Intravascular large B-cell lymphoma as a covert trigger for hemophagocytic lymphohistiocytosis complicated with capillary leak syndrome: a case report and literature review.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma. Patients with hemophagocytic lymphohistiocytosis (HLH)-associated IVLBCL variants exhibit significantly poor survival. Cytokines play pivotal roles in malignancy-associated HLH as well as in capillary leak syndrome (CLS). The pathogenesis of CLS involves hyperpermeability and transient endothelial dysfunction. Here, we report the first case of HLH-associated IVLBCL variant complicated with CLS. The patient presented with fever, refractory hypoproteinemia, hypotension and severe edema, followed by telangiectasias. Treatment with etoposide and dexamethasone and hydroxyethyl starch-based artificial colloid led to transient improvement. The diagnosis of IVLBCL was confirmed after the sixth bone marrow biopsy. Subsequently, the R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone) regimen was administered and resulted in prompt alleviation of CLS and HLH symptoms. The patient has survived for more than 6 years after combination of immunochemotherapy and autologous peripheral stem-cell transplantation. This case provides some insights into the mechanism and clinical management of IVLBCL complicated with HLH and CLS. Similar cases concerning lymphoma-associated CLSs were also reviewed.

Navigating first-line therapies for extensive-stage small-cell lung cancer: a frequentist network meta-analysis and systematic review.

Aim: To identify the optimal first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Materials & methods: We conducted a network meta-analysis (CRD42023486863) to systematically evaluate the efficacy and safety of eight first-line treatment regimens for ES-SCLC, including 15 clinical trials. Results: Our analysis showed that the PD-1/PD-L1 + etoposide combined with platinum (EP) and PD-L1 + vascular endothelial growth factor (VEGF) + EP regimens significantly enhanced overall survival and progression-free survival, with subgroup analysis revealing that serplulimab ranked as the most promising option for improving overall survival. Integrating anti-angiogenesis drugs into immunochemotherapy presents potential benefits, with an increased incidence of adverse events necessitating further investigation. Conclusion: Our findings offer valuable insights for future research and for developing more effective treatment strategies for ES-SCLC, underscoring the critical need for continued innovation in this therapeutic area.

[Box: see text].

Synergistic action of gemcitabine and celecoxib in promoting the antitumor efficacy of anti-programmed death-1 monoclonal antibody by triggering immunogenic cell death.

Background: Emerging evidence suggests that immunogenic chemotherapy not only kills tumor cells but also improves the immune-suppressive tumor microenvironment by inducing immunogenic cell death (ICD), leading to sustained anti-tumor effects. The lack of ICD inducers explored in lung cancer necessitates investigation into new inducers for this context, therefore, this study aims to explore whether the gemcitabine (GEM) and celecoxib can activate the immunogenic chemotherapy progress in lung cancer tissue. Methods: We assessed five chemotherapeutic agents for their ability to trigger ICD using ex vivo and in vivo experiments, including western blotting (WB), flow cytometry, and tumor preventive vaccine assays. Additionally, we evaluated the synergistic effects of GEM, celecoxib, and anti-programmed death 1 monoclonal antibody (aPD-1) in tumor-bearing mice to understand how GEM activates antitumor immunity and enhances immunochemotherapy. Results: GEM was identified as an effective ICD inducer, showing high expression of calreticulin (CRT) and heat shock protein 90 (HSP90). Co-culture with GEM-treated cells [Lewis lung carcinoma (LLC) and CMT-64] enhanced dendritic cell (DC) activity, evidenced by maturation markers and increased phagocytic capacity. Moreover, celecoxib was found to enhance ICD by reducing indoleamine 2,3-dioxygenase 1 (IDO1) expression and increasing reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress. The combination therapy [GEM, celecoxib, and aPD-1 (GCP)] exhibited potent and sustained antitumor activity in immunocompetent mice, with enhanced recruitment of tumor-infiltrating lymphocytes. Conclusions: These findings support the potential use of GCP therapy as a treatment option for lung cancer patients.

Therapeutic liposomal combination to enhance chemotherapy response and immune activation of tumor microenvironment.

