Prognostic scoring system based on indicators reflecting the tumor glandular differentiation and microenvironment for patients with colorectal cancer.

Prognostic stratification is an urgent concern for patients with colorectal cancer (CRC). The desmoplastic reaction (DR) is speculated to mirror the tumor microenvironment. DR types are considered independent prognostic indicators in CRC, but have not been incorporated in previous prognostic nomograms. We aimed to assess the prognostic significance of a novel approach incorporating histopathological indicators reflecting tumor glandular differentiation and microenvironment. We evaluated 329 consecutive patients with CRC who underwent surgical resection at Kansai Medical University. Histological glandular differentiation was scored as 2 (0 point), 3 (1 point), or 4 (2 points). Tumor buddings (TBs) were classified as TB1 (0 point), TB2 (1 point), or TB3 (2 points). pT1 or 2 was considered as 0 point, pT3 or 4 + DR non-immature type as 1 point, and pT3 or 4 + DR immature type as 2 points. Lymph node metastasis was classified as pN0 (0 point), pN1 (1 point), or pN2 (2 points). The preoperative carcinoembryonic antigen levels were categorized as < 5.0 ng/mL (0 point) and ≧5.0 (1 point). Considering these factors, the following D&M (tumor differentiation and microenvironment) scoring system was applied: I (0-2 points), II (3-4 points), III (5-6 points), and IV (7-9 points). Kaplan-Meier curves showed significant differences in disease-specific survival and recurrence-free survival among the assigned scores, highlighting their enhanced utility compared with the American Joint Committee on Cancer 8th edition staging system. The D&M scoring system was valuable as the initial prognostic nomogram, including DR.

Cytological features of a lymphoepithelial cyst of the salivary gland with application of the second edition of Milan System for Reporting Salivary Gland Cytopathology.

Lymphoepithelial cysts (LECs) of the salivary glands are relatively rare, benign cystic lesions. Characteristic histopathological features of LEC include presence of well-circumscribed unilocular cysts surrounded by dense lymphoid tissue with lymphoid follicles. These cysts are lined by a combination of squamous, ciliated, columnar and mucous epithelia. Fine-needle aspiration (FNA) cytology is the standard preoperative diagnostic procedure for salivary gland lesions. Although the cytological diagnosis of cystic salivary gland lesions is difficult, the use of Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) in the cytodiagnosis of cystic salivary gland lesions has been reported. However, only a few studies have described the cytological features of LEC. To the best of our knowledge, the present study reviewed the cytological features of a case series of LEC and evaluated the application of MSRSGC for the first time. This retrospective study included 13 patients with LEC of the salivary glands who underwent pre-operative FNA followed by surgical resection of the cyst. All the lesions were present in the parotid gland. Cytological analysis revealed no epithelial cell component in eight patients (62.5%) along with a proteinaceous background containing lymphocytes and/or foamy cells. Non-keratinising squamous epithelium was observed in three patients. Amylase crystalloids were noted in two patients. None of the patients were cytodiagnosed with LEC. Eight, three, one and one patients were categorised as MSRSGC I, II, III, and IVa, respectively. The results of the present study demonstrated that cytodiagnosis of LEC was difficult due to the absence of epithelial component in 62.5% of the specimens. However, evaluation of its benignity was not difficult. Thus, it can be summarized that MSRSGC may be useful for cytological evaluation of LECs.

Analysis of the clinicopathological features of tailgut cyst with emphasis on the development of neoplastic lesions.

