Obstructions can occur during any stage of colorectal cancer and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared with nonobstructive colorectal cancer, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. In this study, we found that colorectal cancer and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAF). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF1, TGFβ1, and CXCL8, which promoted the activation of normal fibroblasts into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating patients with colorectal cancer with risk of obstruction. Significance: Palmitic acid accumulation activates the NF-κB pathway in colorectal cancer cells to promote cytokine secretion that facilitates the generation of matrix cancer-associated fibroblasts, driving extracellular matrix remodeling and development of obstructions.

The advancement of molecular pathology techniques has led to the discovery of rare EGFR mutations for targeted therapy in lung cancer. Additionally, a substantial body of evidence indicates a connection between the development of lung cancer and genetic variations in the EGFR gene. Here, we present a case report of a patient with multifocal lung adenocarcinoma who possessed a rare germline mutation, EGFR R776H. An investigation into the family history of the patient exposed the notable incidence of lung adenocarcinoma, indicating a plausible genetic vulnerability to the ailment. To be specific, the patient's older brother and sister both suffered from lung cancer, which underlines the hereditary predisposition. Furthermore, it should be noted that the patient's daughter has inherited the germline mutation and also presented with multiple lung ground-glass nodules, emphasizing the clinical importance of this genetic variation. Following the lobectomy, the patient received treatment with almonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), and at the latest follow-up, the patient has achieved partial remission. This case highlights the significance of taking into account germline possibilities when multiple lesions carry the same mutation. It stresses the importance of acquiring a comprehensive family history and performing genetic testing on leukocytes. Moreover, for the infrequent EGFR R776H mutation, third generation EGFR-TKIs may be a viable option.

Introduction: p53 expression is associated with treatment failure and poor prognosis of diffuse large B-cell lymphoma (DLBCL). Bruton's tyrosine kinase (BTK) is a novel regulator of p53 activity and is involved in the cellular response to DNA damage. BTK inhibitors have shown high efficacy in mantle cell lymphoma and chronic lymphocyte leukemia with p53 alterations, and refractory and relapsed DLBCL. This study explored the efficacy and safety of zanubrutinib, a BTK inhibitor, combined with R-CHOP (ZR-CHOP) in patients of newly diagnosed DLBCL with p53 over-expression. Methods: Newly diagnosed DLBCL patients with positive p53 protein expression (immunohistochemistry staining ≥50% of cells) were enrolled at the Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from April 2022 to July 2024. ZR-CHOP regimen (zanubrutinib: 160 mg, bid, D1-21; rituximab: 375 mg/m², D1; cyclophosphamide: 750 mg/m², D2; doxorubicin: 50 mg/m², D2; vincristine: 1.4 mg/m², D2; prednisone: 100 mg/d, D2-D6) was administrated every 21 days for a total 6 cycles. Efficacy was evaluated using PET-CT/enhanced CT per Lugano 2014 criteria. The primary endpoint was the complete response rate (CRR), and secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs). Results: A total of 16 patients were enrolled in the study until July 2024. The median age at diagnosis was 56 years (range 34-67), with 7 patients (43.7%) in Ann Arbor stage III-IV, 2 patients (12.5%) with an ECOG score ≥2, 8 patients (50.0%) with IPI score ≥2, and 5 patients (31.3%) with extranodal involvement. There were 13 cases (81.3%) of double expression of MYC and BCL2, and 15 cases (93.8%) of the non-GCB subtype. By the end of the follow-up period in July 2024, 14 patients were evaluable for efficacy, with an ORR of 100%. 12 patients (85.7%) achieved CR, and 2 patients (14.3%) achieved partial response (PR). With a median follow-up of 11.8 (0.5-20) months, the 1-year PFS and OS rates were 93.8% and 100%, respectively. In terms of safety, common grade 3-4 adverse events included anemia (4 cases), leukopenia (5 cases), neutropenia (4 cases), thrombocytopenia (1 case), and pulmonary infection (2 cases). There were no new safety signals observed. Conclusions: The ZR-CHOP regimen is highly effective and safe for p53 over-expressed newly diagnosed DLBCL. It shows promise in improving the outcomes of p53-positive DLBCL patients.

