Clinicopathological Outcomes Research Articles

SLC1A5 is a key regulator of glutamine metabolism and a prognostic marker for aggressive luminal breast cancer

Cancer cells exhibit altered metabolism, often relying on glutamine (Gln) for growth. Breast cancer (BC) is a heterogeneous disease with varying clinical outcomes. We investigated the role of the amino acid transporter SLC1A5 (ASCT2) and its association with BC subtypes and patient outcomes. In large BC cohorts, SLC1A5 mRNA (n = 9488) and SLC1A5 protein (n = 1274) levels were assessed and correlated their expression with clinicopathological features, molecular subtypes, and patient outcomes. In vitro SLC1A5 knockdown and inhibition studies in luminal BC cell lines (ZR-75-1 and HCC1500) were used to further explore the role of SLC1A5 in Gln metabolism. Statistical analysis was performed using chi-squared tests, ANOVA, Spearman’s correlation, Kaplan–Meier analysis, and Cox regression. SLC1A5 mRNA and SLC1A5 protein expression were strongly correlated in luminal B, HER2 + and triple-negative BC (TNBC). Both high SLC1A5 mRNA and SLC1A5 protein expression were associated with larger tumour size, higher grade, and positive axillary lymph node metastases (P < 0.01). Importantly, high SLC1A5 expression correlated with poor BC-specific survival specifically in the highly proliferative luminal subtype (P < 0.001). Furthermore, SLC1A5 knockdown by siRNA or GPNA inhibition significantly reduced cell proliferation and glutamine uptake in ZR-75-1 cells. Our findings suggest SLC1A5 plays a key role in the aggressive luminal BC subtype and represents a potential therapeutic target. Further research is needed to explore SLC1A5 function in luminal BC and its association with Gln metabolism pathways.

Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis

BackgroundEnolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis.MethodsThe bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays.ResultsENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro.ConclusionOur data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib.

High Frequency of PIK3R1 Alterations in Ovarian Cancers: Clinicopathological and Molecular Associations.

The phosphoinositide 3-kinase (PI3K) pathway is activated in multiple cancers. However, the significance of PIK3R1 encoding the PI3K regulatory subunit, an inhibitor of the PI3K catalytic subunit encoded by PIK3CA, in ovarian cancer development is largely unknown. Here, we investigated PIK3R1 genomic alterations and gene expression by direct sequencing and qPCR methods in 197 ovarian cancers. The results were correlated with clinicopathological and molecular variables and patient outcomes. In addition to mutations (3.5%) and allelic losses (28.4%), we observed a very high frequency of decreased PIK3R1 mRNA levels in ovarian carcinomas (95.8%). Tumors with PIK3R1 mutations mostly represented low-stage cancers of endometrioid and clear-cell type. Tumors with PIK3R1 deletion and underexpression shared similar phenotypes of high-grade carcinomas (p = 0.003 and p = 0.025, respectively). Allelic loss was also associated with advanced stages (p = 0.003) and high-grade serous histotypes (p = 0.004). The PIK3R1 copy number correlated with mRNA levels (p = 0.009). PIK3R1 mutations coexisted with PTEN mutations (p = 0.041), whereas PIK3R1 deletion and underexpression were linked to PIK3CA amplification (p = 0.038 and p = 0.033, respectively). Low PIK3R1 expression diminished the probability of a complete response (OR 0.07, p = 0.03) in patients treated with platinum-based regimens. PIK3R1 alterations may contribute to the development of ovarian cancers with different malignant potential and molecular changes. The high frequency of PIK3R1 aberrations suggests their importance in PI3K pathway deregulation, and they may potentially serve as an alternative to PIK3CA markers for therapy with these pathway inhibitors.

Disparities in Triple Negative Breast Cancer Among Hispanic Population Living in Latin America Versus the United States.