Tailgut cyst is a rare congenital cyst occurring in the retrorectal space and development of neoplastic lesions in tailgut cyst has been reported. Due to the rarity of the tumor, the histogenesis of neoplastic lesions in tailgut cyst has remained elusive. In the present study, the clinicopathological features of tailgut cyst were analyzed with a particular focus on the development of neoplastic lesions. The clinicopathological features of four patients with tailgut cyst (one female and three males) were retrospectively reviewed. No symptoms were present in two patients. Perineal discomfort, and constipation and urinary retention, were described in the other two patients, respectively. Magnetic resonance imaging showed that the cystic lesions were hypointense on T1- and hyperintense on T2-weigted images in all patients. Histopathological analysis revealed that all lesions were multilocular, and cystic walls were covered by squamous and ciliated epithelia without nuclear atypia. The development of neoplastic lesions was noted in two patients. Dysplastic change composed of piling-up proliferation of glandular cells with mild to moderate nuclear atypia was present in one patient, and invasive adenocarcinoma with a dysplasia component was observed in another patient. Dysplasia of the glandular cells, as seen in two patients in the present series, may be a precursor lesion of invasive adenocarcinoma; therefore, adenocarcinoma arsing in tailgut cyst may show a dysplasia-carcinoma sequence. While the reported incidence of neoplastic lesions in tailgut cysts is ~9% or less, their frequency remains to be accurately determined. Therefore, complete surgical resection is important for the management of patients with tailgut cyst. Additional clinicopathological and molecular studies with large cohorts may be required to clarify the histogenesis of neoplastic lesion in tailgut cyst.

Downregulated expression of PBRM1 in sarcomatoid hepatocellular carcinoma.

Sarcomatoid hepatocellular carcinoma (SHCC) is a rare and highly lethal subtype of HCC. The present study aimed to explore the unique markers of SHCC using whole gene expression analysis. Subsequently, gene expression analysis was performed using five sarcomatoid and seven carcinomatoid components of seven tissues from patients with SHCC. The results demonstrated a significant downregulation of polybromo 1 (PBRM1) gene expression in the sarcomatoid components. Immunohistochemical staining also indicated a decreased expression of PBRM1 in the sarcomatoid components. Moreover, gene ontology enrichment analysis revealed that most of the 336 differentially expressed genes between the sarcomatoid and carcinomatoid components were involved in functions associated with DNA replication and histone methylation, which was consistent with the loss of function of PBRM1 which encodes Switch/sucrose-non-fermentable chromatin remodeling complex protein. Therefore, the results of the present study suggested that PBRM1 may be a candidate biomarker for the evaluation of SHCC.

Expression of Preferentially Expressed Antigen in Melanoma, a Cancer/Testis Antigen, in Carcinoma In Situ of the Urinary Tract.

Carcinoma in situ (CIS) of the urinary tract comprises 1-3% of all urothelial malignancies and is often a precursor to muscle-invasive urothelial carcinoma (UC). This study aimed to examine the expression profiles of preferentially expressed antigen in melanoma (PRAME), a cancer/testis antigen, and assess its diagnostic and therapeutic applications in CIS, given that its expression in UC has been minimally studied and has not yet been analyzed in CIS. We selected consecutive patients with CIS who underwent biopsy and/or transurethral tumor resection at the Osaka Medical and Pharmaceutical University Hospital. Immunohistochemical staining for PRAME and p53 was performed. Overall, 53 patients with CIS (6 females and 47 males) were included. Notably, PRAME expression was observed in 23 of the 53 patients (43.4%), whereas it was absent in the non-neoplastic urothelial epithelium. Furthermore, no correlation was found between PRAME expression and aberrant p53 expression. Therefore, PRAME expression may serve as a useful marker for CIS of the urinary tract. Furthermore, PRAME may be a candidate for the novel therapeutic target for standard treatment-refractory CIS patients.

The Impact of FGFR3 Alterations on the Tumor Microenvironment and the Efficacy of Immune Checkpoint Inhibitors in Bladder Cancer.