BACKGROUND Tumor budding (TB) has emerged as a promising independent prognostic biomarker in colorectal cancer (CRC). The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC. However, existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies. Consequently, this study investigated the correlation among TB categories, clinicopathological features, and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification. AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC. METHODS The clinical data of 547 CRC patients were collected for this retrospective study. Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines. RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy (P = 0.004), clinical stage IV (P < 0.001), ≥ 4 regional lymph node metastases (P = 0.004), left-sided colonic cancer (P = 0.040), and Bd 2-3 (P = 0.002) were independent prognostic factors in patients with stage III-IV CRC. Moreover, the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3, both in the tumor stroma and its invasive margin. CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC. It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

The diagnosis of primary lung adenocarcinomas with intestinal or mucinous differentiation (PAIM) remains challenging due to the overlapping histomorphological, immunohistochemical and genetic characteristics with lung metastatic colorectal cancer (lmCRC). This study aimed to explore the protein biomarkers that could distinguish between PAIM and lmCRC. To uncover differences between the two diseases, we used tandem mass tagging (TMT)-based shotgun proteomics to characterize proteomes of formalin-fixed paraffin-embedded (FFPE) tumor samples of PAIM (n = 22) and lmCRC (n = 17).Then three machine learning algorithms, namely support vector machine (SVM), random forest and the Least Absolute Shrinkage and Selection Operator (LASSO), were utilized to select protein features with diagnostic significance. These candidate proteins were further validated in an independent cohort (PAIM, n = 11; lmCRC, n = 19) by immunochemistry (IHC) to confirm their diagnostic performance. In total, 105 proteins out of 7871 proteins were significantly dysregulated between PAIM and lmCRC samples and well-separated two groups by Uniform Manifold Approximation and Projection (UMAP). The upregulated proteins in PAIM were involved in actin cytoskeleton organization, platelet degranulation, and regulation of leukocyte chemotaxis, while downregulated ones were involved in mitochondrial transmembrane transport, vasculature development, and stem cell proliferation. A set of 10 candidate proteins (high-level expression in lmCRC: CDH17, ATP1B3, GLB1, OXNAD1, LYST, FABP1; high-level expression in PAIM: CK7 (an established marker), NARR, MLPH, S100A14) was ultimately selected to distinguish PAIM from lmCRC by machine learning algorithms. We further confirmed using IHC that the five protein biomarkers including CDH17, CK7, MLPH, FABP1 and NARR were effective biomarkers for distinguishing PAIM from lmCRC. Our study depicts PAIM-specific proteomic characteristics and demonstrates the potential utility of new protein biomarkers for the differential diagnosis of PAIM and lmCRC. These findings may contribute to improving the diagnostic accuracy and guide appropriate treatments for these patients.

Abstract Background The relationship between molecular characteristics and the prognosis of colorectal cancer (CRC) patients has not been fully understood. This study explored the impact of targeted therapy on the prognosis of CRC patients with different TP53 mutations, in the context of comprehensive treatment. Methods This study included patients with stage III/IV primary CRC from the electronic medical record system. TP53 mutations were detected via next‐generation sequencing (NGS) using formalin‐fixed paraffin‐embedded (FFPE) tissues. Applying two methods, we classified TP53 mutations as gain of function (GOF)/non‐GOF mutations or known/likely loss of function (LOF) mutations. Kaplan–Meier plot and parametric survival analysis were performed to evaluate the prognosis of CRC patients and identify potential predictors. Results There were 286 patients included, of which 166 (58.04%) patients received targeted therapy and 120 (41.96%) did not. There were 286 patients in the TP53 GOF classification set and 247 in the TP53 LOF classification set. Parametric survival analysis, adjusted for sex, onset, KRAS mutation, sidedness, stage, and surgery, showed that receiving targeted therapy predicted better overall survival (OS) among patients who harbored TP53 GOF mutations (HR 0.40, 95% confidence interval (CI) [0.21, 0.76], p = 0.005) or known LOF mutations (HR 0.21, 95% CI [0.07, 0.60], p = 0.002). However, there was no significant impact of receiving targeted therapy on OS among patients harboring TP53 non‐GOF mutations (HR 1.68, 95% CI [0.50, 5.63], p = 0.403) or likely LOF mutations (HR 0.90, 95% CI [0.34, 2.39], p = 0.837). Conclusions Receiving targeted therapy had a heterogeneous impact on the prognosis of CRC patients harboring different TP53 mutations. These results provide promising value for future personalized treatment and precision medicine.