Triple-negative breast cancer (TNBC) has a prevalence of 12%-24% in the Hispanic population. Previous research has demonstrated that disparities in healthcare access significantly influence patient outcomes. We aimed to compare the clinicopathological characteristics and outcomes of Hispanic females with TNBC living in Latin America (HPLA) to the Hispanic population in the United States (HPUS). We evaluated two retrospective cohorts: patients diagnosed with TNBC at the Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru, during 2000-2015, and HPUS patients with TNBC from the Surveillance, Epidemiology, and End Results Program (SEER). A total of 2007 HPLA and 8457 HPUS patients were included. The HPLA patients were younger and more frequently lived in nonmetropolitan areas. HPLA had higher T and N (p < 0.001) stages. HPLA patients were more likely to present with Stage III disease (51.6% vs. 20.8%), while Stage IV presentations were similar 6.6% vs. 6.8%. HPLA patients with Stages I and II more frequently underwent mastectomy compared to HPUS (56.2 vs. 48.0%). HPLA patients received neoadjuvant chemotherapy (p < 0.001), adjuvant chemotherapy (p < 0.001), and radiotherapy (p < 0.001) more often. While early breast cancer stages had similar overall survival (OS) rates for both populations, HPLA patients had worse 5-year OS rates compared to HPUS patients in Stages III (39.9% vs. 52.3%, p < 0.001) and IV (4.6% vs. 10.7%, p < 0.001). Hispanic females living in Latin America were more frequently diagnosed with advanced stages of TNBC and more often underwent mastectomy, even in early-stage disease. When analyzing advanced stages, HPLA had worse OS rates compared to HPUS.

Clinicopathological Characteristics and Long-Term Outcomes of Cystic vs. Solid Pancreatic Neuroendocrine Tumors: A Multi-Institutional Experience with 1727 Patients.

To investigate the clinicopathological features and long-term outcomes of cystic and solid pancreatic neuroendocrine tumors (PanNETs). PanNETs uncommonly present as cystic lesions. Whether cystic PanNETs represent a distinct clinical entity compared to solid PanNETs is controversial. Clinicopathologic data of patients with resected PanNETs were collected from 4 high-volume centers between 2000-2019. Clinicopathological characteristics and outcomes of patients with cystic and solid PanNETs were compared based on a 3cm tumor size cut-off using the Chi-squared test and Mann-Whitney U test. Survival estimates were calculated with the Kaplan-Meier method and log-rank test and multivariable analysis using a Cox proportional hazard model. Of the 1727 patients undergoing pancreatectomy for PanNET, the median age was 58.1 years (IQR, 18.4), and 53.3% were male. Of these, 177 (10.3%) were cystic and 1550 (89.7%) solid. Cystic PanNETs were more prevalent in patients with hereditary syndromes, less frequently functional, and more often located in the body/tail of the pancreas. After the exclusion of patients with functional tumors, WHO G3 tumors, hereditary syndromes, neoadjuvant treatment, and metastatic stage, 145 cystic PanNETs were compared to 1059 solid PanNETs, and the median follow-up period of the cohort was 64 months. Cystic PanNETs demonstrated significantly fewer high-risk histopathological features, lymph node metastases (5.5% vs. 24.0%, P<0.001), and distant recurrence (4.1% vs. 14.4%; P<0.001). Among tumors ≤3cm, cystic PanNETs had a low rate of lymph node metastases (3.9% vs. 17.8%; P<0.001), recurrence (3.1% vs. 8.4%; P=0.041), and low propensity to recur distantly. Cystic PanNETs had favorable long-term survival regardless of tumor size. Cystic PanNETs have a more benign course than their solid counterparts and conservative management can be considered for EUS-FNA-proven cystic PanNETs ≤3cm. Parenchyma and lymph-node sparing resections are warranted in patients with cystic PanNETs>3cm. Patients with poor baseline performance status may forego cystic PanNET resection and not affect their overall survival.

The Patterns of P53, E-Cadherin, β-Catenin, CXCR4 and Podoplanin Expression in Oral Squamous Cell Carcinoma Suggests a Hybrid Invasion Model: an Immunohistochemical Study on Tissue Microarrays.

