Clinical evaluation of sintilimab in conjunction with bevacizumab for advanced colorectal cancer with microsatellite stable-type after failure of first-line therapy.

To investigate the effects of a PD-1 inhibitor combined with a bevacizumab monoclonal antibody on tumor immune cells in patients with first-line treatment failure in MSS/pMMR advanced colorectal cancer. Control group consisted of 50 patients treated with the FOLFIRI combined with Bevacizumab regimen. The experimental group consisted of 60 patients treated with the Sintilimab combined with Bevacizumab regimen. By comparing the expression levels of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment, short-term efficacy after treatment, and adverse drug reactions between the two groups, we comprehensively evaluated the impact of Sintilimab combined with Bevacizumab on patients with MSS/pMMR advanced colorectal cancer who failed first-line treatment. There was a statistically significant difference in the percentage of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment between the two groups (P<0.05);Immunohistochemical scoring of CD8+ T lymphocytes, TAMs, and CAFs showed significant differences between the groups post-treatment (P<0.05). The experimental group demonstrated statistically significant differences in immunohistochemical scoring of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment (P<0.05). There was a statistically significant difference in the therapeutic effect between the two groups of tumors (P<0.05). The experimental group had greater PFS, mPFS, ORR, and DCR than did the control group. There was no statistically significant difference in the occurrence rate of drug-related adverse reactions after treatment between the two groups (P>0.05). The results of the Cox proportional hazards model analysis indicate that age, gender, and group are independent risk factors affecting MSS/pMMR advanced colorectal cancer patients treated with second-line therapy in this study. Patients aged ≤60 years, male patients, and those in the experimental group showed better treatment responses in this study. By administering immune checkpoint inhibitors in combination with bevacizumab to patients with advanced colorectal cancer with MSS/pMMR disease for whom first-line treatment failed, not only did the patients' prognosis improve, but the adverse drug reactions were also safe and controllable.

e15078 Background: Immune checkpoint blockades (ICBs) have been approved for colorectal cancer (CRC) with microsatellite instability high (MSI-H). However, 50% to 60% MSI-H and almost 100% microsatellite stability (MSS) CRC patients can’t benefit from ICBs treatment. How to warm these “cold tumor” for boosting response to ICBs is still a problem. We aimed to integrate the expression signatures of T cell activation, exclusion and dysfunction to generate immune microenvironment subtypes which may guide precision immunotherapy. Methods: RNA-Seq of 596 CRC patients from The Cancer Genome Atlas were analyzed. T cell activation, dysfunction and exclusion signatures were calculated from TIDE model algorithm. Unsupervised clustering was used to classify CRC into various immune subtypes. Mann Whitney U test and Kruskal test were used to compare the difference among two or more than two groups. COX regression multivariate analysis was applied to analyze the association of subtypes with overall survival (OS). Results: Compared with 543 patients with MSS, 83 patients had significantly higher expression of T cell activation related genes (including CD8A, CXCL9, CXCL10, GZMB, IFNG et al) and immune checkpoint genes (including PD-L1, PD-1, LAG3 et al.), but lower signatures scores of M2-like tumor-associated macrophage (TAM) and T cell exclusion ( all P value&lt;0.001). Based on expression signatures of myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF), M2-like TAM, cytotoxic T-lymphocytes (CTL) and PD-L1, all the patients were clustered into four subtypes. Cluster 4 was enriched by MSI-H and characterized with high T cell activation and moderate T cell dysfunction and exclusion. Comparatively, another MSI-H enriched Cluster 1 had both high CTL and T cell dysfunction which indicated that activated T cell might be escaped by tumor cell. Cluster 2 and Cluster 3 were enriched by MSS and characterized with moderate T cell activation and high T cell exclusion. In survival analysis, Cluster 4 had prolonged OS (HR [95% CI]=0.46 [0.27-0.80]) compared with Cluster 1, 2 and 3, after adjusted for age, pathological stage, tumor residue, MSI status, BRAF and PIK3CA mutations. In MSS, Cluster 4 also had better prognosis than the other three clusters (HR [95% CI]=0.38 [0.20-0.73]). Conclusions: Our findings provide evidence to guide further patient stratification in ICBs treatment. The distinct immune subtypes of CRC also paved the way of combination immunotherapy based on immune microenviroment to turn “cold tumor” into “hot tumor”.

