising strategy for solid cancer treatment.

Immune-Related Pneumonitis Was Decreased by Addition of Chemotherapy with PD-1/L1 Inhibitors: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials (RCTs).

Purpose: Immune-related pneumonitis (IRP) has attracted extensive attention, owing to its increased mortality rate. Conventional chemotherapy (C) has been considered as an immunosuppressive agent and may thus reduce IRP’s risk when used in combination with PD-1/L1 inhibitors. This study aimed to assess the risk of IRP with PD-1/L1 inhibitors plus chemotherapy (I+C) versus PD-1/L1 inhibitors alone (I) in solid cancer treatment. Method: Multiple databases were searched for RCTs before January 2021. This NMA was performed among I+C, I, and C to investigate IRP’s risk. Subgroup analysis was carried out on the basis of different PD-1/L1 inhibitors and cancer types. Results: Thirty-one RCTs (19,624 patients) were included. The I+C group exhibited a lower risk of IRP in any grade (RR, 0.60; 95% CI, 0.38–0.95) and in grade 3–5 (RR, 0.44; 95% CI, 0.21–0.92) as opposed to the I group. The risk of any grade IRP with PD-1 plus chemotherapy was lower than that with PD-1 monotherapy (RR, 0.50; 95% CI, 0.28–0.89), although grade 3–5 IRP was similar. There was no statistically meaningful difference in the risk of any grade IRP between PD-L1 plus chemotherapy and PD-L1 inhibitors monotherapy (RR, 0.95; 95% CI, 0.43–2.09) or grade 3–5 IRP (RR, 0.71;95% CI, 0.24–2.07). In addition, compared with the I group, the I+C group was correlated with a decreased risk in IRP regardless of cancer type, while a substantial difference was only observed in NSCLC patients for grade 3–5 IRP (RR, 0.39; 95% CI, 0.15–0.98). Conclusion: In comparison to PD-1/L1 inhibitor treatment alone, combining chemotherapy with PD-1/L1 inhibitors might reduce the risk of IRP in the general population. Furthermore, PD-1 inhibitors in combination with chemotherapy were correlated with a decreased risk of IRP compared to PD-1 inhibitor treatment alone. In contrast to the I group, the I+C group exhibited a lower risk of IRP, especially for NSCLC patients.

Antibacterial Activity of Pharmaceutical-Grade Rose Bengal: An Application of a Synthetic Dye in Antibacterial Therapies.

Rose bengal has been used in the diagnosis of ophthalmic disorders and liver function, and has been studied for the treatment of solid tumor cancers. To date, the antibacterial activity of rose bengal has been sporadically reported; however, these data have been generated with a commercial grade of rose bengal, which contains major uncontrolled impurities generated by the manufacturing process (80–95% dye content). A high-purity form of rose bengal formulation (HP-RBf, >99.5% dye content) kills a battery of Gram-positive bacteria, including drug-resistant strains at low concentrations (0.01–3.13 μg/mL) under fluorescent, LED, and natural light in a few minutes. Significantly, HP-RBf effectively eradicates Gram-positive bacterial biofilms. The frequency that Gram-positive bacteria spontaneously developed resistance to HP-RB is extremely low (less than 1 × 10−13). Toxicity data obtained through our research programs indicate that HP-RB is feasible as an anti-infective drug for the treatment of skin and soft tissue infections (SSTIs) involving multidrug-resistant (MDR) microbial invasion of the skin, and for eradicating biofilms. This article summarizes the antibacterial activity of pharmaceutical-grade rose bengal, HP-RB, against Gram-positive bacteria, its cytotoxicity against skin cells under illumination conditions, and mechanistic insights into rose bengal’s bactericidal activity under dark conditions.

Initial experience of irreversible electroporation ablation in Brazil: a retrospective analysis

INTRODUCTION: The objective of our study is to present the first Brazilian irreversible electroporation experience in the treatment of solid cancer. MATERIAL AND METHODS: A retrospective study with the ?rst ten patients who underwent percutaneous or surgical IRE to treat solid cancer between March 2021 and May 2021. Preoperative data collection included patient demographics along with previous oncologic treatments. Operative and post-operative assessment involved number of probes, number of pulses, initial and ?nal current and 30-days complications. RESULTS: Primary tumor was locally advanced pancreatic cancer (70%), colorectal hepatic metastasis (20%), and cholangiocarcinoma (10%). All patients had previously undergone chemotherapy with stable disease in 80% and partial response in 20% before IRE. Eighty percent of the procedures was performed surgically and 20% percutaneously CT-guided. The mean procedure time of IRE was 38 minutes. Adverse events occurred in 4 patients (40%), all being grade I-II complications.

Comparative effectiveness of larotrectinib and entrectinib for TRK fusion cancer.

Larotrectinib and entrectinib are tumor-agnostic tropomyosin receptor kinase (TRK) inhibitors that are indicated for the treatment of advanced or metastatic solid tumor cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusions. Regulatory approval of both agents was based on data from single-arm phase 1/2 studies, including tumor-agnostic basket trials. In the absence of randomized controlled trials, there remains a paucity of data to demonstrate the comparative effectiveness of larotrectinib and entrectinib vs established standard-of-care treatments in cancers with NTRK gene fusions. Furthermore, no studies have directly compared the 2 agents. This article reviews what is known about the comparative effectiveness of larotrectinib and entrectinib vs standard therapies in TRK fusion cancer and examines the comparative effectiveness of the 2 TRK inhibitors. Historical and intrapatient comparisons suggest that TRK inhibitors improve disease response compared with preexisting treatments across most tumor histologies; indirect and limited comparisons of phase 1/2 data and preliminary simulation modeling suggest a potential advantage for larotrectinib over entrectinib in terms of clinical response and survival. Although limited, these data provide some insight into the position of these treatments in established treatment paradigms for TRK fusion cancer, a setting where real-world evidence will be slow to accrue due to the rare nature of these tumors but may be the only way in the future to answer the outstanding questions regarding these 2agents. Meanwhile, we need to try to obtain the maximum benefit that can be achieved for our patients using the currently available knowledge.