Oral squamous cell carcinoma (OSCC) is a significant public health challenge associated with high mortality rates primarily due to its invasive and metastatic behavior. This study aimed to evaluate the expression patterns of five critical biomarkers: β-catenin, E-cadherin, podoplanin (PDPN), CXCR4, and p53 in OSCC tissues and to investigate their correlations with clinicopathologic features and patient outcomes. We conducted an immunohistochemical analysis utilizing tissue microarrays (TMAs) from 95 patients diagnosed with primary OSCC. The expression levels of the five biomarkers were quantified using H-scores. Statistical analyses, including Kruskal-Wallis tests, Dunn's post-hoc tests, and correlation analyses, were performed to explore the associations between biomarker expression, clinicopathologic parameters, and overall patient survival. The study found that loss of E-cadherin and β-catenin expression was significantly associated with increased tumor depth and lymphatic invasion, corroborating their role in the process of epithelial-mesenchymal transition (EMT). High levels of PDPN were noted in both early and late-stage OSCC, indicating its potential involvement in initiating invasive behaviors. Notably, CXCR4 expression exhibited positive correlations with E-cadherin and β-catenin, suggesting a hybrid invasion phenotype incorporating both EMT and collective invasion strategies. Although Cox regression analysis did not reveal significant associations between biomarker expression and overall survival (OS) or disease-specific survival (DSS), factors such as alcohol consumption, tumor size, lymph node involvement, and advanced clinical stage emerged as significant negative predictors of both OS and DSS. The expression profiles of β-catenin, E-cadherin, PDPN, CXCR4, and p53 in OSCC tissues provide valuable insights into a hybrid model of invasion that integrates mechanisms of EMT with an important rule in the tumor invasion. This nuanced understanding of OSCC progression highlights the potential of PDPN and CXCR4 as novel therapeutic targets, emphasizing the need for further investigation into their roles in OSCC biology and the development of targeted treatments that could improve patient outcomes and survival rates.

Investigating the association of VHL gene variants with disease risk and clinicopathological outcomes in ccRCC patients from West Bengal, India.

Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive malignancy, with the von Hippel-Lindau (VHL) gene playing a critical role in its pathogenesis. However, the association between VHL gene variants and sporadic ccRCC risk remains unexplored in the Indian population. This study aimed to investigate the somatic and germline variants of the VHL gene in sporadic ccRCC patients from West Bengal, India, and their association with disease risk and clinicopathological parameters. A total of 210 ccRCC patients and 255 ethnicity-matched healthy controls were enrolled. Genomic DNA from blood and tissue samples was analyzed using PCR-based Sanger sequencing. The association of VHL variants with ccRCC risk was assessed using Chi-square tests. The impact of genetic variants on patient clinicopathological features and overall survival was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. We identified twenty-three single nucleotide variants (SNVs) in the VHL gene, including 3 novel variants, OR250433 T > G, OR125589 C > T and OQ627404 G > C. The intronic variant rs61758376 G > C and 3'UTR variant rs1642742 A > G were significantly associated with an increased risk of ccRCC (OR = 1.676, P = 0.0074; OR = 1.735, P = 0.0171, respectively). The rs1642742 GG genotype was also significantly associated with larger tumor size (P < 0.05) and advanced tumor stage (pT4). Kaplan-Meier analysis indicated poorer overall survival for patients with the rs1642742 GG genotype (log-rank P = 0.029). Our study is the first to document the association of VHL gene variants with sporadic ccRCC risk and clinical outcomes in the Indian population. The identified variants, particularly rs61758376 and rs1642742, could serve as potential biomarkers for ccRCC susceptibility and prognosis.

The role of hyperaccuracy CT three-dimensional reconstruction technology in partial nephrectomy for completely endophytic renal cell carcinoma: A retrospective propensity-matched cohort study.

To compare the clinicopathological, perioperative, functional, and oncological outcomes of completely endophytic renal cell carcinoma (RCC) patients who underwent partial nephrectomy (PN) with or without preoperative hyperaccuracy CT three-dimensional (HACT3D) reconstruction. A retrospective cohort study was conducted on 154 completely endophytic RCC patients treated with PN at our medical center from January 2018 to December 2023. Patients were divided into two groups based on whether they received preoperative HACT3D reconstruction. To control for selection bias, we implemented 1:1 propensity score matching based on baseline characteristics. In the original cohort, 47 patients in the HACT3D group had higher RENAL scores (P=0.014) and PADUA scores (P=0.012). After matching, each group contained 47 RCC patients with no significant baseline differences (P>0.05). In the matched cohort, patients in the HACT3D group had significantly shorter warm ischemia time (WIT) (22.3 vs. 26.7min, p<0.001), shorter total length of hospital stay (LOS) (10.0 vs. 11.6 days, p=0.012), shorter postoperative LOS (5.8 vs. 7.3 days, p=0.003), and higher trifecta achievement rate (83.0% vs. 36.2%, p<0.001). Among functional variables, patients in the HACT3D group exhibited a smaller increase in postoperative serum creatinine (SCR) (7.5 vs. 16.5μmol/L, p=0.012), and a smaller decrease in postoperative estimated Glomerular Filtration Rate (eGFR) (-6.9 vs. -14.1mL/min/1.73m2, p=0.011). No significant differences were found in pathological outcomes and prognosis between the two groups (p>0.05). For completely endophytic RCC patients, HACT3D reconstruction can assist clinicians in performing precise parameter measurements, designing personalized surgical approaches, and providing intraoperative image guidance.