Multiple oxaliplatin-resistance mechanisms have been proposed such as increase of anti-inflammatory M2 macrophages and lack of cytotoxic T-cells. Thereby oxaliplatin chemotherapy promotes an immunosuppressive tumor microenvironment and inhibits anti-tumor efficacy. It has been shown that toll-like receptor (TLR) agonists are capable of triggering broad inflammatory responses, which may potentially reduce oxaliplatin-resistance and improve the efficacy of chemotherapy. In this study, we established colorectal tumor-bearing zebrafish and mice, and investigated the effects of TLR agonists and oxaliplatin in macrophage function and anti-tumor T cell immunity as well as tumor growth control in vivo. To increase the potential of this strategy as well minimize side effects, neutral liposomes carrying oxaliplatin and cationic liposomes co-loaded with TLR agonists Poly I:C and R848 were employed for maximum immune activation. Both of two liposomal systems exhibited good physicochemical properties and excellent biological activities in vitro. The combination strategy delivered by liposomes showed more pronounced tumor regression and correlated with decreased M2 macrophage numbers in both zebrafish and mice. Increasing numbers of dendritic cells, DC maturation and T cell infiltration mediated via immunogenic cell death were observed in treated mice. Our study offers valuable insights into the potential of liposomal combination therapy to improve cancer treatment by reprogramming the tumor microenvironment and enhancing immune responses.

[Comparison of Short-term Efficacy of Neoadjuvant Immunotherapy Combined with Chemotherapy and Surgery Alone for Locally Advanced Resectable 
Non-small Cell Lung Cancer].

BACKGROUND: Lung cancer is the cancer with the highest incidence and mortality rates in China, and non-small cell lung cancer (NSCLC) accounts for 80%-85% of all malignant lung tumors. Currently, surgical treatment remains the primary treatment modality for lung cancer. In recent years, the effectiveness of immune checkpoint inhibitors for NSCLC has become a consensus, and neoadjuvant immunochemotherapy (nICT) has shown promising efficacy and safety in early to intermediate stage NSCLC. However, there are fewer studies related to nICT for locally advanced NSCLC. This study aims to evaluate the efficacy and safety of nICT therapy in locally advanced resectable NSCLC. METHODS: 85 confirmed resectable stage IIIA and IIIB patients treated in the Department of Thoracic Surgery, Second Hospital of Lanzhou University, from January 2021 to April 2024, were divided into the nICT group (n=32) and the surgery alone group (n=53). Clinical baseline data, perioperative indicators, postoperative complications, imaging response rate, pathological response rate, incidence of adverse events, and quality of life were compared between the two groups. RESULTS: There were no statistically significant differences in clinical baseline data between the two groups (P>0.05). Incidence of choosing thoracotomy was higher in the nICT group than in the surgery alone group (P=0.002). There were no significant differences in surgical time, intraoperative blood loss, number of dissected lymph nodes, duration of chest tube placement, postoperative hospital stay, and R0 resection rate between the two groups (P>0.05). The overall incidence of postoperative complications was 31.25% in the nICT group and 22.64% in the surgery alone group, with no statistically significant difference (P=0.380). In the nICT group, the objective response rate (ORR) was 84.38%, with 5 cases of complete response (CR)(15.63%), 22 cases of partial response (PR)(68.75%), 15 cases of pathological response rate (pCR)(46.88%), and 11 cases of major pathological reaponse (MPR) (34.38%). During nICT treatment, 12 cases (37.50%) experienced grade 3 treatment-related adverse events, no death induced by adverse events or immune related adverse events. Moreover, the symptoms of the patients were improved after nICT treatment. CONCLUSIONS: Neoadjuvant immunochemotherapy shows promising efficacy in locally advanced resectable NSCLC, with manageable treatment-related adverse events. It is a safe and feasible neoadjuvant treatment modality for locally advanced resectable NSCLC.

Association of the Scottish inflammatory prognostic score with treatment-related adverse events and prognosis in esophageal cancer receiving neoadjuvant immunochemotherapy.