e14553 Background: The tumor microenvironment (TME) plays a crucial role in tumor growth and progression and has a significant influence on response to therapy. The TME consists of myeloid-derived cells, stroma (e.g. fibroblasts and extracellular matrix (ECM)), and the vasculature that together support tumor growth and progression. Studies in animal models and in humans show that myeloid- derived cells such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) engage in activities that support tumor growth and progression. These cells also promote immune suppression in the TME that blunts the efficacy of the anti-cancer drugs and immune-targeted therapies such as immune checkpoint inhibitors. In addition to MDSCs, cancer-associated fibroblasts (CAFs) in the TME support tumor progression via production of pro-tumor and pro-angiogenic growth-factors, remodeling of the ECM via production of proteases, and suppression of anti-tumor immune function. CAF abundance in the TME is a negative prognostic factor for several solid tumors and is associated with negative outcomes and poor response to immune-targeted therapies like immune checkpoint inhibitors. ONP-302 nanoparticles fabricated from biodegradable poly (lactic-co-glycolic acid)(PLGA) polymer have been previously described in the literature for the treatment of acute inflammatory conditions via immuno-modulatory effects on myeloid derived cells. Here, we evaluated the efficacy of ONP-302 nanoparticles at inhibiting tumor growth via targeted inhibition of myeloid-derived cells and reshaping of the TME. Methods: ONP-302 anti-tumor efficacy was evaluated in syngeneic mouse tumor models using both immunocompetent and immunodeficient mice. We examined the effect of ONP-302 treatment tumor growth kinetics and effects on the major cellular constituents of the TME such as myeloid-derived cells and CAFs. Results: Therapeutic treatment with ONP-302 in vivo resulted in a marked delay in tumor growth in three different syngeneic tumor models in immunocompetent mice. ONP- 302 efficacy persisted with depletion of CD8+ T cells in immunocompetent mice and also was effective in immune deficient mice. We found ONP-302 treatment caused a gene expression shift in TAMs toward the pro-inflammatory M1 type and substantially inhibited the expression of genes associated with the pro-tumorigenic function of CAFs. ONP-302 also induced apoptosis in CAFs in the TME. Conclusions: Our data indicate that the slowing of tumor growth after ONP-302 treatment is due to disruptions in known signaling pathways involving TAMs and CAFs, pathways typically supporting tumor growth. These data taken in concert indicate the activity of ONP-302 is pleotropic and affects multiple pathways.

Background/Aim: Tumor microenvironment plays supportive roles for cancer cells of proliferating, invading and spreading systemically. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are deemed to be essential constituents forming cancer-surrounding niche. However, the cross-talks between CAFs and TAMs in the settings of hepatocellular carcinoma (HCC) has yet to be deciphered. The lack of a reliable system simulating in vivo-microenvironment has been one of the obstacles hampering investigation of CAFs and TAMs. By using the newly-established model consisting of fibroblasts directly recovered from the disease liver, we aimed to clarify the mechanisms of CAFs modulating the macrophage differentiation and malignant potential of cancer cells in order to search for therapeutic targets. Methods: We enrolled three patients who underwent the resection of HCC and two who did living donor liver transplantation. From the resected or the explanted livers, fibroblasts from cancer and its adjacent tissues were separated by tissue digestion. We examined their ontogeny by the expression of fibroblast-specific markers. For the functional analyses, we examined invasiveness of HuH7 cells on matrigel and migratory response of monocytes in the presence of conditioned media (CM) from the fibroblasts. We assessed the phenotypes/function of macrophages after the differentiation from monocytes in the presence of M-CSF and the CM. We comprehensively assayed cytokine/chemokine in the CM to identify functionally-relevant factors. Results): After the culture, we established three types of fibroblasts, CAFs, cirrhotic liver fibroblasts (LCFs) and non-cancerous fibroblasts (NFs). All of these were positive for vimentin, SMA, PDGFRa and FAP (&amp;gt;99%), confirming that they are ontologically fibroblasts instead of being HCC, hepatocytes or biliary cells. The invasiveness of HuH7 were higher in the presence of the CAF- or LCF-CM compared to those with NF-CM. Similar superiority was observed with the CAF- or LCF-CM in the migratory ability of monocytes. In the process of macrophage differentiation, the CAF- or LCF-CM were capable of polarizing macrophages into TAM/M2 subtypes, as evidenced by their higher production of IL-10 but lesser IL-12. In the CAF- or LCM-CM, the levels of IL6, IL-8, CCL2 and GRO were higher than those in the NF-CM. Conclusion: The CAFs as well as LCFs directly recovered from the cirrhotic liver are functionally competent of driving TAM/M2 differentiation and providing malignant potential to cancer cells, thereby tuning the microenvironment favoring HCC development. Citation Format: Yohei Mano, Tatsuya Kanto, Hirotaka Shoji, Schiyo Yoshio, Masaya Sugiyama, Yosuke Osawa, Kiminori Kimura, Ken Shirabe, Yoshihiko Maehara, Masashi Mizokami. Cancer-associated or cirrhosis fibroblasts recovered from hepatocellular carcinoma promote macrophages and cancer cells to progressive phenotype. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3354. doi:10.1158/1538-7445.AM2015-3354