BACKGROUND: Currently, only limited knowledge is available regarding the phenotypic association between fibroblast growth factor receptor 3 (FGFR3) alterations and the tumor microenvironment (TME) in bladder cancer (BLCA). METHODS: A multi-omics analysis on 389 BLCA and 35 adjacent normal tissues from a cohort of OMPU-NCC Consortium Japan was retrospectively performed by integrating the whole-exome and RNA-sequence dataset and clinicopathological record. A median follow-up duration of all BLCA cohort was 31 months. RESULTS: FGFR3 alterations (aFGFR3), including recurrent mutations and fusions, accounted for 44% of non-muscle invasive bladder cancer (NMIBC) and 15% of muscle-invasive bladder cancer (MIBC). Within MIBC, the consensus subtypes LumP was significantly more prevalent in aFGFR3, whereas the Ba/Sq subtype exhibited similarity between intact FGFR3 (iFGFR3) and aFGFR3 cases. We revealed that basal markers were significantly increased in MIBC/aFGFR3 compared to MIBC/iFGFR3. Transcriptome analysis highlighted TIM3 as the most upregulated immune-related gene in iFGFR3, with differential immune cell compositions observed between iFGFR3 and aFGFR3. Using EcoTyper, TME heterogeneity was discerned even within aFGFR cases, suggesting potential variations in the response to checkpoint inhibitors (CPIs). Among 72 patients treated with CPIs, the objective response rate (ORR) was comparable between iFGFR3 and aFGFR3 (20% vs 31%; p = 0.467). Strikingly, a significantly higher ORR was noted in LumP/aFGFR3 compared to LumP/iFGFR3 (50% vs 5%; p = 0.022). This trend was validated using data from the IMvigor210 trial. Additionally, several immune-related genes, including IDO1, CCL24, IL1RL1, LGALS4, and NCAM (CD56) were upregulated in LumP/iFGFR3 compared to LumP/aFGFR3 cases. CONCLUSIONS: Differential pathways influenced by aFGFR3 were observed between NMIBC and MIBC, highlighting the upregulation of both luminal and basal markers in MIBC/aFGFR3. Heterogeneous TME was identified within MIBC/aFGFR3, leading to differential outcomes for CPIs. Specifically, a favorable ORR in LumP/aFGFR3 and a poor ORR in LumP/iFGFR3 were observed. We propose TIM3 as a potential target for iFGFR3 (ORR: 20%) and several immune checkpoint genes, including IDO1 and CCL24, for LumP/iFGFR3 (ORR: 5%), indicating promising avenues for precision immunotherapy for BLCA.

Impact of Trinal Histological Glandular Differentiation Grade on the Prognosis of Patients with Intrahepatic Cholangiocarcinoma: a Multicenter Retrospective Study.

INTRODUCTION: It is unclear whether the histological glandular differentiation (HGD) score that evaluates the tumor grade of two dominant components is prognostic for survival in patients with intrahepatic cholangiocarcinoma (ICC). METHOD: We retrospectively analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at 5 university hospitals in the Kansai region of Japan. RESULTS: Survival was statistically significantly stratified by trinal HGD grade (p < 0.05). Median disease-free survival (DFS) of patients with high HGD grade was significantly shorter compared with moderate HGD grade (13.0 vs 31.2 months, respectively; p = 0.004). By Cox proportional hazards regression analysis, HGD grade had the fifth-highest hazard ratio (HR = 1.77, p = 0.002) for DFS after vascular and/or biliary invasion, extrahepatic invasion, lymph node metastasis and multiple tumors. Multivariate logistic regression analysis revealed four predictors of early recurrence after hepatectomy (lymph node metastasis: odds ratio [OR] = 3.74, p = 0.001; tumor size > 50 mm: OR = 2.80, p = 0.002; HGD grade, high: OR = 2.11, p = 0.012; and vascular or biliary tract invasion: OR = 2.11, p = 0.048). CONCLUSION: Trinal HGD grade had a significant prognostic impact on the survival of patients with ICC after radical hepatectomy.

Tertiary lymphoid structure and neutrophil-lymphocyte ratio coordinately predict outcome of pembrolizumab.

Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil-lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum-refractory mUC patients (50 cases with whole-exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS- and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression-free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune-checkpoint genes revealed that ICOSLG (B7-H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood.

Prognostic impact of soluble PD-L1 derived from tumor-associated macrophages in non-small-cell lung cancer.

Programmed cell death-ligand 1 (PD-L1) on tumor cells can be degraded to soluble form (sPD-L1) and enter circulation, however, the clinical significances of sPD-L1 in peripheral blood remains to be elucidated in non-small-cell lung cancer (NSCLC). We monitored plasma sPD-L1 levels during perioperative periods and evaluated PD-L1-positive cells in tumor tissues in patients with operable NSCLC. Then the correlation between preoperative plasma sPD-L1 levels and relapse-free survival (RFS) was analyzed retrospectively. In patients who underwent radical surgery (n = 61), plasma sPD-L1 levels (median; 63.5 pg/mL) significantly increased 1 month after surgery (72.2 pg/mL, P < 0.001). The combined score of PD-L1-positive cells including tumor cells and tumor-associated macrophages (TAMs) was significantly associated with preoperative plasma sPD-L1 levels. In patients with high levels of preoperative plasma sPD-L1, the probability of 5-year RFS was significantly poor for patients with low PD-L1 expression intensity of tumor cells (tcPD-L1) compared with those with high tcPD-L1 (33.3% vs. 87.5%, respectively, P = 0.016; 95% CI, 0.013-0.964). In former group, PD-L1-positive TAMs were markedly infiltrating compared with those from latter group (246.4 vs. 76.6 counts/mm2, respectively, P = 0.003). In NSCLC, plasma sPD-L1 can reflect the accumulation of PD-L1-posotive TAMs, not just PD-L1-positive tumor cells. In patients with high levels of preoperative plasma sPD-L1, the prognoses after surgery depends on which PD-L1-positive cells, tumor cells or TAMs, are the primary source of the sPD-L1. Thus, measuring both plasma sPD-L1 levels and PD-L1 expression status of tumor cells and TAMs is of benefit for assessment of postoperative prognosis in operable NSCLC.

Ocular and extraocular sebaceous carcinomas: A retrospective study with emphasis on the presence of in situ lesion and discussion and review of the histogenesis of extraocular sebaceous carcinoma.

Sebaceous carcinoma (SC) is a rare carcinoma classified as ocular or extraocular. Ocular SC is believed to arise from the meibomian glands or the glands of Zeis. However, the origin of extraocular SC is controversial because there is no evidence of carcinoma arising from pre-existing sebaceous glands. Several hypotheses about the origin of extraocular SC have been proposed, including one suggesting an origin from intraepidermal neoplastic cells. Although extraocular SCs have been shown to occasionally comprise intraepidermal neoplastic cells, no study has investigated whether intraepidermal neoplastic cells possess sebaceous differentiation. The present study analyzed the clinicopathological features of ocular and extraocular SC, with an emphasis on the presence of in situ (intraepithelial) lesions. It retrospectively reviewed the clinicopathological features of eight patients with ocular and three patients with extraocular SC (eight women and three men; median age, 72 years), respectively. In situ (intraepithelial) lesions were observed in four of the eight ocular SC cases and one of the three extraocular SC cases and an apocrine component was noted in one patient with ocular SC (seboapocrine carcinoma). In addition, immunohistochemical analyses showed that the androgen receptor (AR) was expressed in all ocular SCs and two of the three extraocular SC cases. Adipophilin expression was observed in all ocular and extraocular SC. In situ lesions of extraocular SC showed positive immunoreactivity for both AR and adipophilin. The present study is the first to demonstrate sebaceous differentiation in in situ lesions of extraocular SC. The possible origin of extraocular SC is speculated to be the progenitor cells present in the sebaceous duct or interfollicular epidermis. The results of the present study and reported cases of SC in situ indicate that extraocular SC also arises from intraepidermal neoplastic cells.