Background: To investigate the relationship between the Scottish inflammatory prognostic score (SIPS), treatment-related adverse events (TRAEs), and prognostication in patients with neoadjuvant immunochemotherapy (NICT) for esophageal squamous cell carcinoma (ESCC). Methods: A retrospective investigation was carried out on 208 ESCC patients treated with NICT. The relationships between the SIPS, TRAEs, and prognosis [disease-free survival (DFS) and overall survival (OS)] were analyzed. Results: The patients, comprising 62 (29.8%) cases of SIPS0, 103 (49.5%) cases of SIPS1, and 43 (20.7%) cases of SIPS2, were categorized into three groups based on SIPS. Among patients with SIPS2, the oldest age (P=0.006), lowest BMI (P=0.001), longest tumor length (P=0.001), most advanced ypT stage (P=0.014), and ypN stage (P<0.001) were identified. Pathological complete response (PCR) rates showed statistically significant variations between the three groups (SIPS0: 45.2%, SIPS1: 27.2%, SIPS2: 16.3%, P=0.004). All TRAEs were found in 63.9% (133 cases) of the cases, with serious TRAEs (grade 3-4) accounting for 13.9% (29 cases). TRAEs themselves were not linked with SIPS (P=0.668), while serious TRAEs had a significant correlation with SIPS (P=0.002). Multivariate logistic analysis showed that SIPS2 seemed to confer serious TRAEs [odds radio (OR)=4.044; 95% CI: 1.395-11.722; P=0.010]. For patients classified as SIPS0, 1, or 2, the 3-year DFS was 83.9%, 58.3%, and 39.5% (P<0.001). The 3-year OS for those with SIPS0, 1, or 2 was 88.7%, 72.8%, and 53.5%, respectively (P<0.001). SIPS was substantially correlated with DFS (but not with OS) and could be utilized as an independent predictor [SIPS2: hazard ratio (HR)=3.743, 95% CI: 1.770-7.914, P=0.001; SIPS1: HR=2.303, 95% CI: 1.149-4.616, P=0.019]. Conclusion: The SIPS is associated with serious TRAEs and can be used as a predictor of serious TRAEs in ESCC receiving NICT. SIPS may be employed for pretreatment assessment since it was found to be substantially correlated with DFS.

Predictive model based on multiple immunofluorescence quantitative analysis for pathological complete response to neoadjuvant immunochemotherapy in lung squamous cell carcinoma.

Objective: This study aims to establish a prediction model for neoadjuvant immunochemotherapy (NICT) in lung squamous cell carcinoma to guide clinical treatment. Methods: This retrospective study included 50 patients diagnosed with lung squamous cell carcinoma who received NICT. The patients were divided into the pathological complete response (PCR) group and the non-PCR group. HE staining and multiple immunofluorescence (mIF) techniques were utilized to analyze the differences in the immune microenvironment between these groups. LASSO regression and optimal subset regression were employed to identify the most significant variables and construct a prediction model. Results: The PCR group showed higher densities of lymphocyte nuclei and karyorrhexis based on HE staining. Furthermore, based on mIF analysis, the PCR group showed higher cell densities of CD8+, PD-L1+, and CD8+PD-L1+ in the tumor region, while showing lower cell densities of CD3+Foxp3+, Foxp3+, and CD163+. Logistic univariate analysis revealed CD8+PD-L1+, PD-L1+, CD8+, CD4+LAG-3+, lymphocyte nuclei, and karyorrhexis as significant factors influencing PCR. By using diverse screening methods, the three most relevant variables (CD8+, PD-L1+, and CD8+PD-L1+ in the tumor region) were selected to establish the prediction model. The model exhibited excellent performance in both the training set (AUC=0.965) and the validation set (AUC=0.786). In the validation set, In comparison to the conventional TPS scoring criteria, the model attained superior accuracy (0.85), specificity(0.67), and sensitivity (0.92). Conclusion: NICT treatment might induce anti-tumor effects by enriching immune cells and reactivating exhausted T cells. CD8+, PD-L1+, and CD8+PD-L1+ cell abundances within the tumor region have been closely associated with therapeutic efficacy. Incorporating these three variables into a predictive model allows accurate forecasting of treatment outcomes and provides a reliable basis for selecting NICT treatment strategies.

Epidemiological, clinical and therapeutic profiles of mantle cell lymphoma cared for in a Moroccan center: a review of 14 cases.