Proximal Gastrectomy Is Associated with Lower Incidence of Anemia and Vitamin B12 Deficiency Compared to Total Gastrectomy in Patients with Upper Gastric Cancer.

Proximal gastrectomy is an alternative to total gastrectomy (TG) for early gastric cancer (EGC) treatment in the upper stomach. However, its benefits in terms of perioperative and long-term outcomes remain controversial. The aim of this study was to compare the perioperative, body compositional, nutritional, and survival outcomes of patients undergoing proximal gastrectomy with double-tract reconstruction (PG-DTR) and TG for pathological stage I gastric cancer in upper stomach. The study included 506 patients who underwent gastrectomy for pathological stage I gastric cancer in the upper stomach between 2015 and 2019. Clinicopathological, perioperative, body compositional, nutritional, and survival outcomes were compared between the PG-DTR and TG groups. The PG-DTR and TG groups included 197 (38.9%) and 309 (61.1%) patients, respectively. The PG-DTR group had a lower rate of early complications (p=0.041), lower diagnosis rate of anemia and vitamin B12 deficiency (all p < 0.001), and lower replacement rate of iron and vitamin B12 compared to TG group (all p < 0.001). The PG-DTR group showed reduced incidence of sarcopenia at 6-months postoperatively, preserved higher amount of visceral fat after surgery (p=0.032 and p=0.040, respectively), and showed a higher hemoglobin level (p=0.007). Oncologic outcomes were comparable between the groups. The PG-DTR for EGC located in the upper stomach offered advantages of fewer complications, lower incidence of anemia and vitamin B12 deficiency, less decrease in visceral fat volume, and similar survival compared to TG. Consequently, PG-DTR may be considered a superior alternative treatment option to TG.

Clinical significance of glomerular IgM deposit in IgA nephropathy: a 5-year follow-up study

The significance of glomerular IgM deposit intensity in IgA Nephropathy (IgAN) remained ambiguous and requires further research. Patients with biopsy-proven IgAN in our hospital from January 2018 to May 2023 were recruited into this retrospective single-center study. Patients who presented with positive IgM deposit were included in IgM + cohort while patients with negative IgM deposit were included in IgM– cohort. Of the IgM+, patients whose IF intensity of IgM deposits exceeded 1+ formed IgM-H cohort while patients whose IF intensity of IgM deposits was equal to 1+ consisted IgM-L cohort. Pairwise comparisons were performed among these cohorts to determine clinical disparities, following the propensity score matching process. Among 982 IgAN patients, 539 patients presented with positive IgM deposit. The Kaplan–Meier analysis showed that the IgM deposit did not contribute adversely to the outcomes (eGFR decreased from the baseline ≥ 50% continuously or reached end-stage renal disease). However, the Cox regression analysis showed that increased intensity of IgM deposit was an independent risk factor (p = 0.03) in IgM+. The IgM-H exhibited more pronounced segmental glomerulosclerosis (p = 0.02) than the IgM-L, which may also be associated more directly with higher urine protein levels (p = 0.02). Moreover, our generalized linear mixed model demonstrated a remarkably higher urine albumin/creatinine ratio (p < 0.01) and serum creatinine (p = 0.04) levels as well as lower serum albumin (p < 0.01) level in IgM-H persistently during the 5-year follow-up. This study concluded that increased intensity of glomerular IgM deposits may contribute adversely to clinicopathologic presentation and outcome in those IgM + patients.

Perihilar and Intrahepatic Cholangiocarcinoma after Resection: Clinicopathological Characteristics, Outcomes, and Implications for Addition of Chemoradiotherapy.

