Immune checkpoint inhibitor (ICI)-based treatment beyond progression with prior immunotherapy in patients with driver-gene negative advanced non-small cell lung cancer.

BACKGROUND: No definite conclusion has yet to be reached for immunotherapy beyond progression(IBP) of first-line immunotherapy as the second-line treatment for advanced NSCLC patients with negative driver genes. Therefore a retrospective study was conducted to evaluate the efficacy of IBP in this population and investigated whether the cycles best response and progressive mode of first-line immunotherapy could affect the results. PATIENTS AND METHODS: The clinical data of patients with advanced NSCLC whose response was evaluated as progressive disease (PD) after receiving a PD-1/PD-L1 inhibitors as first-line therapy were retrospectively collected and the patients were assigned to the IBP and non-IBP groups. The overall survival (OS), progression-free survival (PFS) were evaluated between the two groups. The survival effects of cycles best response and progressive mode of first-line immunotherapy were also evaluated. RESULTS: Between January 2019 and January 2022, a total of 121 patients was evaluated as PD after first-line immunotherapy in our institution; 53 (43.8%) patients were included in the IBP group and 68 (56.2%) patients were included in the non-IBP group. The OS and PFS were no significantly different between the two groups in whole population. Further analysis revealed the OS was prolonged with the prolongation of first-line medication cycle. The median OS was 15.4m (15.4 vs 10.8 p=0.047) 16.1m (16.1 vs 10.8 p=0.039), 16.3m (16.3 vs 10.9 p=0.029) for patients with ≥4, ≥6, ≥8 cycles in first-line immunotherapy, respectively. The advantages of OS and PFS were also seen in the subgroup of PR (best response) and oligo progression of first-line immunotherapy. CONCLUSIONS: The clinical outcomes of IBP were similar to those of non-IBP in patients with PD after first-line immnuotherapy in advanced NSCLC. But more cycles, PR as best response and oligo progression in first-line was benefit.

Immunotherapy combined with cranial radiotherapy for driver-negative non-small-cell lung cancer brain metastases: a retrospective study.

Background: This study assesses immune checkpoint inhibitors' efficacy for non-small-cell lung cancer (NSCLC) with brain metastases (BM) and explores the role of cranial radiation therapy (CRT) in the immunotherapy era. Methods: The retrospective analysis screened NSCLC patients with BMs from July 2018 to December 2021. Treatment involved chemotherapy combined with immune checkpoint inhibitors as the first-line, with patients divided into CRT and non-CRT groups. Overall survival (OS), progression-free survival and intracranial progression-free survival were calculated and compared. Results: Among 113 patients, 74 who received CRT had significantly better median OS (not reached vs 15.31 months), particularly among those with one to three BMs. Factors correlating with better OS included CRT, PD-L1 expression and diagnosis-specific graded prognostic assessment scores. Conclusion: Integrating CRT with anti-PD-1 therapy notably enhanced long-term survival in NSCLC patients with BMs.

Prognostic value of cranial radiotherapy and optimal timing stratified by lung-molGPA for NSCLC patients with brain metastases.

PURPOSE: The updated Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (lung-molGPA) index provide more accurate survival prediction for patients diagnose with advanced non-small cell lung cancer (NSCLC) with brain metastases (BM). Given that the value of cranial radiotherapy (CRT) is still controversial for NSCLC patients with BM, this retrospective study aimed to evaluate the value of CRT and optimal timing in NSCLC patients with initial BM after stratified with lung-molGPA index. METHODS: This study screened NSCLC patients with initial BM in our cancer center from February 2012 to July 2018. The prognosis value of CRT and optimal timing was evaluated with Kaplan-Meier survival analysis and the patients were classified into lung-molGPA0-2 and lung-molGPA2.5-4 group. Upfront CRT was defined as received CRT within 3 months after initial diagnosis and without BM progression, other CRT was classified into deferred CRT. RESULTS: Overall, 288 patients were enrolled in our study, 156 patients received CRT. The median follow-up time was 47 months. In the entire cohort, the median PFS and OS were 9.2 and 17.0 months, respectively. In the lung-molGPA2.5-4 group, CRT can bring significantly overall survival benefit for NSCLC patients with initial BM (HR: 0.48, 95% CI: 0.34-0.68, P < 0.0001), and the upfront CRT can further expand this survival benefits compared with deferred CRT (HR: 0.49, 95% CI: 0.27-0.89, P = 0.0026). But this phenomenon was not observed in lung-molGPA0-2 group patients. CONCLUSION: Upfront CRT could bring significantly overall survival benefit for these patients with lung-molGPA2.5-4 but not for patients with lung-molGPA0-2.