Background: Persistent hyperglycemia in diabetes mellitus (DM) is considered the leading cause of morbidity and mortality associated with both microvascular and macrovascular complications, having a greater economic impact. This study aimed to assess the impact of socioeconomic status, prescribing patterns, and patient compliance in type 2 diabetes mellitus patients. Method: This study was carried out at the Department of Medicine and Diabetic Clinic of Hakeem Abdul Hameed (HAH) Centenary Hospital at Hamdard University, New Delhi, India. We conducted a prospective observational study on prescribing patterns and monitoring adverse drug reactions (ADRs) in patients with type 2 DM (T2DM) under standard care. We enrolled 150 confirmed cases, and data was obtained from pre-validated questionnaires and then coded and analyzed to observe the association between variables. Results: The glycosylated haemoglobin level in 56% of the cases was between 6.4 to 8.0, and cardiovascular complications were observed as the major comorbidities. 45.33 % of the cases were on mono drug therapy, and metformin (23. 52 %) was the drug of choice, followed by glimepiride (23.52 %). Among the dual drug therapies, sitagliptin with metformin and triple-drug therapy, glimepiride concurrent with metformin and voglibose was the most preferred drug in the treatment of T2DM. Sitagliptin was observed to be a major patient burden (46.213 USD). In only 7.33 % of the cases, we observed definite ADR in T2DM patients. Underprivileged awareness, mainly due to low literacy, was a major concern in the development of new cases of T2DM. Conclusion: We observed better patient compliance; however, a disease awareness program must be implemented. The use of oral hypoglycaemic drugs is still dominant in clinical practice and cardiovascular disorders as comorbidities emerge as a greater challenge in terms of patient outcome and cost burden.

BackgroundWe aimed to evaluate the clinical significance of microvessel density (MVD), lymphatic vessel density (LVD), and cancer-associated fibroblasts (CAFs) in relation to tumor location in advanced colorectal cancer (CRC).MethodsUsing immunohistochemistry, we examined 181 advanced CRC patients for CD31 and D2-40 to measure MVD and LVD, respectively, α-smooth muscle actin (SMA) and desmin to identify CAFs, and PTEN to examine genetic changes of CAFs. To evaluate the regional heterogeneity of these properties, we examined tissue from four sites (the center and periphery of the primary cancer, a distant metastasis, and a lymph node metastasis) in each patient.ResultsMVD, LVD, and CAFs showed significant heterogeneity with respect to the tumor location. LVD was the greatest in the center of the primary cancers and the amount of CAFs was the lowest in distant metastases. In distant metastases, those from the lung had higher LVD and MVD, but fewer CAFs than those from the liver, peritoneum, or ovary. Patients with low MVD and LVD in the center of the primary cancer had worse outcomes and patients with few CAFs in distant metastases and in the primary tumor had a lower survival rate. PTEN expression in CAFs in distant metastases was lost in 11 of 181 CRC patients (6.1%), which was associated with a worse prognosis.ConclusionsThe microenvironment, including cancer-associated microvasculature and fibroblasts, is heterogeneous with respect to the tumor location in CRC patients. Therefore, heterogeneity of microenvironments should be taken into account when managing CRC patients.