The purpose of the present study was to evaluate clinicopathological characteristics, patterns of recurrence, survival outcomes, and implications for the addition of chemoradiotherapy for patients with resected perihilar and intrahepatic cholangiocarcinoma (CCA). For the present retrospective study, we identified 38 and 10 patients with resected perihilar and intrahepatic CCA. In perihilar CCA, adjuvant treatment was given as chemotherapy (n = 13) or chemoradiotherapy (n = 10). In intrahepatic CCA, neoadjuvant treatment was given with transarterial chemoembolization (TACE, n = 1) or chemotherapy plus stereotactic body radiation therapy (SBRT, n = 1), and adjuvant treatment was given to 7 patients with chemotherapy or chemoradiotherapy. In perihilar CCA, preoperative biliary drainage procedures were performed in 27 out of 30 patients with jaundice. The adjacent liver showed secondary sclerosing cholangitis (n = 5) and fibrosis (n = 19). Locoregional recurrence involved the hepaticojejunostomy anastomotic site and lymph nodes. In intrahepatic CCA, the adjacent liver revealed cirrhosis (n = 1), secondary sclerosing cholangitis (n = 1), and fibrosis (n = 6). The sites of recurrence were in the remnant liver and lymph nodes (n = 6). In perihilar CCA, the median overall survival (OS) and disease-free survival (DFS) rates were 30.1 months (95% CI: 22.9-37.4) and 15.1 months (95% CI: 9.74-20.5), respectively. The 2-year and 3-year OS were 60.5% and 44.7%, respectively. Multivariate analysis revealed a significant association of no adjuvant treatment with decreased DFS (p = 0.004), HR 4.03 (95% CI: 1.57-10.4). Recurrence showed an unfavorable association with OS (p = 0.056), HR 2.90 (95% CI: 0.98-8.66). In intrahepatic CCA, the median OS and DFS rates were 41.2 months (95% CI: 13.5-68.9) and 10.8 months (95% CI: 1.98-19.6), respectively. The 2-year and 3-year OS were 66.7% and 53.3%, respectively. The patient with multiple intrahepatic CCA lesions and treated with neoadjuvant chemotherapy and SBRT showed partial pathological necrosis after resection and was disease-free at 3.5 years. The present study showed the effectiveness of the combination of chemoradiotherapy with resection in improving locoregional disease control and survival in patients with perihilar and intrahepatic CCA. Sahai P, Rastogi A, Gupta A, et al. Perihilar and Intrahepatic Cholangiocarcinoma after Resection: Clinicopathological Characteristics, Outcomes, and Implications for Addition of Chemoradiotherapy. Euroasian J Hepato-Gastroenterol 2024;14(2):134-144.

Comparison of robotic and laparoscopic approaches in short- and long-term outcomes of lateral pelvic lymph node dissection for advanced rectal cancer: a Japanese multicenter study.

Lateral pelvic lymph node dissection (LPND) is a challenging surgical technique with complex anatomy and narrow pelvic manipulation. The outcomes of robotic and laparoscopic surgery for LPND are still unclear. We retrospectively reviewed 169 consecutive patients who underwent rectal cancer surgery with LPND between 2016 and 2023. Patients were divided into two groups according to whether LPND was performed by robotic surgery (R group, n = 40) or laparoscopic surgery (L group, n = 129). Clinicopathological feature and outcomes were compared between groups. Frequency of surgery with combined resection of adjacent structures (5.0% vs. 19.4%, p = 0.023), frequency of patients with distant metastasis (5.0% vs. 19.4%, p = 0.028), and estimated blood loss from bilateral LPND (74 mL vs. 132 mL, p = 0.013) were all lower in the R group than in the L group. Type of surgical approach did not correlate with postoperative complications. Median follow-up was 31.0 months (range, 1.0-69.0 months). No patients in the R group experienced local recurrence, compared to 4.6% in the L group. Multivariate analysis revealed laparoscopic surgery (odds ratio 3.687, 95% confidence interval 1.505-6.033; p = 0.004) as an independent predictor of poor relapse-free survival. Robotic surgery for LPND appears to have good prognostic value in some, but not all, oncologic cases. However, large prospective studies are desirable to validate these findings.

Adult minimal change disease: Clinicopathologic characteristics, treatment response and outcome at a single center in Pakistan.