To the best of the author’s knowledge, studies of mature plasmacytoid dendritic cell proliferation associated with T lymphoblastic lymphoma were extremely rare in the literature. Here, we report a patient who underwent both mature plasmacytoid dendritic cell proliferation and T lymphoblastic lymphoma. With the findings of lymph node biopsy taken from the right cervical and inguinal regions, we identified eye-catching mature plasmacytoid dendritic cells that were considered to be responsible for this lesion at the beginning, until the immunostaining of Ki67 and TDT showed a small group of positive cells hiding in these plasmacytoid dendritic cells. A bone marrow biopsy was also performed on this patient. Microscopically, the hematopoietic tissue was almost completely replaced by lymphoblastoid cells with condensed chromatin, inconspicuous nucleoli and scanty cytoplasm, which were basically the same as those seen in the lymph nodes in morphology. However, there was no sign of plasmacytoid dendritic cells or Langerhans cells in the bone marrow biopsy. With the help of bone marrow biopsy, our final diagnosis of the lymph node was T lymphoblastic lymphoma coexisting with mature plasmacytoid dendritic cell proliferation. Although accumulations of plasmacytoid dendritic cells may occur in some infections or reactive lymphadenopathy, the presence of extensive nodules or infiltration of plasmacytoid dendritic cells strongly reminds the pathologist to carefully evaluate the bone marrow or peripheral blood status of the patient to exclude a hidden myeloid or other neoplasm.

This study develops a method combining a convolutional neural network model, INSIGHT, with a self -atten-tion model, WiseMSI, to predict microsatellite instability (MSI) based on the tiles in colorectal cancer patients from a multicenter Chinese cohort. After INSIGHT differentiates tumor tiles from normal tissue tiles in a whole slide image, features of tumor tiles are extracted with a ResNet model pre-trained on ImageNet. Attention -based pooling is adopted to aggregate tile-level features into slide-level representation. INSIGHT has an area under the curve (AUC) of 0.985 for tumor patch classification. The Spearman correlation coefficient of tumor cell fraction given by expert pathologist and INSIGHT is 0.7909. WiseMSI achieves a specificity of 94.7% (95% confidence interval [CI] 93.7%-95.7%), a sensitivity of 84.7% (95% CI 82.6%-86.9%), and an AUC of 0.954 (95% CI 0.948-0.960). Comparative analysis shows that this method has better performance than the other five classic deep learning methods.