Neuroendocrine carcinoma of the small intestine diagnosed as a result of paraneoplastic neurological syndrome.

Paraneoplastic neurological syndromes, a diverse group of neurological syndromes, are associated with small cell lung, testicular, ovarian, and breast cancers; however, their association with neuroendocrine carcinoma of the small intestine remains unreported. In this report, we present the case of a 78-year-old man diagnosed with neuroendocrine carcinoma of the small intestine and experienced symptoms such as subacute progressive numbness of the extremities and impaired gait. These symptoms were diagnosed as tumor-associated neurological syndrome. The patient had also undergone pyloric gastrectomy for early-stage gastric cancer several years prior to the appearance of the neurological symptoms. Therefore, we could not determine whether the tumor-related neurologic syndrome was owing to gastric cancer or neuroendocrine carcinoma of the small intestine; however, one of these conditions was the cause of the neuropathy. The gait disturbance and numbness relatively improved after surgery for the neuroendocrine carcinoma of the small intestine, suggesting that the neuroendocrine carcinoma of the small intestine likely caused the paraneoplastic neurological syndrome. Collectively, we present a unique report highlighting the putative relationship between small bowel neuroendocrine carcinoma and tumor-associated neurologic syndromes.

Autophagy Inhibition Increased Sensitivity of Pancreatic Cancer Cells to Carbon Ion Radiotherapy.

BACKGROUND/AIMS: Pancreatic cancer has the poorest survival rate among all cancer types. Therefore, it is essential to develop an effective treatment strategy for this cancer. METHODS: We performed carbon ion radiotherapy (CIRT) in human pancreatic cancer cell lines and analyzed their survival, apoptosis, necrosis, and autophagy. To investigate the role of CIRT-induced autophagy, autophagy inhibitors were added to cells prior to CIRT. To evaluate tumor formation, we inoculated CIRT-treated murine pancreatic cancer cells on the flank of syngeneic mice and measured tumor weight. We immunohistochemically measured autophagy levels in surgical sections from patients with pancreatic cancer who received neoadjuvant chemotherapy (NAC) plus CIRT or NAC alone. RESULTS: CIRT reduced the survival fraction of pancreatic cancer cells and induced apoptotic and necrotic alterations, along with autophagy. Preincubation with an autophagy inhibitor accelerated cell death. Mice inoculated with control pancreatic cancer cells developed tumors, while those inoculated with CIRT/autophagy inhibitor-treated cells showed significant evasion. Surgical specimens of NAC-treated patients expressed autophagy comparable to control patients, while those in the NAC plus CIRT group expressed little autophagy and nuclear staining. CONCLUSION: CIRT effectively killed the pancreatic cancer cells by inhibiting their autophagy-inducing abilities.

Impact of neoadjuvant therapy on gut microbiome in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND: /Objectives: Effects of chemotherapy on gut microbiota have been reported in various carcinomas. The current study aimed to evaluate the changes in the gut microbiota before and after neoadjuvant chemotherapy (NAC) in patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) and understand their clinical implications. METHODS: Twenty patients diagnosed with R/BR-PDAC were included in this study. Stool samples were collected at two points, before and after NAC, for microbiota analysis using 16S ribosomal RNA (16S rRNA) gene sequences. RESULTS: Of the 20 patients, 18 (90%) were treated with gemcitabine plus S-1 as NAC, and the remaining patients received gemcitabine plus nab-paclitaxel and a fluorouracil, leucovorin, irinotecan, and oxaliplatin combination. No significant differences were observed in the α- and ß-diversity before and after NAC. Bacterial diversity was not associated with Evans classification (histological grade of tumor destruction by NAC) or postoperative complications. The relative abundance of Actinobacteria phylum after NAC was significantly lower than that before NAC (P = 0.02). At the genus level, the relative abundance of Bifidobacterium before NAC in patients with Evans grade 2 disease was significantly higher than that in patients with Evans grade 1 disease (P = 0.03). Patients with Evans grade 2 lost significantly more Bifidobacterium than patients with Evans grade 1 (P = 0.01). CONCLUSIONS: The diversity of gut microbiota was neither decreased by NAC for R/BR-PDAC nor associated with postoperative complications. Lower incidence of Bifidobacterium genus before NAC may be associated with a lower pathological response to NAC.