Minimal change disease (MCD) is a significant cause of idiopathic nephrotic syndrome (INS) in adults, representing approximately 10%-15% of INS cases. The data is scanty on clinicopathological features, treatment responses, and long-term outcomes of MCD in adults. To determine the clinicopathologic characteristics, treatment responses, and medium-term outcomes of adult patients with MCD in Pakistan. This retrospective cohort study included all adult patients with biopsy-proven MCD treated at the adult nephrology clinic, Sindh institute of urology and transplantation, between January 2010 and December 2020. The data was retrieved from the original renal biopsy request forms in the histopathology archives and the case files. Data on demographics, clinical presentation, laboratory findings, treatment regimens, and outcomes were collected and analyzed. Complete remission (CR), partial remission (PR), relapse, and steroid resistance were defined according to standard criteria. Statistical analyses were performed using statistical product and service solutions, Version 22. The study cohort included 23 adults [15 (65.2% males), mean age 26.34 ± 10.28 years]. Hypertension was found in 7 (30.4%) and microscopic hematuria in 10 (43.4%) of participants. Laboratory findings revealed a mean serum creatinine of 1.03 ± 1.00 mg/dL, mean serum albumin of 1.94 ± 0.90 g/dL and mean 24-hour urinary proteins of 4.53 ± 2.43 g. The mean follow-up time was 38.09 ± 22.3 months. Treatment with steroids was effective in 16/18 (88.8%) of patients, with 10/16 (62.5%) achieving CR and 6/16 (37.5%) achieving PR. Two patients were resistant to steroids and required second-line immunosuppressive therapy. Relapse occurred in 4/20 (19.04%) of patients, with a mean time to first relapse of 6.5 ± 3.31 months. At the last follow-up, 18/20 (85.7%) of patients were in remission, and 16/20 (76.1%) maintained normal renal function. No patients progressed to end-stage renal disease or died. MCD in adults shows a favorable response to steroid therapy, with a majority achieving remission. However, relapses are common, necessitating second-line immunosuppressive treatments in some cases. The study highlights the need for standardized treatment guidelines for adult MCD to optimize outcomes.

Long-term survival after local immunotherapy for malignant gliomas: a retrospective study with 20 years follow-up

PurposeImmunotherapy is a promising treatment for cancers but should be optimized for malignant gliomas. Because of immune privilege feature of the brain, local administration of immunotherapy may be a promising strategy for malignant glioma treatment. Identification of patients who may benefit from local immunotherapy is essential.MethodsWe retrospectively reviewed the clinicopathological characteristics and outcomes of six malignant glioma patients who received local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor resection cavity. Profiles of tumor genome, transcriptome and immune microenvironment were also investigated by genomic target sequencing, RNA sequencing, electrochemiluminescence assay and immunohistochemistry (IHC) staining.ResultsFour patients died from tumor progression and the overall survival ranged from 10.0 to 33.9 months. Remarkably, two patients, including one diagnosed as diffuse hemispheric glioma H3 G34-mutant (G34-DHG, WHO grade 4) and the other diagnosed as astrocytoma (IDH1 mutation, WHO grade 3) survived more than 20 years without evidence of recurrence. The distinctive clinical feature of the two long-term survivors was tumor gross total resection (GTR) before CIK therapy. NTRK1 mutation was uniquely present and 353 genes were differentially expressed in the long-term survivors compared with the short-term survivors. These differential expression genes were highly associated with immune function. Electrochemiluminescence assay and IHC staining revealed higher expressions of cytokines and lower infiltrations of tumor-associated macrophages in the tumors of the long-term survivors.ConclusionThese findings suggest that certain patients diagnosed as malignant gliomas, including G34-DHG (WHO grade 4), can acquire long-term survival after local immunotherapy. Tumor GTR before local immunotherapy and relatively weaker immunosuppressive tumor microenvironment are the favorable factors for long-term survival. Larger, controlled studies with standardized treatment protocols, including consistent use of GTR, are warranted to further evaluate the potential benefits of locally delivered immunotherapy.

Serovar Australis replaces serovar Copenhageni as the most common cause of canine leptospirosis in New South Wales, Australia.