Mantle cell lymphoma (MCL) accounts for 3-10% of non-Hodgkin's lymphomas (NHL). We identified 14 patients with mantle cell lymphoma, with an average number of 3.5 new cases/year. A male predominance was observed with a sex ratio equal to 6. The average age of our patients was 64.4±14.1 years, with an average diagnostic delay of 6.57 months. Regarding the clinical presentation, adenopathy was the most reported physical sign (78.6%) followed by B symptoms (57.1%). Disseminated stages were the most frequent in our series: stages IV (78.5%) and III (7.1%) versus stages I (0%) and II (7.1%). The extra-ganglionic localizations observed were hepatic 5 cases (31.1%), pulmonary 04 cases (25%), medullary 4 cases (25%), pleural 2 cases (12.5%) and prostate 1 case (6.2%). All diagnosed cases are mantle cell lymphomas, of which 12 cases (85.7%) are classical and 2 cases (14.3%) indolent. The high-risk group is, according to international prognostic index (MIPI) MCL prognostic score, the most represented in our series: 0-3 = 6 cases (42.9%), 6-11 = 8 cases (57.1%). The therapeutic protocol chosen 1st line: 9 patients treated with R-DHAP, three with R-CHOP, one with DHAOX and one with R-CVP. Second line: two patients treated with R-DHAP, one after R-CHOP and the other after R-CVP. Two patients received autologous hematopoietic stem cell transplant at the end of the treatment. The evolution was marked by the death of 7 patients, 3 lost to follow-up and 4 still followed. Additionally, the study highlights characteristics and treatment patterns of mantle cell lymphoma, emphasizing its predominance in males, delayed diagnosis, frequent dissemination, and high-risk classification, with chemotherapy as the primary treatment modality and a challenging prognosis contributing to a comprehensive understanding of mantle cell lymphoma presentation and management.

Appropriate Treatment Intensity for Diffuse Large B-Cell Lymphoma in the Older Population: A Review of the Literature.

Most patients with diffuse large B-cell lymphoma (DLBCL) are >65 years of age, with the number of patients expected to increase in the coming years. A comprehensive geriatric assessment that carefully evaluates fitness status and comorbidities is essential for selecting the appropriate treatment intensity. Although generally healthy patients or those <80 years of age may benefit from standard immunochemotherapy, unfit/frail patients or patients >80 years old may require reduced-intensity chemotherapy or less-toxic drugs. Some new drugs are currently being tested as single or combined agents for first-line treatment, aiming to improve the outcomes of conventional chemotherapy. This review systematically collates and discusses the outcomes associated with the use of immunochemotherapy in older patients with DLBCL, as well as considering the impact of full-dose immunochemotherapy on quality of life in older and frail patients, summarizing the rationale for reduced dosing in the older population, and presenting recommendations for selecting patients likely to benefit from reduced dosing. If preliminary efficacy and safety data are confirmed in future clinical trials, non-chemotherapy-based immunotherapy approaches could become an alternative potentially curative option in frail patients and those >80 years of age with DLBCL.

CT-based quantification of intratumoral heterogeneity for predicting pathologic complete response to neoadjuvant immunochemotherapy in non-small cell lung cancer.