To the Editor: Colorectal cancer (CRC) is a major cause of cancer-related death worldwide, and several pathogens with carcinogenic potential, such as Schistosoma, have been associated with an increased risk of CRC. As a frequently mutated gene in CRC patients, kirsten rat sarcoma viral oncogene homolog (KRAS) helps to determine the selection of CRC therapies. Therefore, we aimed to elucidate the association among Schistosoma infection, KRAS mutation status, and the prognosis of CRC in this study. We enrolled 489 CRC patients (schistosomal CRC [SCRC]: n = 30, non-schistosomal CRC [NSCRC]: n = 459) who were pathologically diagnosed at Union Hospital, Tongji Medical College of Huazhong University of Science and Technology from January 1, 2010 to June 31, 2019 in this corhort study. Each patient was pathologically diagnosed with primary CRC [Figure 1A], and the degree of differentiation and histological type were described according to the American Joint Committee on Cancer criteria. The criteria for positive infection included the presence of intact or calcified eggs, active granulomas, or adult worms [Figure 1A]. Those with metastatic disease and/or unconfirmed tumor information were excluded. The clinical features, including sex, age, year of diagnosis, stage, histological type, tumor differentiation, primary site, primary tumor size, chemotherapy, radiotherapy, KRAS mutation status (verified by quantitative polymerase chain reaction [qPCR]), survival time, and survival status, were collected. The study was approved by the Medical Ethics Committee of Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology (No. 2018-S377).Figure 1: Association between Schistosoma infection and prognosis of colorectal cancer. (A) Hematoxylin–eosin staining of CRC tissues, scale bar: 500 μm. Left: NSCRC; Right: SCRC. The arrows indicated deposited Schistosoma eggs. (B) Overall survival of SCRC and NSCRC patients. (C) Disease-free survival of SCRC and NSCRC patients. CRC: Colorectal cancer; MST: Mean survival time; NSCRC: Non-schistosomal colorectal cancer; SCRC: Schistosomal colorectal cancer.All statistical analyses were performed using SPSS statistics software (version 26.0, IBM Corporation, Armonk, NY, USA). The statistical significance of baseline clinicopathological characteristics was assessed with the Chi-squared test or Fisher's exact test as appropriate. Univariate and multivariate Cox analyses were conducted to estimate the relationship between Schistosoma infection and the overall survival (OS) of patients with CRC. The Kaplan–Meier test was performed for survival analysis. Propensity score matching (PSM) was applied to balance the clinicopathological variables of the patients at a 1:4 ratio with the Schistosoma infection (yes or no) as the dependent variable and confounding factors (sex, age, histology, and primary site) as the covariates. A two-sided P value < 0.05 was considered statistically significant. Baseline characteristics of the CRC patients were shown in Supplementary Table 1, https://links.lww.com/CM9/B784. Kaplan–Meier survival analysis revealed that patients with SCRC exhibited statistically significantly worse OS (mean survival time [MST] of SCRC: 51.9 months [95% confidence interval [CI]: 43.0–60.7] vs. MST of NSCRC: 65.3 months [95% CI: 62.9–67.6], χ2 = 9.908, P = 0.002) and disease-free survival (DFS, MST of SCRC: 51.5 months [95% CI: 42.4–60.6] vs. MST of NSCRC: 63.1 months [95% CI: 60.7–65.6], χ2 = 5.298, P = 0.021) compared to those with NSCRC [Figures 1B and 1C]. Moreover, univariate and multivariate Cox regression analyses showed that Schistosoma infection was an independent risk factor for CRC in terms of OS. Specifically, compared with NSCRC patients, worse OS was associated with SCRC patients (univariate Cox analysis: hazard ratio [HR], 2.689; 95% CI, 1.416–5.108; P = 0.003. Multivariate Cox analysis: HR, 2.507; 95% CI, 1.275–4.932; P=0.008) [Supplementary Table 2, https://links.lww.com/CM9/B784]. For DFS, the univariate Cox regression analysis identified Schistosoma infection as a risk factor for CRC (HR, 2.062; 95% CI, 1.098–3.873; P = 0.024). However, after controlling for potential confounding factors in the multivariate Cox regression analysis, Schistosoma infection was no longer an independent risk factor for CRC (HR, 1.849; 95% CI, 0.956–3.575; P = 0.068) [Supplementary Table 3, https://links.lww.com/CM9/B784]. There was no statistically significant difference in the mutation rate of overall KRAS (verified through qPCR) between the SCRC and NSCRC groups (63.3% [19/30] vs. 48.8% [224/459], χ2 = 2.379, P = 0.123). However, a detailed analysis of specific mutation sites revealed an interesting distinction. Patients with SCRC were more likely to have KRASG12S/D mutations than patients with NSCRC (43.3% [12/30] vs. 18.1% [83/459], χ2 = 11.379, P = 0.001) [Supplementary Table 4, https://links.lww.com/CM9/B784]. Due to limitations of the KRAS mutation qPCR detection kit (where detection primers for the G12S and G12D sites are combined in one reaction tube), mutations at G12S or G12D were indistinguishable. To address this limitation, we expanded our analysis by performing next-generation sequencing on an additional 230 colorectal cancer patients. After applying 1:4 PSM, a well-balanced study population was obtained, consisting of a SCRC group (n = 8) and a matched NSCRC group (n = 32). It is worth noting that in the SCRC group, the mutation rate of KRASG12D was statistically significantly higher compared to the NSCRC group (4/8 vs. 3/32, χ2 = 4.773, P=0.029) [Supplementary Table 5, https://links.lww.com/CM9/B784]. Notably, the KRASG12S mutation was absent in both groups [Supplementary Table 5, https://links.lww.com/CM9/B784]. Finally, The Kaplan–Meier survival analysis showed that KRAS mutations were not associated with OS (MST of SCRC: 64.1 months [95% CI, 60.9–67.4] vs. MST of NSCRC: 64.9 months [95% CI: 61.7–68.0], χ2 = 0.063, P = 0.802) or DFS (MST of SCRC: 62.4 months [95% CI: 59.2–65.7] vs. MST of NSCRC: 62.4 months [95% CI: 59.0–65.8], χ2 = 0.025, P = 0.874) among CRC patients. Similarly, KRASG12S/D mutations were not associated with OS (MST of SCRC: 63.4 months [95% CI: 58.6–68.1] vs. MST of NSCRC: 64.7 months [95% CI: 62.2–67.2], χ2 = 0.016, P = 0.899) or DFS (MST of SCRC: 61.9 months [95% CI: 57.0–66.8] vs. MST of NSCRC: 62.3 months [95% CI: 59.7–65.0], χ2 = 0.005, P = 0.944) in this patient population [Supplementary Figure 1, https://links.lww.com/CM9/B784]. Increasing evidence indicates that schistosomiasis is associated with the development of certain malignancies (such as bladder cancer, liver cancer, and other urogenital tumors), but the effects of Schistosoma infection on the prognosis of CRC have rarely been studied. A report from the National Cooperative Group on Pathology and Prognosis of CRC indicated that CRC patients with schistosomiasis had a 5-year survival rate of 45.6% [196/430], significantly lower than that of patients without schistosomiasis (50.9% [1383/2717]).[1] The study by Wang et al[2] on 30 patients with Schistosoma japonicum-associated rectal cancer revealed that schistosomiasis was an independent prognostic factor for worse DFS and OS in CRC. In this study, the Kaplan–Meier survival analysis showed that SCRC patients had worse OS and DFS than NSCRC patients, which further supported the association between Schistosoma infection and worse prognosis in CRC. A previous study conducted by Soliman et al[3], including 59 Egyptian colorectal carcinoma patients, found that schistosomiasis was linked to KRAS mutations. This finding prompted us to investigate the correlation between Schistosoma infection and KRAS mutations in a Chinese population. Although we did not find an association between overall KRAS mutations and Schistosoma infection, upon further analysis of mutation sites, we observed a statistically significantly higher mutation rate of KRASG12D in SCRC patients compared to NSCRC patients. While we did not replicate the exact results found by Soliman et al[3], we consider that this discrepancy may be attributed to differences in ethnic backgrounds, Schistosoma species, or potentially limited sample sizes. Additionally, it is worth noting that KRASG12D is the most common mutation in KRAS-mutant tumors (5894/17,741, 33.2%).[4] Nevertheless, the development of KRASG12D inhibitors has been notably hampered because of the structural characteristics of the KRASG12D site. The high KRASG12D mutation rate in SCRC means that there may be fewer treatments for SCRC than for NSCRC. However, we did not discover any associations between KRAS mutations and OS or DFS in CRC patients in this study. This is consistent with a previous study from our group, in which we revealed that the KRAS mutation was not found to be an independent predictive factor for OS in CRC patients.[5] Therefore, it is possible that the prognosis of schistosomiasis is not directly driven by KRAS mutations. Strengths of our study include a large sample size, comprehensive clinical and pathological information, and the use of PSM to address confounding factors. We also ensured diagnostic accuracy through a rigorous review by experienced pathologists. This study investigates the association between Schistosoma infection and the KRAS mutation sites, providing valuable insights into the underlying mechanisms. In summary, this study highlights the association of Schistosoma infection with poor prognosis and a higher KRASG12D mutation rate in CRC patients. KRAS mutations lead to resistance to anti-epithelial growth factor receptor treatment, and no effective inhibitor exists for KRASG12D, making SCRC patients more likely to encounter inadequate treatment options. The prevention and treatment of schistosomiasis require further investigation. Future research should focus on elucidating the relationship between Schistosoma infection and KRASG12D mutation in CRC patients. Funding This work was supported by grants from the National Key Research and Development Program of China (Nos. 2022YFF1203300 and 2018YFC1313300), the National Natural Science Foundation of China (Nos. 81702392 and 81472707), the Chinese South Western Oncology Group (No. CSWOG-CCET005), and the Beijing Bethune Public Welfare Foundation (No. BJ-GYQZHX2021006). Conflicts of interest None.