e15582 Background: An increasing number of patients with advanced colorectal cancer tend to receive third-line treatment. Although there are several treatment options, concerns about efficacy and adverse events still remained. Regorafenib seems to enhance the effect of immune checkpoint inhibitors (ICIs) by modulate tumor microenvironment. In the absence of stage III clinical trial data, the real-world study might show certain clinical value. Methods: From Aug 2019 to June 2020, 23 advanced MSS colorectal cancer patients underwent third-line treatment of regorafenib combined with ICI. All patients received regorafenib 80 mg QD for 21 days, as a 28-day cycle, combined with ICIs until disease progression or intolerable adverse events. We retrospectively collected the overall response data, survival data and adverse events data from these patients. Results: The characteristics of all 23 patients is shown in the table. All patients had received at least 2 lines of prior systemic chemotherapy, the median time from diagnosis to third-line treatment was 31 months. The overall response rate was 26% (6/23), including one complete response. Almost all the responders were male (5/6) and with pulmonary metastasis (5/6). The disease control rate was 60% (14/23). The progression free survival ranges from 0.69 month to 19.3 months (median 4.8 months), with 6 patients continued response and constantly treatment. Duration of response range from 6.4 months to 19.4 months. Serious adverse events were hepatitis occurred in two patients and lead to the termination of subsequent anticancer therapy, which was considered to be related to immunotherapy. Conclusions: Regorafenib combined with ICIs might favor a certain group of advanced colorectal cancer patients, with a acceptable response rate and comparatively long duration of response. Interestingly, this retrospective pilot study was in consistence with that of REGONIVO trials to some extent for that the male patients with pulmonary metastasis appeared to response better. Key words: colorectal cancer; regorafenib; immune check point inhibitors Clinical characteristics of 23 patients.[Table: see text]

Immunotherapy, especially immune checkpoint inhibitors, has revolutionized the standard-of-care of multiple types of tumors. For colorectal cancer, the clinical development of immune checkpoint inhibitors is mainly separated according to the status of microsatellite instability or mismatch repair in a tumor. High-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer generally has a tumor microenvironment with infiltration of T cells, associated with a favorable response to immune checkpoint inhibitors. Immune checkpoint inhibitors, including pembrolizumab (anti-PD-1 inhibitor) and nivolumab (anti-PD-1 inhibitor) with or without ipilimumab (anti-CTLA-4 inhibitor), have been integrated into the standard-of-care for high-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer. Conversely, limited T-cell infiltration in the tumor microenvironment of microsatellite stable/proficient mismatch repair metastatic colorectal cancer, which constitutes the majority of metastatic colorectal cancer, is assumed to be a major resistant mechanism to immune checkpoint inhibitors. Currently, clinical trials to improve the clinical activity of immune checkpoint inhibitors by immunomodulation are ongoing for metastatic colorectal cancer. Furthermore, immune checkpoint inhibitors are under development in neoadjuvant and/or adjuvant setting. Here, we review the existing clinical data with ongoing trials and discuss the future perspectives with a focus on the immunotherapy of colorectal cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer, offering durable clinical benefits to a subset of patients. However, long-term survival is heterogeneous, and effective risk-stratification biomarkers for this subgroup are needed. This study investigated the prognostic significance of baseline serum uric acid (UA) levels in patients with dMMR/MSI-H colorectal cancer undergoing ICI therapy. This retrospective study enrolled 171 patients with advanced dMMR/MSI-H colorectal cancer receiving ICIs (monotherapy or combined with chemotherapy/targeted agents). Serum UA was measured within three days pre-treatment. An optimal UA cut-off was determined by receiver operating characteristic (ROC) curve analysis. Kaplan-Meier estimates and Cox proportional hazards models assessed the UA-overall survival (OS) association. Median follow-up was 21.1 months (range: 1.2-48.0). ROC analysis identified an optimal serum UA threshold of 274 µmol/L (Area Under Curve (AUC) = 0.82; sensitivity = 70.0%; specificity = 70.8%). Patients with UA ≥ 274 µmol/L exhibited significantly shorter OS compared to those with lower UA (Hazard Ratio (HR) = 2.31; 95% CI: 1.04-6.12; p = 0.001). Multivariate analysis confirmed elevated UA as an independent predictor of poorer OS (HR = 2.73; 95% CI: 1.37-6.16; p = 0.015), alongside stage IV disease, concurrent use of multiple ICI agents and the use of immunotherapy in the ≥ 3rd-line setting. Elevated baseline serum UA is associated with poorer long-term survival in patients with dMMR/MSI-H advanced colorectal cancer receiving immunotherapy. As an accessible and cost-effective biomarker, UA shows potential for early risk-stratification and guiding individualized treatment strategies within this immunotherapy-sensitive population.