Role of consolidative thoracic radiation in extensive-stage small-cell lung cancer with first-line chemoimmunotherapy: a retrospective study from a single cancer center.

OBJECTIVE: To investigate the role of consolidative thoracic radiation (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) receiving first-line chemo-immunotherapy followed by immunotherapy maintenance. PATIENTS AND METHODS: Outcomes of patients without disease progression after first-line chemotherapy were retrospectively reviewed (January 2020 to December 2021). Based on TRT or not, patients were allocated to TRT group or non-TRT group. Progression-free survival (PFS), overall survival (OS) and local-recurrence free survival (LRFS) were calculated by the Kaplan-Meier method and compared by log-rank test. RESULTS: Of 100 patients, 47 received TRT and 53 non-TRT. The median follow-up was 20.3 months. The median PFS and OS in TRT were 9.1 months and 21.8 months, versus 8.8 months (p = 0.93) and 24.3 months (p = 0.63), respectively, in non-TRT. The median LRFS time in TRT was not reached, but significantly longer than 10.8 months in non-TRT (HR = 0.27, p < 0.01). Second-line chemotherapy significantly prolonged survival compared to that with chemo-free patients (mOS: 24.5 vs. 21.4 months, p = 0.026). The subgroup analysis showed a trend of patients with brain metastases benefit from TRT (21.8 versus 13.7 months, HR 0.61, p = 0.38) while liver metastases did not. Of 47 patients with TRT, only 10.6% of patients experienced grade 3 radiation-induced pneumonitis, while no grade 4 or 5 adverse events occurred. CONCLUSION: Consolidative TRT in the period of immunotherapy maintenance followed first-line chemo-immunotherapy did not prolong OS and PFS but associated with improved LRFS in ES-SCLC.

Programmed cell death 1 pathway inhibitors improve the overall survival of small cell lung cancer patients with brain metastases.

PURPOSE: The objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitors in small cell lung cancer patients with brain metastases. METHODS: We retrospectively reviewed the records of small cell lung cancer patients with brain metastases treated with chemotherapy and radiotherapy for brain metastases with or without immune checkpoint inhibitors at our institution from January 2019 to January 2021. Patients were divided into two groups. In Group A, patients received chemotherapy and radiotherapy for brain metastases. In Group B, patients received chemotherapy, radiotherapy for brain metastases and at least four cycles of immunotherapy. Overall survival and intracranial progression-free survival were assessed using Kaplan-Meier estimates and Cox regression models. RESULTS: A total of 282 patients were enrolled in our study. At the end of the study (May 12, 2021), the median overall survival was 13.3 months among 218 patients in Group A and 33.4 months among 64 patients in Group B (hazards ratio [HR] 0.320, 95% confidence interval [CI], 0.189-0.545, P < 0.001). Both univariate and multivariate analyses suggested that two factors were significantly correlated with overall survival: the inclusion of immunotherapy in the regimen and the presence of extracranial metastases. The median intracranial progression-free survival was 6.93 months in Group A and 10.73 months in Group B (HR = 0.540, 95% CI, 0.346-0.841, P = 0.006). The intracranial objective response rate of Group B was greater than that of Group A, but the intracranial disease control rate was similar between the groups. CONCLUSION: Immunotherapy plus chemotherapy and radiotherapy for brain metastases showed promising efficacy for small cell lung cancer patients with brain metastases.

Fatal toxicity induced by anti-PD-1 immune checkpoint inhibitor in thymic epithelial tumor.

A standard treatment for advanced thymic epithelial tumors (TETs) after initial treatment remains unavailable to date. Targeted immune checkpoint inhibitors (ICIs) of the programmed cell death-1 (PD-1) pathway may produce objective responses in TETs, notably thymic carcinoma. Findings of clinical trials suggested ICIs are a practical choice. However, the risk of severe immuno-related adverse events is higher in TETs. Concerning histologic subtypes, thymomas are more frequently associated with autoimmune disorders than carcinomas, so close monitoring is needed for thymomas. In this article, we describe four cases of fatal toxicity caused by anti-PD-1 therapy in TETs. Four patients with metastatic thymomas or carcinoma difficult to treat with first-line standard chemotherapy were treated with the anti-PD-1 drug pembrolizumab or sintilimab. The association of PD-1 inhibitors with a high proportion of severe immuno-related adverse events in TETs necessitates attentive monitoring during treatment.