Abstract Objectives To investigate if different methods of pancreatoduodenectomy (with or without pyloric preservation) would have different impacts on postoperative nutrition and body composition changes among pancreatic cancer patients. Methods Demographic and clinicopathological data, perioperative data were collected, body composition (e.g. skeletal muscle cross‐sectional area [CSA], visceral fat area [VFA]) were evaluated with abdominal CT before and after surgery. Sarcopenia patients' proportion changes were also recorded. Results The hospital stay in the PRPD group was significantly less than that in the PPPD group (p < 0.05). A significant difference was found in CSA, skeletal muscle index (SMI), VFA, VFA/CSA and albumin (ALB) in both groups between preoperative, 3, and 12 months after surgery. The loss of visceral fat in the PRPD group was more prominent than that in the PPPD group at 3 months and 12 months after surgery (p < 0.05). VFA/CSA was higher in the PPPD group than in the PRPD group (3 months: p < 0.05, 12 months: p < 0.001). The proportion of sarcopenic patients increased significantly over time in the PPPD and PRPD groups (p < 0.001). Conclusions Postoperative CSA and VFA continued to significantly decrease in both PPPD and PRPD groups, while the incidence of sarcopenia continued to increase. Compared with PRPD, PPPD has a protective effect on visceral fat. PPPD may contribute to better maintaining visceral fat mass and blood ALB levels. CT quantification can be an objective and effective method to evaluate the nutritional status of pancreatic cancer patients during the pre‐ and postoperative period and can provide a useful objective basis for guiding clinical treatment.