Objectives: To investigate the prediction of pathologic complete response (pCR) in patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant immunochemotherapy (NAIC) using quantification of intratumoral heterogeneity from pre-treatment CT image. Methods: This retrospective study included 178 patients with NSCLC who underwent NAIC at 4 different centers. The training set comprised 108 patients from center A, while the external validation set consisted of 70 patients from center B, center C, and center D. The traditional radiomics model was contrasted using radiomics features. The radiomics features of each pixel within the tumor region of interest (ROI) were extracted. The optimal division of tumor subregions was determined using the K-means unsupervised clustering method. The internal tumor heterogeneity habitat model was developed using the habitats features from each tumor sub-region. The LR algorithm was employed in this study to construct a machine learning prediction model. The diagnostic performance of the model was evaluated using criteria such as area under the receiver operating characteristic curve (AUC), accuracy, specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). Results: In the training cohort, the traditional radiomics model achieved an AUC of 0.778 [95% confidence interval (CI): 0.688-0.868], while the tumor internal heterogeneity habitat model achieved an AUC of 0.861 (95% CI: 0.789-0.932). The tumor internal heterogeneity habitat model exhibits a higher AUC value. It demonstrates an accuracy of 0.815, surpassing the accuracy of 0.685 achieved by traditional radiomics models. In the external validation cohort, the AUC values of the two models were 0.723 (CI: 0.591-0.855) and 0.781 (95% CI: 0.673-0.889), respectively. The habitat model continues to exhibit higher AUC values. In terms of accuracy evaluation, the tumor heterogeneity habitat model outperforms the traditional radiomics model, achieving a score of 0.743 compared to 0.686. Conclusion: The quantitative analysis of intratumoral heterogeneity using CT to predict pCR in NSCLC patients undergoing NAIC holds the potential to inform clinical decision-making for resectable NSCLC patients, prevent overtreatment, and enable personalized and precise cancer management.

Perioperative Outcomes and Survival after Neoadjuvant Immunochemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aimed to compare the difference in perioperative outcomes and prognosis between neoadjuvant immunochemotherapy (nICT) and neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESCC). METHODS: The LA-ESCC patients receiving nICT or nCRT were identified from a prospectively maintained database at Zhongshan Hospital of Fudan University between Jan 2018 and March 2022. Propensity score matching (PSM) was performed to balance the two groups. RESULTS: A total of 124 patient pairs were enrolled in the final analysis. The complete pathological response rate (20.2% vs. 29.0%, p=0.140) was similar in the two groups while the lower major pathological response rate (44.4% vs. 61.3%, p=0.011) was observed in the nICT group. nICT was associated with a lower rate of adverse events (42.7% vs. 55.6%, p=0.047) without additional postoperative complications (38.7% vs. 35.5%, p=0.693). The nICT group had lower distant metastasis (6.5% vs. 16.1%, p=0.027) and overall recurrence (11.3% vs. 23.4%, p=0.019) in the postoperative 1 year. Also, nICT was associated with better progression-free survival (HR=0.50; 95% CI: 0.32-0.77; p=0.002). Cox proportional hazard analysis showed that nICT (univariable: HR=0.55; 95% CI: 0.37-0.82; p=0.003; multivariable: HR=0.44; 95% CI: 0.29-0.65; p<0.001) was one of the independent prognostic factors for progression-free survival. The two groups had similar overall survival (HR=0.62; 95%CI: 0.36-1.09; p=0.094) at the latest follow-up. CONCLUSION: This retrospective study showed that nICT was safe and effective for LA-ESCC patients. Further verification is needed in the randomized controlled trials.

Prognostic Nutritional Index as a Prognostic Indicator for the Occurrence of Postoperative Complications in Patients with Esophageal Squamous Cell Carcinoma Following Neoadjuvant Immunochemotherapy.

Background & Aims: The objective of this study was to evaluate the prognostic nutritional index (PNI) as a predictor of short-term postoperative complications in esophageal squamous cell carcinoma patients undergoing neoadjuvant immunochemotherapy. Methods: Clinical data were collected from 77 patients undergoing radical esophageal cancer surgery after neoadjuvant immunochemotherapy at Tongji Hospital from January 2022 to January 2023. The receiver operating characteristic curve (ROC) was utilized to establish the optimal cut-off point for the PNI. Subsequently, patients were stratified into low and high PNI groups according to this cut-off point, and comparisons were made between the two groups in terms of clinical data and postoperative complications. Results: Out of the 77 patients included in the study, 31 were categorized in the low PNI group and 46 in the high PNI group, with a defined cutoff point of 47.38. Significant statistical variances were noted in the occurrence rates of general complications (P < 0.001), pulmonary infections (P < 0.001), and anastomotic fistula (P = 0.034) between the two groups. The low PNI group displayed elevated rates of these complications in comparison to the high PNI group. Conclusion: The research findings indicate that preoperative nutritional assessment using the PNI can effectively predict short-term postoperative complications in esophageal squamous cell carcinoma patients who have undergone neoadjuvant therapy. Furthermore, the results suggest that implementing nutritional interventions for patients with moderate-to-severe malnutrition, as indicated by preoperative PNI evaluation, may help reduce the incidence of postoperative complications.