Background:The aim of this study was to determine the regional heterogeneity and clinicopathological significance of microRNA-21 (miR-21) in advanced colorectal cancer (CRC) patients with distant metastasis.Methods:miR-21 expression was investigated by using locked nucleic acid– fluorescence in situ hybridization in the center and periphery of the primary cancer and in distant metastasis from 170 patients with advanced CRC. In addition, α-smooth muscle actin and desmin were evaluated to identify cancer-associated fibroblasts (CAFs) by using immunohistochemistry.Results:The miR-21 signal was observed in the cancer stroma. The expression of miR-21 (a score of 1–4) in the center and periphery of the primary cancer and in distant metastasis was observed in specimens from 133 (78.2%), 105 (61.8%), and 91 (53.5%) patients, respectively. miR-21 expression was heterogeneous in advanced CRC. Discordance between miR-21 expression in the center of the primary cancer and either the periphery of the primary cancer or distant metastasis was 31.7% or 44.7%, respectively. miR-21 stromal expression in the periphery of the primary cancer was significantly associated with a better prognosis (p=.004). miR-21 expression was significantly associated with CAFs in the center of the primary cancer (p=.001) and distant metastases (p=.041).Conclusions:miR-21 expression is observed in cancer stroma related to the CAF quantity and frequently presents regional heterogeneity in CRC. Our findings indicate that the role of miR-21 in predicting prognosis may be controversial but provide a new perspective of miR-21 level measurement in cancer specimens.

BackgroundThe most effective treatment with immune checkpoint inhibitors (ICIs) is limited to the microsatellite instability high (MSI-H) subgroup of advanced colorectal cancer. ICIs are completely ineffective in microsatellite stabilized (MSS) patients with advanced colorectal cancer. Fruquintinib, a tyrosine kinase inhibitor (TKI) domestically made in China that specifically inhibits vascular endothelial growth factor receptors, is used to treat refractory metastatic colorectal cancer (mCRC). Researches showed that anti-angiogenic therapy combined with immunotherapy induces a long-lasting antitumor immune response. Here, we aimed to evaluate antitumor efficacy and safety of fruquintinib with anti-programmed death-1 (PD-1) antibody toripalimab in Chinese patients with non-MSI-H/mismatch repair proficient (pMMR) mCRC.MethodsThis was a single-arm, single-center, prospective, phase II clinical trial. A total of 19 MSS patients with refractory or advanced mCRC were enrolled They received fruquintinib (5 mg, orally, once daily for 3 weeks followed by 1 week off in 4-week cycles) and toripalimab (240 mg, intravenously administered on day 1 once every 3 weeks) until disease progression or unacceptable toxicity. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), 1-year PFS rate, disease control rate (DCR), and toxicity were reviewed and evaluated. The Cox regression model was used to analyze the influence on OS and PFS.ResultsAmong the 19 patients, the median age was 52 years (range, 30–71 years); 4 patients (21.05%) achieved partial response, 10 patients (52.63%) experienced stable disease, and 4 patients (21.05%) experienced progressive disease. The ORR was 21.05%. The median PFS and OS were 5.98 months and 11.10 months, respectively. Patients with peritoneal metastasis received greater benefit from combination therapy, with a longer PFS (P=0.043) in the univariate analysis. The most common treatment-related adverse reactions were fatigue (57.89%), hepatic dysfunction (42.11%) and hypertension (36.84%). No serious adverse effects or adverse effect-related deaths were reported.ConclusionsOur study provides evidence supporting fruquintinib combined with an anti-PD-1 monoclonal antibody have the better effect than fruquintinib alone in the third-line setting for Chinese patients with MSS advanced colorectal cancer. Primary lesion excision and peritoneal metastasis were independent prognostic factors of PFS. Further well-designed, prospective, large-scale studies are needed to validate this outcome.