Primary gastrointestinal melanoma (PGIM) has received more attention because of its inferior prognosis. Less is known about the incidence and survival rate of PGIM. PGIM data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The incidence was estimated by age, sex, race, and primary site. Trends in incidence were described as annual percent change (APC). Cancer-specific survival (CSS) and overall survival (OS) rates were estimated and compared using log-rank tests. Cox regression analyses were performed to identify independent prognostic factors. The overall incidence of PGIM was 0.360/1,000,000 with a significant upward trend (APC = 1.77

Background Anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several mesenchymal tumors, with significant implications for diagnosis, therapy and prognosis. However, few studies have investigated the correlation between ALK expression status and clinicopathological characteristics in patients with gastrointestinal stromal tumors (GISTs). Methods A total of 506 GIST patients were enrolled. Sanger sequencing was employed to detect c-KIT and PDGFRA gene mutations. The tissue microarray (TMA) technique and immunohistochemistry were employed to identify the ALK (clone: 1A4 and D5F3) expression status in the tumor tissues. The ALK gene variants of IHC-positive cases were analyzed by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). The clinicopathological data were analyzed using SPSS Statistics 26.0. Results Among the 506 GIST patients, the c-KIT mutation accounted for 84.2% (426/506), followed by PDGFRA mutation (10.3%, 52/506), while the wild-type accounted for the least (5.5%, 28/506). ALK-positive expression was detected in PDGFRA -mutant GISTs (7.7%, 4/52) but negative for c-KIT -mutant or wild-type GISTs by IHC. Four ALK IHC-positive patients were all male. The tumors all occurred outside the stomach. The predominant patterns of growth were epithelioid (2/4), spindle (1/4), and mixed type (1/4). They were all identified as high-risk classification according to the National Institutes of Health (NIH) classification. Aberrant ALK mutations were not identified by DNA-based NGS except in one of the 4 cases with amplification by FISH. Conclusion Our study revealed 7.7% (4/52) of ALK expression in PDGFRA -mutant GISTs, indicating that molecular tests were required to rule out the possibility of PDGFRA -mutant GISTs when encountering ALK-positive mesenchymal tumors with CD117-negative or weakly positive in immunohistochemical staining.

Background To clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations. Methods A total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists. Results Forty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility. Conclusions The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Some patients with marginal zone lymphoma (MZL) experience histological transformation to diffuse large B-cell lymphoma (DLBCL). Because of the paucity of long-term data on transformation, we conducted a population-based study to estimate the risk of transformation and its impact on survival in MZL. Using the Surveillance, Epidemiology and End Results database, we identified 23 221 patients with histology-proven MZL between 2000 and 2018. Competing risk method, Kaplan-Meier and Cox proportional hazards regression were performed to analyze time-to-event outcomes. Based on 420 events of transformation, the 10-year cumulative incidence rate of transformation is 2.23% (95% CI: 2.00%-2.46%) in MZL, 1.5% (95% CI: 1.3%-1.8%), 2.7% (95% CI: 2.3%-3.2%) and 5.8% (95% CI: 4.6%-7.1%) in extranodal, nodal and splenic MZL (EMZL, NMZL and SMZL), respectively. Patients with SMZL (subdistribution hazard ratio [SHR], 2.96; 95% CI: 2.21-3.96) or NMZL (SHR, 1.49; 95% CI: 1.17-1.90) have a higher risk of transformation than those with EMZL. For each MZL subtype, patients with transformation had a significantly shorter overall survival. Patients with transformation >18 months since MZL diagnosis had longer OS than those who presented within 18 months (5-year rate, 87.4% [95% CI: 83.7%-91.2%] vs 47.9% [95% CI: 38.8%-59.0%]; P < .001). Compared to patients with matched de novo DLBCL, those whose DLBCL was transformed from MZL had a shorter OS (5-year rate, 56.6% [95% CI: 51.9%-61.8%] vs 46.1% [95% CI: 40.9%-51.9%]; P < .001). We concluded that patients with SMZL had the highest risk of transformation. Regardless of MZL subtype, transformation resulted in significantly increased mortality.