Induction Immunochemotherapy Yields a Higher Conversion Rate and Better Overall Survival than Chemotherapy in Initially Unresectable Esophageal Squamous Cell Carcinoma.

INTRODUCTION: This study compared the surgical conversion rate and overall survival (OS) between induction chemotherapy (iC) and induction immunochemotherapy (iIC) for patients with initially unresectable esophageal squamous cell carcinoma (iuESCC). METHODS: In this multicenter, retrospective cohort study, patients from four high-volume institutions with unresectable diseases were included. The primary endpoints were the conversion surgery rate and OS. A multivariate Cox regression analysis was used to identify the independent significant prognostic factors associated with OS. The stabilized inverse probability of treatment weighting was applied to confirm the survival comparison between the iIC and iC cohorts. RESULTS: A total of 309 patients (150 in the iIC cohort and 159 in the iC cohort) were included. A significantly higher conversion surgical rate was observed in the iIC cohort (iIC vs. iC: 127/150, 84.7% vs. 79/159, 49.7%, P < 0.001). The pathological complete response rates were 22.0% and 5.1% in the iIC and the iC cohorts, respectively (P = 0.001). A significant difference in the OS was observed between the iIC (not reached) and iC cohorts (median 95% CI 36.3 [range 27.2-45.5]). The stabilized inverse probability of treatment weighting yielded similar results. Regimen (iIC vs. iC, HR 0.215, 95% CI 0.102-0.454, P < 0.001) and operation (yes vs. no, HR 0.262, 95% CI 0.161-0.427, P < 0.001) were the significant prognostic factors for OS. CONCLUSIONS: Immunochemotherapy plus conversion surgery in the induction setting may be a better treatment option to achieve high pathological responses and improve OS in iuESCC patients.

Alterations in Peripheral Lymphocyte Subsets under Immunochemotherapy in Stage IV SCLC Patients: Th17 Cells as Potential Early Predictive Biomarker for Response.

UICC stage IV small-cell lung cancer (SCLC) is a highly aggressive malignancy without curative treatment options. Several randomized trials have demonstrated improved survival rates through the addition of checkpoint inhibitors to first-line platin-based chemotherapy. Consequently, a combination of chemo- and immunotherapy has become standard palliative treatment. However, no reliable predictive biomarkers for treatment response exist. Neither PD-L1 expression nor tumor mutational burden have proven to be effective predictive biomarkers. In this study, we compared the cellular immune statuses of SCLC patients to a healthy control cohort and investigated changes in peripheral blood B, T, and NK lymphocytes, as well as several of their respective subsets, during treatment with immunochemotherapy (ICT) using flow cytometry. Our findings revealed a significant decrease in B cells, while T cells showed a trend to increase throughout ICT. Notably, high levels of exhausted CD4+ and CD8+ cells, alongside NK subsets, increased significantly during treatment. Furthermore, we correlated decreases/increases in subsets after two cycles of ICT with survival. Specifically, a decrease in Th17 cells indicated a better overall survival. Based on these findings, we suggest conducting further investigation into Th17 cells as a potential early predictive biomarkers for response in patients receiving palliative ICT for stage IV SCLC.

Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice.

Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.

To develop a prognostic model for neoadjuvant immunochemotherapy efficacy in esophageal squamous cell carcinoma by analyzing the immune microenvironment.