Highly fatal canine leptospirosis emerged in urban Sydney dogs in 2017, and serovar Copenhageni, against which a registered monovalent vaccine is available, was predominant until 2020. This study was conducted to (1) determine serological characteristics of canine leptospirosis in New South Wales (NSW) between 2021 and 2023; (2) describe the geospatial distribution of leptospirosis; and (3) evaluate if clinicopathological abnormalities and outcome differ between the dominant infecting serovars, Copenhageni versus Australis. Cases were identified through referral or direct veterinarian contact and included if clinical and clinicopathological findings confirmed leptospirosis. Between 2021 and 2023 leptospirosis was confirmed in 61 dogs in NSW. In 2022 two major outbreaks occurred in the local government areas of Shoalhaven (n = 23) and Lake Macquarie (n = 7). The most common serovar identified by microscopic agglutination test (MAT) was Australis (n = 23) followed by Copenhageni (n = 8), Pomona (n = 2), Robinsoni (n = 2) and Bratislava (n = 1). In 16/18 cases from Shoalhaven in which serological results were available, serovar Australis was identified. Dogs infected with serovar Copenhageni were significantly (P < 0.05) more likely to have hepatic involvement with significantly higher liver enzyme activities, bilirubin concentration and icterus, whereas dogs with serovar Australis were significantly (P < 0.01) more likely to have glucosuria. Overall case fatality rate was 40% and was not different between infecting serovars. There are regional differences of infecting serovars with distinct leptospirosis hotspots, and differences in clinicopathological findings. The apparent emergence of serovar Australis highlights the need for bi- or multivalent vaccines and ongoing case surveillance of causal serovars is needed. Glucosuria should prompt leptospirosis testing in endemic areas.

Prognostic role of long noncoding RNA CASC11 in cancer patients: A meta-analysis.

Long noncoding RNA (lncRNA) is a significant component of the noncoding genome and refers to RNA molecules that exceed 200 nucleotides in length. It plays a crucial role in both promoting and suppressing cancer by regulating the proliferation, invasion, and metastasis of tumor cells. We have found a correlation between cancer susceptibility candidate 11 (CASC11) experssion and tumorigenesis development prognosis in a number of studies on tumors. Hence, this meta-analysis was conducted to further investigate the effects of CASC11 expression on clinicopathological features and outcome. Furthermore, CASC11 can act both as a therapeutic target and a cancer biomarker. We conducted a thorough search of PubMed, Embase, Web of Science, and Cochrane Library to identify all eligible studies until September 20, 2023. These studies examined the potential relationship between the expression levels of CASC11 and survival or the range of pathological feature in cancer patients. The impact of CASC11 expression on overall survival (OS) was evaluated using pooled hazard ratios and 95% confidence intervals (CI). The relationship between CASC11 expression and clinicopathological features was assessed through pooled odds ratios and 95% CI. A total of 11 studies, involving 660 patients, were examined in this analysis. The results revealed that the overexpression of CASC11 was significantly associated with poor OS (hazard ratios = 2.07, 95%CI = 1.64-2.60) in cancer. Further subgroup analysis demonstrated that the overexpression of CASC11 was consistently linked to poorer OS in diverse types of cancer, including digestive system neoplasm, respiratory neoplasms, and gynecologic tumor. Overall, this analysis established a strong correlation between CASC11 expression and tumor prognosis, suggesting its potential as a predictive marker for tumor progression in diverse cancer types.

Clinicopathological characteristics of light chain proximal tubulopathy: a multicentre case series

AimsLight chain proximal tubulopathy (LCPT) is a rare complication of paraprotein-related diseases. We report a case series to present the clinicopathological characteristics and outcomes of LCPT.MethodsA multicentre retrospective case series...

Emerging biologic and clinical implications of miR-182-5p in gynecologic cancers.

MicroRNAs (miRNAs) have emerged as important regulators of gene expression in various biological processes, including cancer. miR-182-5p has gained attention for its potential implications in gynecologic cancers, including breast, ovarian, endometrial, and cervical cancers. miR-182-5p dysregulation has been associated with multiple facets of tumor biology in gynecologic cancers, including tumor initiation, progression, metastasis, and therapeutic response. Studies have highlighted its involvement in key signaling pathways and cellular processes that contribute to cancer development and progression. In addition, miR-182-5p has shown potential as a diagnostic and prognostic biomarker, with studies demonstrating its correlation with clinicopathological features and patient outcomes. Furthermore, the therapeutic potential of miR-182-5p is being explored in gynecologic cancers. Strategies such as miRNA mimics or inhibitors targeting miR-182-5p have shown promise in preclinical and early clinical studies. These approaches aim to modulate miR-182-5p expression, restoring normal cellular functions and potentially enhancing treatment responses. Understanding the biologic and clinical implications of miR-182-5p in gynecologic cancers is crucial for the development of targeted therapeutic strategies and personalized medicine approaches. Further investigations are needed to unravel the specific target genes and pathways regulated by miR-182-5p. It is important to consider the emerging biologic and clinical implications of miR-182-5p in gynecologic cancers.

Window entrapment trauma in cats: clinical, neurological and clinicopathological findings and outcome (70 cases).