Objectives Survivors of diffuse large B-cell lymphoma (DLBCL) are at an increased risk of developing second primary malignancies. However, the risk of secondary acute myeloid leukaemia (sAML) has not been previously described in detail, and the outcomes of patients with sAML are also undiscovered compared with their de novo counterparts (de novo acute myeloid leukaemia, dnAML).Design This study is a retrospective database study.Setting and participants A total of 70 280 patients with primary DLBCL, diagnosed between 2000 and 2016, were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Another cohort with dnAML matching with sAML was also obtained from SEER database.Results The standardised incidence ratio was 6.23 (95% CI: 5.50 to 7.03) for sAML among survivors of DLBCL. The estimated cumulative incidence of sAML was 0.61% 15 years after the diagnosis of DLBCL. Patients aged 60–74 years were more likely to have sAML than those <60 years (subdistribution HR (sHR)=1.417; 95% CI: 1.087 to 1.850), whereas patients aged ≥75 years were less likely to have sAML (sHR=0.648; 95% CI: 0.452 to 0.930). Patients with advanced-stage DLBCL were more prone to sAML than those with early-stage disease (sHR=1.307; 95% CI: 1.012 to 1.690). There was a significant difference of survival between patients with dnAML and those with sAML (HR=1.25; 95% CI: 1.01 to 1.53).Conclusions The risk of developing sAML after DLBCL is substantial. Patients aged 60–74 years and with advanced-stage are more prone to sAML. And, compared with their dnAML counterparts, patients with sAML have a worse prognosis.

Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and proficient DNA mismatch repair (pMMR) exhibit heterogeneous tumor characteristics, distinct responses to immunotherapy, and different survival outcomes. However, it is unclear whether gut microbiota is distinct between CRCs with different MMR status. In this study, we used immunohistochemistry for four major MMR proteins to determine the MMR status in 230 CRC patients. The gut microbiota was profiled in cancerous and adjacent normal tissues by using bacterial 16S rRNA sequencing. The differences in microbiota diversity, composition and related metabolic pathways between patients with dMMR and pMMR CRCs were explored. Linear discriminant analysis effect size (LEfSe) analysis was further applied to validate the significant taxonomic differences at the genus level. In our study cohort, dMMR status was identified in 29 of 230 (12.61%) tumors. The richness (alpha-diversity) of gut microbiome in dMMR tumor tissue was higher compared with pMMR tumor tissues. The microbial community composition (beta-diversity) between the two groups was significantly different. The dMMR group was enriched considerably for some microbiota, including Fusobacteria, Firmicutes, Verrucomicrobia, and Actinobacteria at the phylum level and Fusobacterium, Akkermansia, Bifidobacterium, Faecalibacterium, Streptococcus, and Prevotella bacteria at the genus level. However, the pMMR group was dominated by Proteobacteria at the phylum level and Serratia, Cupriavidus and Sphingobium at the genus level. Moreover, a wide variety of microbiota associated functional pathways were observed with different MMR status. KEGG pathway analysis indicated a higher abundance of the biosynthesis and metabolic pathways of glycan and nucleotide, cell growth and death pathways, genetic replication and repair pathways in dMMR samples compared with the pMMR group. These findings demonstrate that CRC patients with different MMR status have distinct gut bacterial community richness, compositions and related metabolic pathways, suggesting basis that may explain the effectiveness of immunotherapy in dMMR tumors.