Thymic epithelial tumors are the most common malignancy of the anterior mediastinum in adults, with the occurrence of approximately 1.5 cases/million. Surgery is usually the treatment of choice. However, treatment options for advanced disease are poorly understood, and data are limited. Several studies have assessed the objective responses of immune checkpoint inhibitors in patients with advanced thymic epithelial tumors. Anti-cancer immunity also increases the risk of developing adverse events related to immunotherapy. Some patients can experience lethal toxicity. This article presents four cases of developing severe adverse events to exercise caution in prescribing these agents for thymic epithelial tumor, in particular thymoma.

Severe Pulmonary Toxicity With Concurrent Anlotinib and Chemoradiotherapy in Stage III NSCLC: The ALTER-L042 Phase 1 Clinical Trial.

Introduction: Anlotinib has brought about marked progression-free survival and overall survival benefit compared with placebos as third-line or further treatment in advanced NSCLC. Nevertheless, the safety and efficacy of concurrent anlotinib and chemoradiotherapy are still unclear. Methods: Patients with histologically or cytologically confirmed stage III NSCLC suitable for concurrent chemoradiotherapy were enrolled in this study. The enrolled patients were treated with concurrent two cycles of anlotinib and chemoradiotherapy followed by anlotinib consolidation until disease progression or intolerance toxicity. The primary end point was the maximum tolerance dose of anlotinib, whereas the secondary end point was the overall response rate. Results: Seven patients were enrolled in this study. Six patients completed concurrent anlotinib and chemoradiotherapy and then entered the consolidation period. Among the patients, 28.57% (two of seven patients) developed fatal treatment-related adverse events (fatal pneumonitis and fatal hemoptysis). In addition, two other patients developed grade 3 radiation pneumonitis; one was induced by a cold, and the patient received only 18 Gy per nine fractions of radiotherapy. This study was terminated early owing to the high rate of fatal adverse events and radiation pneumonitis. Conclusions: This study presented severe pulmonary toxicity with concurrent anlotinib and chemoradiotherapy. Several previous clinical trials evaluated the safety of concurrent bevacizumab and radiotherapy or chemoradiotherapy; all were terminated owing to severe treatment-related toxicity. Results of these studies suggest that concurrent antiangiogenic and thoracic radiotherapy should be avoided until appropriate safety data are presented, at least for bevacizumab and anlotinib.

Radiation therapy for extensive-stage small-cell lung cancer in the era of immunotherapy.

Unlike non-small-cell lung cancer (NSCLC), the progression of small-cell lung cancer (SCLC) is slow. Extensive-stage SCLC (ES-SCLC) is a serious threat to human health, with a 5-year survival rate of <7%. Chemotherapy has been the first-line treatment for the past 30 years. The anti-PD-L1 checkpoint blockades durvalumab and atezolizumab have greatly prolonged overall survival and have become the standard first-line therapy for ES-SCLC since the CASPIAN and IMpower133 trials. In the era of chemotherapy, radiation therapy (RT), including thoracic radiation therapy (TRT) and brain radiation therapy (BRT), has shown clinical effects in randomized and retrospective studies on ES-SCLC. RT-immunotherapy has shown exciting synergistic effects in NSCLC. For ES-SCLC, the clinical effects of combining TRT/BRT with immunotherapy have not yet been systematically explored. In this review, we found that studies on RT-immunotherapy in ES-SCLC are relatively few and limited to early phase studies focusing on toxicity. The efficacy and safety profiles of early phase studies encourage prospective clinical trials. In this review, we discuss the best population, optimum TRT dose, proper TRT time, and strategies for reducing radiation-induced neurotoxicity. Furthermore, we suggest that biomarkers and patient performance status should be fully assessed before RT-immunotherapy treatment. Prospective trials are needed to provide more evidence for RT-immunotherapy applications in ES-SCLC.

Clinical Outcomes for PD-1 Inhibitor Plus Chemotherapy as Second-Line or Later Therapy Compared to PD-1/PD-L1 Inhibitor Alone in Advanced Non-small-cell Lung Cancer.