Window entrapment in cats can lead to reduced blood flow to the spinal cord, muscles and nerves, resulting in ischaemic neuromyelomyopathy. The severity and duration of entrapment greatly influence clinical and neurological outcomes, as well as prognosis. The aim of the present retrospective multicentric study (2005-2022) was to describe clinical, neurological and selected clinicopathological findings, as well as the outcome of cats trapped in bottom-hung windows, presented to both first-opinion and referral-only clinics. The study included cats with detailed clinical and neurological evaluations at admission, along with at least one of the following biochemical parameters: creatine kinase (CK), aspartate transaminase (AST), alanine aminotransferase (ALT) activities, urea and/or creatinine. Clinical and neurological parameters evaluated in the study included rectal temperature, femoral pulse, gait, urinary bladder function, tail function and survival to discharge. Odds ratios (ORs) were calculated for survival and each clinical, neurological and biochemical variable. Of the 70 cats that met the inclusion criteria, only seven (10%) died or were euthanased during hospitalisation. Nevertheless, with the available data, we found evidence of an association between clinical and neurological status and survival, with tail function being the strongest association. Cats lacking tail sensation, motor function and/or tonus were more likely to die than cats with normal tail function or only mild abnormalities (OR = 24). Similarly, cats with severe hypothermia or an absent femoral pulse were less likely to survive (OR = 12.75 and 7.5, respectively). In this sample (with a relatively low number of deaths), we did not find evidence of an association between CK, AST and ALT activity with survival. However, the only two cats with severe increases in creatinine died. Assessment of gait, urinary bladder function, femoral pulse, rectal temperature and particularly tail function is promising for predicting outcomes in cats with window entrapment trauma.

Lung adenocarcinomas with mucinous histology: clinical, genomic, and immune microenvironment characterization and outcomes to immunotherapy-based treatments and KRASG12C inhibitors

BackgroundApproximately 10% of lung adenocarcinomas (LUAD) have mucinous histology (LUADMuc), which is associated to a light/absent smoking history and a high prevalence of KRAS mutations. We sought to characterize LUADMuc by comparing it to LUAD without mucinous histology (LUADnon-muc) and determine the relative benefit of current treatments. Patients and MethodsPatients with LUAD from five institutions and TCGA PanCancer Atlas classified as LUADMuc or LUADnon-muc were included. Clinicopathologic, genomic, immunophenotypic, transcriptional features, and treatment outcomes were compared between LUADMuc and LUADnon-muc. ResultsOf 4,082 patients with LUAD, 9.9% had LUADMuc. Compared to LUADnon-muc, patients with LUADMuc had a lighter smoking history (median: 15 vs 20 pack-years, P=0.008), lower PD-L1 TPS (median: 0% vs 5%, P<0.0001), and lower tumor mutation burden (median: 6.8 vs 8.5 mutations/megabase, P<0.0001). Mutations in KRAS, NKX2-1 (TTF-1), STK11, SMARCA4, GNAS, and ALK rearrangements were enriched in LUADMuc, while TP53, EGFR, BRAF, and MET mutations were enriched in LUADnon-muc. At stage IV diagnosis, LUADMuc was more likely to have contralateral lung metastasis (55.2% vs 36.9%, P<0.0001) and less likely to have brain metastases (23.3% vs 41.9%, P<0.0001). Compared to LUADnon-muc, LUADMuc cases showed lower intratumor CD8+, PD-1+, CD8+PD-1+, and FOXP3+ cells. Among metastatic cases receiving ICIs, compared to LUADnon-muc (N=1,511), LUADMuc (N=112) had lower objective response rate (ORR, 8.4% vs 25.9%, P<0.0001), and shorter median progression-free survival (mPFS, 2.6 vs 3.9 months, P<0.0001) and overall survival (mOS, 9.9 vs 17.2 months, P<0.0001). Similarly, patients with LUADMuc had worse outcomes to chemo-immunotherapy. LUADMuc (N=18) and LUADnon-muc (N=150) had similar ORR (16.7% vs 34.9%, P=0.12) and mPFS (4.6 vs 5.6 months, P=0.17) to treatment with KRASG12C inhibitors, but LUADMuc had shorter mOS (6.8 vs 10.8 months, P=0.018). ConclusionLUADMuc represents a distinct LUAD subpopulation with unique clinicopathologic, genomic, immunophenotypic, and transcriptional features, achieving worse outcomes to standard immunotherapy-based treatments.