Abstract Objective: Tumor spread through air spaces(STAS) is a poor prognostic factor for early-stage non-small-cell cancers. This investigation sought to determine the correlations of preoperative peripheral blood parameters with STAS and survival outcomes in pathological stage I lung adenocarcinoma (ADC). Methods: We retrospectively reviewed 633 stage I ADC patients who underwent radical surgical resection for the presence of STAS using HE-stained pathological sections. The baseline clinicopathological features, preoperative peripheral blood indexes and follow-up data were analysed. Independent indicators of STAS were identified using multivariate logistic regression. Kaplan‒Meier analyses were used to examine overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox regression analysis wasused to identifyindependent prognostic variables. Results: STAS was discovered in 285 (45.0%) of the 633 patients. STAS positivity was related to gender, smoking status, disease stage, predominant histological pattern, and differentiation. The multivariate logistic regression identified a level of carcinoembryonic antigen (CEA) ≥5 ug/L and absolute monocyte count (AMC) ≥0.38 G/L as an independent predictor of STAS (p=0.005; p=0.013) among the hematological parameters. STAS positivity was an independent poor prognostic factor for RFS and OS in the CEA <5 µg/L subgroup but not in the CEA ≥5 µg/L subgroup (RFS: HR=2.616, 95% CI=1.414-4.839, p=0.002; OS: HR=5.534, 95% CI=1.186-25.816, p=0.029). In STAS-negative patients but not in STAS-positive patients, CEA demonstrated an independent predictive influence for recurrence and death (RFS: HR=6.488, 95% CI=2.475-17.010, p=0.005; OS: HR=19.569, 95% CI=2.487-153.983, p=0.005). Conclusions: Preoperative hematological examination can be prioritised in predicting the presence of STAS, and CEA ≥5 ug/L and AMC ≥ 0.38 G/L were independent risk predictors for STAS in pathological stage I lung adenocarcinoma. Combining preoperative hematological markers with STAS can optimize the prediction of cancer mortality or recurrence following patient subclassification.

Background:Patients with Lynch syndrome are at an increased risk of developing simultaneous or metachronous tumors, while sarcomas have been occasionally reported. Sarcomas are generally not considered part of the common Lynch syndrome tumor spectrum. However, more and more studies and case reports suggested that sarcoma could be a rare clinical manifestation of Lynch syndrome, leading to new treatment strategies for sarcoma. Case summary:We report the case of a 74-year-old male patient with Lynch syndrome who had rectal mucinous adenocarcinoma and prostate adenocarcinoma and then developed undifferentiated sarcoma of the left neck two years later. Mismatch repair deficiency (dMMR) was confirmed by immunohistochemical staining for the mismatch repair proteins MSH2, MSH6, MLH1 and PMS2. The result of polymerase chain reaction (PCR) microsatellite instability (MSI) testing of sarcoma showed high-level microsatellite instability (MSI-H). Additionally, a pathogenic germline mutation in MSH2 (c.2459-12A>G) was detected by next-generation sequencing (NGS). Taking into account HE morphology, immunohistochemical phenotype, MSI status, NGS result, medical history and germline MSH2 gene mutation, the pathological diagnosis of left neck biopsy tissue was Lynch syndrome related undifferentiated sarcoma with epithelioid morphology. The patient has been receiving immunotherapy (sintilimab) combined with chemotherapy (tegafur, gimeracil and oteracil potassium capsules) and currently has stable disease. We also reviewed the literature to understand the association between sarcoma and Lynch syndrome. Conclusion:Sarcoma may now be considered a rare clinical manifestation of Lynch syndrome. Attention and awareness about the association between Lynch syndrome and sarcoma need to be increased. Therefore, timely detection of MMR proteins and validation at the gene level for suspicious patients are the keys to avoiding missed or delayed diagnosis and to identifying patients suited for immunotherapy, which may also help to provide appropriate genetic counseling and follow-up management for patients.

Background Gastrointestinal stromal tumours (GISTs) rarely arise in the esophagus. The clinical course and treatment options for esophageal GISTs are poorly understood because of their rarity. In general, the mutation spectrum of esophageal GISTs resembles that of gastric GISTs. Wild-type (WT) GISTs lacking KIT and PDGFRA gene mutations occasionally occur in adults; primary esophageal GISTs are commonly WT . Case presentation Herein, we report the case of a 41-year-old female patient who presented with a 1-week history of anterior upper chest pain. Chest computed tomography revealed a 3.7 cm × 2.8 cm × 6.7 cm soft tissue mass in the right posterior mediastinum adjacent to the esophagus. The patient underwent thoracoscopic mediastinal tumor resection and was subsequently diagnosed with an esophageal GIST. Neither KIT nor PDGFRA mutations were detected by Sanger sequencing; however, next-generation sequencing (NGS) identified an FGFR2-KIAA1217 gene fusion in the tumor tissue. No relapse was observed in this patient during the 8-month treatment-free follow-up period. Conclusion To the best of our knowledge, this report is the first to describe an FGFR2-KIAA1217 fusion in a patient with a quadruple WT esophageal GIST. When WT KIT/PDGFRA GISTS are suspected, intensive genetic analysis is recommended, and obtaining a better molecular characterization of these tumours might reveal novel therapeutic avenues.