BACKGROUND: Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor monotherapy has been approved as second-line or later therapy in advanced non-small-cell lung cancer (NSCLC). The study aimed to compare the clinical outcomes of PD-1 inhibitor plus chemotherapy with PD-1/PD-L1 inhibitor monotherapy as second-line or later therapy in advanced NSCLC. METHODS: The clinical data of patients with advanced NSCLC who received PD-1/PD-L1 inhibitors as second-line or later line therapy was retrospectively collected. Patients were assigned to one of the two groups according to the therapeutic modality used: PD-1/PD-L1 inhibitor monotherapy group or PD-1 inhibitor plus chemotherapy combination therapy group. Disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated between the two groups. The prognostic effect of the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) on the outcomes was also evaluated. RESULTS: From April 2017 to October 2019, a total of 84 patients were enrolled in the current study. Twenty-six patients (PD-1 inhibitor, n = 25; PD-L1 inhibitor, n = 1) received PD-1/PD-L1 inhibitor monotherapy, and fifty-eight patients received PD-1 inhibitor plus chemotherapy. The chemotherapy regimens used were as follows: liposome paclitaxel (n = 15); nab-paclitaxel (n = 12); docetaxel (n = 9); pemetrexed (n = 6); and others (n = 16). The DCR and OS were not significantly different between the two groups. The PFS of the monotherapy group was longer than that of the combination therapy group (mPFS: 9.6 vs. 4.6 months, P = 0.01). Univariate and multivariate analyses suggested that LDH and sex were independent prognostic factors of PFS. In the second-line therapy subgroup of 38 patients, OS and PFS were not significantly different between the two groups. In the subgroup of 46 patients treated beyond the 2nd line, the monotherapy group had a longer PFS (mPFS: 9.6 vs. 4.2 months, P = 0.01). The incidence of any-grade adverse events was not significantly different between the monotherapy group and the combination therapy group (19.2 vs. 18.9%, P = 1.000). One patient in the PD-1 inhibitor plus chemotherapy group died of immune-related pneumonitis. CONCLUSION: The clinical outcomes of PD-1 inhibitor plus chemotherapy as second-line or later therapy were similar to those of PD-1/PD-L1 inhibitor alone in advanced NSCLC.

An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib.

Our study is the first to report an especially high rate of grade 2 or worse radiation pneumonitis in patients treated with thoracic radiotherapy and simultaneous Osimertinib, despite total lung V5, V20 and MLD seeming unlikely to induce radiation pneumonitis.

A 4-month-old boy with gastrointestinal stromal tumor of mesocolon.

Gastrointestinal stromal tumors (GISTs) are very uncommon in pediatric patients, and they are distinct clinical-pathological and molecular deviations from their adult counterparts. Most pediatric GISTs lack the c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes mutations. To date, there is no published standard guidelines available for the best treatment of pediatric GISTs, especially for infant GIST. Therefore, we report a case of 4-month-old infant with GIST of mesocolon without KIT/PDGFRA mutation. We also review the clinical, biological, and genetic features of pediatric GISTs and re-think several questions that could affect clinical practice.

Primary non-Hodgkin's lymphoma of the vagina: A case report.

Primary non-Hodgkin's lymphoma (NHL) of the vagina is uncommon. The present case study reports the case of a 54-year-old female with a palpable mass between the rectum and vagina. The patient presented with symptoms consistent with vaginal cancer but lacked any of the 'B' symptoms often associated with systemic lymphoma, including fever, weight loss, night sweats and fatigue. The mass was resected under anesthesia. Immunohistochemistry and biopsy confirmed diffuse large B-cell NHL (DLBCL). Following surgery, six cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone were administered. Subsequently, a vertebral body metastasis was observed using a computed tomography scan and whole-body bone imaging. The patient received palliative radiation for the vertebral body metastasis. Additionally, the available literature was reviewed in order to further characterize this rare disease.

Ovarian metastasis from lung adenocarcinoma with ALK-positive rearrangement detected by next generation sequencing: A case report and literatures review.