Objective: The choice of neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC) is controversial. This study aims to provide a basis for clinical treatment selection by establishing a predictive model for the efficacy of neoadjuvant immunochemotherapy (NICT). Methods: A retrospective analysis of 30 patients was conducted, divided into Response and Non-response groups based on whether they achieved major pathological remission (MPR). Differences in genes and immune microenvironment between the two groups were analyzed through next-generation sequencing (NGS) and multiplex immunofluorescence (mIF). Variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves to establish a predictive model. An additional 48 patients were prospectively collected as a validation set to verify the model's effectiveness. Results: NGS suggested seven differential genes (ATM, ATR, BIVM-ERCC5, MAP3K1, PRG, RBM10, and TSHR) between the two groups (P < 0.05). mIF indicated significant differences in the quantity and location of CD3+, PD-L1+, CD3+PD-L1+, CD4+PD-1+, CD4+LAG-3+, CD8+LAG-3+, LAG-3+ between the two groups before treatment (P < 0.05). Dynamic mIF analysis also indicated that CD3+, CD8+, and CD20+ all increased after treatment in both groups, with a more significant increase in CD8+ and CD20+ in the Response group (P < 0.05), and a more significant decrease in PD-L1+ (P < 0.05). The three variables most closely related to therapeutic efficacy were selected through LASSO regression and ROC curves: Tumor area PD-L1+ (AUC= 0.881), CD3+PD-L1+ (AUC= 0.833), and CD3+ (AUC= 0.826), and a predictive model was established. The model showed high performance in both the training set (AUC= 0.938) and the validation set (AUC= 0.832). Compared to the traditional CPS scoring criteria, the model showed significant improvements in accuracy (83.3% vs 70.8%), sensitivity (0.625 vs 0.312), and specificity (0.937 vs 0.906). Conclusion: NICT treatment may exert anti-tumor effects by enriching immune cells and activating exhausted T cells. Tumor area CD3+, PD-L1+, and CD3+PD-L1+ are closely related to therapeutic efficacy. The model containing these three variables can accurately predict treatment outcomes, providing a reliable basis for the selection of neoadjuvant treatment plans.

Impact of treatment interval between neoadjuvant immunochemotherapy and surgery in lung squamous cell carcinoma.

OBJECTIVE: The optimal timing for surgery following neoadjuvant immunochemotherapy for lung squamous cell carcinoma appears to be a topic of limited data. Many clinical studies lack stringent guidelines regarding this timing. The objective of this study is to explore the effect of the interval between neoadjuvant immunochemotherapy and surgery on survival outcomes in patients with lung squamous cell carcinoma. METHODS: This study conducted a retrospective analysis of patients with lung squamous cell carcinoma who underwent neoadjuvant immunochemotherapy between January 2019 and October 2022 at The First Affiliated Hospital, Zhejiang University School of Medicine. Patients were divided into two groups based on the treatment interval: ≤33 days and > 33 days. The primary observational endpoints of the study were Disease-Free Survival (DFS) and Overall Survival (OS). Secondary observational endpoints included Objective response rate (ORR), Major Pathological Response (MPR), and Pathological Complete Remission (pCR). RESULTS: Using the Kaplan-Meier methods, the ≤ 33d group demonstrated a superior DFS curve compared to the > 33d group (p = 0.0015). The median DFS for the two groups was 952 days and 590 days, respectively. There was no statistical difference in the OS curves between the groups (p = 0.66), and the median OS was not reached for either group. The treatment interval did not influence the pathologic response of the tumor or lymph nodes. CONCLUSIONS: The study observed that shorter treatment intervals were associated with improved DFS, without influencing OS, pathologic response, or surgical safety. Patients should avoid having a prolonged treatment interval between neoadjuvant immunochemotherapy and surgery.

Clinical outcomes associated with neoadjuvant therapy for the treatment of resectable non-small cell lung cancer in real-world practice.

BACKGROUND: In order to improve survival outcomes in resectable non-small cell lung cancer (NSCLC), strategies for neoadjuvant therapy need to be revisited. We evaluated and compared the efficacy of different neoadjuvant therapeutic modalities in a real-world setting. METHODS: A total of 258 patients with clinical stage IIA to IIIB NSCLC was included. All the patients underwent surgical resection after one to four cycles of neoadjuvant treatment consisting of chemotherapy (83), immunotherapy (23), and immunotherapy plus chemotherapy (152). RESULTS: The radiologic response rate in the combined immunochemotherapy group was 67.8%, higher than that of 48.2% in the chemotherapy group and 4.3% in the immunotherapy group (p < 0.001). An improved major pathological response (MPR) was also achieved in the combined therapy group compared with the chemotherapy group and the immunotherapy group (53.9% vs. 10.8% vs. 8.7%, p < 0.001). Patients in the combined therapy group had a significant trend toward longer disease-free survival than those in the chemotherapy alone group (3-year disease-free survival [DFS] of 68.79% vs. 50.81%; hazard ratio [HR] for progression or death, 0.477; p = 0.003). Multivariate Cox analysis identified radical surgery (HR, 0.328; p = 0.033), ypN0-1 stage (HR, 0.591; p = 0.038) and MPR result (HR, 0.362; p = 0.007) to be independent prognostic factors for DFS. CONCLUSIONS: Neoadjuvant treatment with a combination of immunotherapy plus chemotherapy appears to achieve higher radiological and pathological responses than monotherapy for IIA-IIIB NSCLC. Log-rank analysis showed that a better outcome could be expected in patients with the addition of immunotherapy to neoadjuvant chemotherapy if compared with patients with chemotherapy alone in terms of DFS.