Case report: administration of immune checkpoint inhibitor for SMARCB1 (INI1)-negative rhabdoid carcinoma with microsatellite instability (MSI)-high in the right colon.

BACKGROUND: Malignant tumors with rhabdoid features are rare, highly aggressive, and some of them are characterized by SMARCB1 (INI1) loss. Although cases of rhabdoid carcinoma are extremely rare, its occurrence in the colon has been reported previously. CASE PRESENTATION: A 71-year-old Japanese female patient presented with loss of appetite, fatigue, and weight loss. Computed tomography demonstrated a tumor in the right colon that infiltrated the surrounding kidneys and swelling of the left supraclavicular and periaortic lymph nodes. Laparotomy revealed that the tumor was unresectable because it had directly invaded the head of the pancreas and duodenum. Therefore, ileocecal vascularized bulky lymph nodes were sampled, and gastrojejunostomy with Braun's anastomosis and ileotransversostomy were performed as palliative procedures. Histopathological examination of the lymph nodes revealed that the neoplastic cells had rich eosinophilic cytoplasm and eccentrically located large nuclei characteristic of rhabdoid carcinoma. In addition, these neoplastic cells lacked SMARCB1 expression; therefore, the patient was diagnosed with SMARCB1-negative rhabdoid carcinoma. The postoperative course was uneventful. Molecular analysis confirmed that the neoplastic cells had high microsatellite instability (MSI); therefore, two cycles of pembrolizumab were administered. However, no clinical benefit was noted, and the patient died 3 months postoperatively. CONCLUSION: This is the first report of a case of SMARCB1-negative rhabdoid colon carcinoma with high MSI treated with pembrolizumab. Rhabdoid carcinoma is highly aggressive; therefore, additional studies are required to determine the therapeutic strategy for SMARCB1-negative rhabdoid colorectal carcinoma.

MMP14 expression levels accurately predict the presence of extranodal extensions in oral squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: Extranodal extension (ENE) is an adverse prognostic factor for oral squamous cell carcinoma (OSCC), and patients with OSCC along with ENE require neck dissection. In this study, we developed a novel ENE histology-based pathological predictor using MMP14 expression patterns in small biopsy specimens. METHODS: A total of 71 surgically resected tissue, 64 dissected lymph node (LN), and 46 biopsy specimens were collected from 71 patients with OSCC. Immunohistochemical analyses of total MMP14 expression in the tumour nest and cancer-associated fibroblasts (CAFs) were performed using the MMP14 co-scoring system (high- or low-risk). The association analysis of MMP14 expression in metastatic LNs was performed with respect to the presence and absence of ENE. Clinicopathological analyses and multivariate examinations were performed to assess the risks of metastasis and ENE presence. The predictive value of ENE and the impact of ENE and MMP14 expression on 5-year overall survival were examined. RESULTS: High-risk MMP14 expression was detected in metastatic LN specimens with ENE. MMP14 expression in tumour nests and CAFs and its overexpression at the tumour-stromal interface significantly correlated with the presence of ENE. The MMP14 co-scoring system was an independent risk predictor for ENE, with sensitivity, specificity, and accuracy of over 80% in biopsy samples; patients with a high risk in the MMP14 co-scoring system had significantly worse prognoses in both resections and biopsies. CONCLUSION: The MMP14 co-scoring system accurately predicted ENE presence and poor prognosis via immunohistochemical evaluation of small biopsies. This system is a simple, accurate, and inexpensive immunohistochemical approach that can be used in routine pathological diagnosis for effective treatment planning.