Ovarian metastasis is an exceptionally rare condition in lung adenocarcinoma patients and is often difficult to distinguish from primary ovarian carcinoma. ALK (anaplastic lymphoma kinase) tyrosine kinase inhibitors elicit a significant objective response rate and are well-tolerated in advanced ALK-positive lung cancer. Hence, we report a case of a 41-year-old woman with ovarian metastases from NSCLC. After receiving a 6 course first line chemotherapy and 8 course maintenance therapy, the patient suffered acute abdominal pain, so surgery was performed. ALK rearrangement was detected by next generation sequencing, with a 13% abundance of ALK fusion. Crizotinib was administered, and the disease remained stable after 10 months of crizotinib therapy. Further, we reviewed the literature related to characteristics of metastatic ovarian malignancies that form from lung tumors, the utility of ALK inhibition for treating ALK-positive NSCLC, the molecular diagnosis of ALK rearrangement and the role of next generation sequencing for ALK rearrangement detection.

CT-detected solitary thyroid calcification: an important imaging feature for papillary carcinoma.

PURPOSE: To evaluate computed tomography (CT) detection of solitary thyroid calcification for identifying thyroid papillary carcinoma and to determine whether the predictive ability changes when the size increases after enhancement. MATERIALS AND METHODS: CT scans on all 96 patients with thyroid nodules who underwent both enhanced CT examination of neck and thyroidectomy from 2014 to 2016 in the Shandong Cancer Hospital affiliated to Shandong University were reviewed. The cases without calcification and the cases with peripheral calcification, multiple coarse calcifications, or punctate calcification were excluded. Imaging features, including location and size of the lesions, were reviewed on plain and contrast-enhanced CT. The patients were grouped by histological results. The comparisons were evaluated by using Fisher's exact test and binary logistic regression. RESULTS: The study population consisted of 96 patients (74 females, 22 males; mean age 49.8±11.3 years). Papillary thyroid carcinoma was observed in both solitary calcified thyroid nodules (85.4%) and solely coarse calcifications surrounded by low-density focus (58.2%). The difference was significant (P=0.006). Of 64 patients with an amplification of lesions after contrast enhancement, 58 (90.6%) were diagnosed with a malignant lesion. At the same time, of the 32 patients with no increase in size, 10 (31.2%) were diagnosed with carcinoma and 22 (68.8%) with nodular goiter. This difference was significant (P<0.001), and after binary logistic regression, increasing size was an independent risk factor for cancer. CONCLUSION: Solitary calcified thyroid nodules detected on CT represent a high risk for papillary thyroid carcinoma, especially when the size of the lesions increases after contrast- enhanced CT.

Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma: A Case Report and Literatures Review.

Malignant pleural mesothelioma (MPM) is a lethal disease with poor prognosis. The combination of cisplatin and pemetrexed has been confirmed as the standard of care for nonoperable MPM. Data have shown that the adoption of pemetrexed maintenance therapy (PMT) following first-line treatment appears extremely promising.We describe a 57-year-old man diagnosed as advanced MPM. We treated this patient with PMT after first-line cisplatin-based bevacizumab-containing chemotherapy and residual tumor disappeared after 6 course of PMT. A perfect response and a long progression-free survival (PFS) were reached with tumor mass disappearing and 14 months duration of PFS.This case suggests that adding bevacizumab to standard first-line chemotherapy is feasible and that PMT could be promising and useful for treating advanced MPM. We further entail a review of the literature on the first-line treatment, continuation maintenance therapy, switch maintenance therapy, and second-line treatment of patients with advanced MPM.

Delineation of clinical target volume for postoperative radiotherapy in stage IIIA-pN2 non-small-cell lung cancer.

With the high locoregional relapse rate and the improvement of radiation technology, postoperative radiotherapy (PORT) has been widely used in the treatment of completely resected stage IIIA-pN2 non-small-cell lung cancer (NSCLC). However, there is still no definitive consensus on clinical target volume for the pN2 subgroup. This review will discuss how to delineate the clinical target volume (CTV) for pN2 subgroups of IIIA-N2 NSCLC based on the published literature and to investigate the optimal PORT CTV in this cohort of patients. Besides overall survival (OS), locoregional recurrence (LR), and radiotherapy-related toxicity of this subset of the population in the modern PORT era, selection of proper patients will also be considered in this review. In summary, it is appropriate to include involved lymph node stations and uninvolved stations at high risk in PORT CTV for patients with pN2 disease when PORT is administered. PORT can reduce LR and has the potential to improve OS. In the current era of modern radiation technology, PORT can be administered safely with well-tolerated toxicity. Clinicopathological characteristics may be helpful in selecting proper candidates for PORT.