We characterized immune cell exclusion in estrogen receptor positive (ER+) breast cancer through the study of spatial relationships among various subsets of cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and other immune cells using a novel in-situ spatial transcriptomic technology. ER+ breast cancer is the most common breast cancer subtype. While endocrine therapy and immune checkpoint inhibitors have considerably reduced relapse and mortality for breast cancer patients, tumor resistance to treatment remains a major challenge. The tumor microenvironment (TME) plays an important role in this mechanism of resistance. Our previous spatial proteomic analysis of ER+ breast FFPE samples demonstrated the intricate relationship between tumor and immunosuppressive cells such as CAFs and TAMs via the CXCR4-CXCL12 axis associated with the exclusion of CD8 T cells from the TME. However, the limited number of antibodies in the panel made it challenging to investigate the diversity of those CAF and TAM populations and better understand their contribution to T cell exclusion. For this purpose, we further characterized the TME of 4 human ER+ breast cancer FFPE cores using the Xenium in-situ transcriptomic platform with a breast cancer-focused panel of 280 genes from 10x Genomics plus 100 additional genes selected from literature and publicly available single cell datasets to delineate CAF and TAM sub-populations. Image analysis enabled the quantification and spatial mapping of the target genes within each cell boundary. Cells were manually annotated through unsupervised clustering of over 1 million cells. The cell phenotyping analysis allowed us to annotate major cell types including tumor cells, macrophages, T cells and fibroblasts. With our curated panel, we further characterized CAF and TAM sub-populations by identifying myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen-presenting CAFs (apCAFs) in addition to M1 and M2-like macrophages as reported in the literature. We then performed spatial neighborhood analysis based on the similarity of the cell type composition in the vicinity of each cell. The results showed that myCAFs and M2-like macrophages are found in proximity to tumor cells and may play a role in T-cell exclusion. In addition, iCAFs mainly express CXCL12, a chemokine known to attract immunosuppressive cells such as regulatory T cells and M2-like macrophages as well as repel cytotoxic T cells from infiltrating the tumor via the CXCR4-CXCL12 axis. Overall, our work shows the potential of spatial transcriptomics to elucidate the spatial distribution of cells and their contribution to the immunosuppressive TME, which may enable researchers to improve understanding of tumor biology and drug target discovery efforts. Citation Format: Julien Tessier, Sandra Curras-Alonso, Joon Sang Lee, Fabien Delahaye, Hong Ma, Katie Malley, Dinesh Bangari, Donald Jackson, Angela Hadjipanayis. Spatial characterization of the immunosuppressive tumor microenvironment in estrogen receptor positive breast cancer at single cell level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5485.

Colorectal cancer (CRC) is the second most common cause of cancer mortality, with mismatch repair proficient (pMMR) and/or microsatellite stable (MSS) CRC making up more than 80% of metastatic CRC. Programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) immune checkpoint inhibitors (ICIs) are approved as monotherapy in many cancers including a subset of advanced or metastatic colorectal cancer (CRC) with deficiency in mismatch repair (dMMR) and/or high microsatellite instability (MSI-H). However, proficient mismatch repair and microsatellite stable (pMMR/MSS) cold CRCs have not shown clinical response to ICIs alone. To potentiate the anti-tumor response of PD-L1/PD-1 inhibitors in patients with MSS cold cancer, combination strategies currently being investigated include dual ICI, and PD-L1/PD-1 inhibitors in combination with chemotherapy, radiotherapy, vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors, mitogen-activated protein kinase (MEK) inhibitors, and signal transducer and activation of transcription 3 (STAT3) inhibitors. This paper will review the mechanisms of PD-1/PD-L1 ICI resistance in pMMR/MSS CRC and potential combination strategies to overcome this resistance, summarize the published clinical experience with different combination therapies, and make recommendations for future avenues of research.

We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TBFQ+) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TBFQ+ patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal <2 µg/mL) and AUC0-24 was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.

Background: For decades, it has been observed that mental health is shrouded in stigma and discrimination. The scope, severity, and expense of impairment and costs to people, families, and societies are staggering. Mental illnesses are among the most frequent illnesses, affecting over a quarter of the population in any given year. According to national institute of mental health and neurosciences, Bangalore, the prevalence of schizophrenia has been considered as 4/1000 for all ages and both sexes. Aim and Objectives: The objectives of this study were to as follows: (1) To evaluate adverse drug reactions (ADRs) in patients with schizophrenia who received antipsychotic treatment and (2) to compare ADRs in typical versus atypical antipsychotic agents in schizophrenic patients. Materials and Methods: A total of 50 schizophrenic patients were enrolled for evaluating adverse effects to antipsychotic drugs. During the research, all ethical precautions were taken. All patients were followed up by medical history, history of drugs, and any severity of adverse drug reaction. Causality assessment was graded by Naranjo scale. Result: Among all of the antipsychotic drugs, risperidone (05%), quetiapine (04%), and aripiprazole (04%) have shown lowest propensity to cause serious adverse event. These drugs are most commonly prescribed drugs and are least likely to affect quality of life of patient. However, the risk of extrapyramidal symptoms is lower with olanzapine (05%) than haloperidol (34%) and even in case with risperidone at higher dose (20%). Although atypical antipsychotics such as olanzapine (46%) have shown maximum potential to produce metabolic side effect such as dyslipidemia and hyperglycemia compared to that of other antipsychotics. Conclusion: The most common adverse effects were found with typical and atypical antipsychotics such as weight gain, drowsiness, constipation, sedation, dyslipidemia, and hypotension.