Reevaluation of regional lymph nodes in patients with pancreatic ductal adenocarcinoma in the pancreatic body and tail.

Introduction: In patients with pancreatic ductal adenocarcinoma (PDAC) in the pancreatic body (Pb) and tail (Pt), the appropriate area for lymphadenectomy is controversial. This study aimed to reevaluate the extent of lymph node (LN) metastasis in Pb- and Pt-PDAC, and to define the optimal area of LN dissection. Patients and methods: This single-center retrospective study evaluated patients with Pb- and Pt-PDAC who underwent distal pancreatectomy with extended lymphadenectomy between 2006 and 2020. LN metastasis in >3.0% of patients were defined as new regional LN. Results: The study cohort included 135 patients with Pb-PDAC and 42 patients with Pt-PDAC. In patients with Pb-PDAC, LNs around the splenic artery (SPA) had the highest metastasis-positive rate (54.1%). LNs along the left gastric artery, common hepatic artery, celiac axis (CA), superior mesenteric artery (SMA), and splenic hilus were defined as new regional LNs. In patients with Pt-PDAC, LNs at the splenic hilum had the highest metastasis-positive rate (38.1%). The station and LN around the SPA were defined as new regional LNs in those with Pt-PDAC. Metastasis beyond the newly defined regional LNs was not associated with survival. The incidence of LN metastasis was lower in patients who received preoperative chemotherapy than in those who underwent upfront surgery in both Pb- and Pt-PDAC. Conclusion: Although it needs to be verified in future multicenter studies, LN of both the CA and SMA systems should be dissected in patients with Pb-PDAC. However, only those around the SPA and splenic hilus should be dissected routinely in those with Pt-PDAC.

Tumor budding may be a promising prognostic indicator in intrahepatic cholangiocarcinoma: A multicenter retrospective study.

Purpose: This retrospective study evaluated our hypothesis that high tumor budding (≥10 buds) may help determine the appropriate T category for more accurate staging of intrahepatic cholangiocarcinoma (ICC). Methods: We analyzed the clinical and histopathologic data of 235 consecutive patients with histologically confirmed ICC following hepatectomy at five university hospitals in the Kansai region of Japan between January 2009 and December 2020. ICC staging was based on the Liver Cancer Study Group of Japan (LCSGJ) staging system, 6th edition. Results: Patients with ICC with high budding showed significantly shorter disease-specific survival (DSS) and disease-free survival (DFS) than patients with low/intermediate budding. Cox proportional hazards regression analysis showed a hazard ratio of 2.2-2.3 (P < 0.05) for high budding. Based on these results, we modified the T category of ICC in the LCSGJ staging system by adding severity of tumor budding as a fourth determinant. This proposed staging system for ICC has significantly improved the prognostic accuracy for both DSS and DFS (both: P < 0.05). Conclusions: High tumor budding is a new candidate for an additional determinant of the T category in staging ICC. An LCSGJ staging system containing an additional evaluation of tumor budding may lead to improved staging accuracy.

Gastric hamartomatous inverted polyp: Report of three cases with a review of the endoscopic and clinicopathological features.