Regulating tumor innervation by nanodrugs potentiates cancer immunochemotherapy and relieve chemotherapy-induced neuropathic pain.

Sympathetic nerves play a pivotal role in promoting tumor growth through crosstalk with tumor and stromal cells. Chemotherapy exacerbates the infiltration of sympathetic nerves into tumors, thereby providing a rationale for inhibiting sympathetic innervation to enhance chemotherapy. Here, we discovered that doxorubicin increases the density and activity of sympathetic nerves in breast cancer mainly by upregulating the expression of nerve growth factors (NGFs) in cancer cells. To address this, we developed a combination therapy by co-encapsulating small interfering RNA (siRNA) and doxorubicin within breast cancer-targeted poly (lactic-co-glycolic acid) (PLGA) nanoparticles, aiming to suppress NGF expression post-chemotherapy. Incorporating NGF blockade into the nanoplatform for chemotherapy effectively mitigated the chemotherapy-induced proliferation of sympathetic nerves. This not only bolstered the tumoricidal activity of chemotherapy, but also amplified its stimulatory impact on the antitumor immune response by increasing the infiltration of immunostimulatory cells into tumors while concurrently reducing the frequency of immunosuppressive cells. Consequently, the combined nanodrug approach, when coupled with anti-PD-L1 treatment, exhibited a remarkable suppression of primary and deeply metastatic tumors with minimal systematic toxicity. Importantly, the nanoplatform relieved chemotherapy-induced peripheral neuropathic pain (CIPNP) by diminishing the expression of pain mediator NGFs. In summary, this research underscores the significant potential of NGF knockdown in enhancing immunochemotherapy outcomes and presents a nanoplatform for the highly efficient and low-toxicity treatment of breast cancer.

Survival outcomes of neoadjuvant immunochemotherapy versus chemotherapy for locally advanced esophageal squamous cell carcinoma.

PURPOSE: Neoadjuvant chemotherapy (NCT) is the standard preoperative treatment for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Some studies reported neoadjuvant immunochemotherapy (NICT) could improve pathological response with manageable safety. However, few studies have compared the efficacy and safety of NICT and NCT, especially survival outcomes. In this study, we compared the efficacy and safety of NICT and NCT after a median follow-up of 36.0 months. METHODS: This was a retrospective study with a 1:1 propensity score matching (PSM). Locally advanced ESCC patients treated with neoadjuvant sintilimab plus chemotherapy or chemotherapy followed by esophagectomy were reviewed. The primary outcome was recurrence-free survival (RFS). RESULTS: Forty-five patients were identified in each group by PSM. The pathological complete response (pCR) rate in NICT and NCT group were 28.9% and 8.9% (P = 0.02). The hazard ratio (HR) was 0.396 (95% CI 0.171-0.919, p = 0.025) for RFS and 0.377 (95% CI 0.145-0.981, p = 0.038) for overall survival (OS), 3-year RFS was 80.6% and 62.1%, 3-year OS was 86.2% and 68.1%. Patients with pCR, MPR or downstaging had better 3-year RFS and 3-year OS. The incidences of postoperative complications and treatment-related adverse events (TRAEs) were similar. CONCLUSION: This trial preliminarily shows that NICT improves pathological and survival outcomes over NCT for resectable locally advanced ESCC, with acceptable and manageable safety.