Objectives: A gastric hamartomatous inverted polyp (GHIP) is a rare submucosal tumor characterized histopathologically by a submucosal inverted proliferation of cystically dilated hyperplastic gastric glands. Only 42 GHIPs have been reported in English literature. Few GHIPs have been reported to accompany adenocarcinomas. We reported on three patients with a GHIP and reviewed the clinicopathological and endoscopic features of GHIPs. Methods: This study included two men and one woman with a GHIP. The endoscopic, histopathological, and immunohistochemical features of the endoscopically resected specimens were analyzed. A gene mutation analysis was also performed. Results: All the tumors were located in the body of the stomach, with a median size of 20 mm. Two tumors were sessile, and the remaining tumor had a pedunculated appearance. The overlying mucosa mainly appeared normal but was reddish in one tumor. The histopathological examination of the tumors revealed a well-circumscribed and lobular submucosal proliferation of cystically dilated hyperplastic glands. The immunohistochemical analysis revealed that the MUC5AC-positive foveolar epithelium was located in the center, and MUC6-positive pseudo-pyloric or pepsinogen-I and H+/K+ ATPase-positive fundic-type glands were located at the periphery of two tumors. No carcinomatous components were noted in any of the tumors. Moreover, no significant mutations in oncogenes or tumor suppressor genes were noted. Conclusions: Our review revealed that approximately three fourths of GHIP cases showed an submucosal tumor-like feature, whereas endoscopic features, including the endoscopic ultrasonography findings, were not characteristic. Because an endoscopic diagnosis of a GHIP may be difficult, complete endoscopic resection may be required for a pathological diagnosis.

Survival impact of occult liver metastasis and peritoneal dissemination compared with radiologically defined distant organ metastasis in pancreatic ductal adenocarcinoma.

BACKGROUND: Characteristics and prognoses of patients with occult metastases (OM) of pancreatic ductal adenocarcinoma (PDAC) compared with radiologically defined metastases (RM) have been rarely reported. OBJECTIVE: We aimed to clarify the prognosis of OM compared with RM and to establish a treatment strategy for PDAC patients with OM. METHODS: This single-institution, retrospective study evaluated patients with unresectable PDAC between 2008 and 2018. OM was defined as abdominal metastasis that was detected by staging laparoscopy or open laparotomy but not in the initial assessment of radiological images. RESULTS: OM and RM were identified in 135 and 112 patients, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS), neutrophil to lymphocyte ratio (NLR), tumor diameter, and rate of local unresectability were significantly lower in the OM group. Median overall survival (OS) of OM was significantly better than that of RM (13.0 vs 8.9 months, p < 0.001). In multivariate analysis of OS, ECOG PS ≥ 1 (HR 1.64, p = 0.009), NLR ≥5 (HR 1.97, p = 0.004), carbohydrate antigen (CA) 19-9 ≥1000 (HR 1.68, p = 0.001), tumor diameter ≥40 mm (HR 1.40, p = 0.027), conversion surgery (HR 0.12, p < 0.001), and multiple lines of chemotherapy (HR 0.38, p < 0.001) were independent predictors. However, type of metastasis (OM vs RM) not an independent predictor (HR 1.10, p = 0.590). CONCLUSION: The prognosis of PDAC with OM was relatively better than that with RM, but general and nutritional statuses, primary tumor size and CA19-9, conversion surgery and multiple lines of chemotherapy were independent predictors but not tumor burden.

Significance of placental CD200 expression in patients with preeclampsia: Comparison between early­ and late­onset patients.

Preeclampsia, characterized by high blood pressure and proteinuria during pregnancy, causes serious complications in both the mother and the fetus. Although there have been several studies on the causes of preeclampsia, the detailed mechanism of this disease remains unclear. Moreover, a few reports have focused on the causes of preeclampsia in number of weeks at onset. The present study aimed to elucidate the differences between early­ and late­onset preeclampsia. This study enrolled patients with preeclampsia from January 2014 to December 2020. They were classified into early­ (<34 weeks) and late­onset (≥34 weeks) preeclampsia groups. The expression profiles of 770 immune­related genes were studied in the placental tissue from five patients each in the early­ and late­onset groups. The expression of CD200 in the trophoblasts of the placenta of 26 and 27 patients in early­ and late­onset groups, respectively, was also analyzed using immunostaining. Analysis of extracted RNA indicated that CD200 was significantly upregulated in the early­onset group compared with late­onset group and normal control. Immunostaining for CD200 demonstrated a significantly increased expression in the early­onset group compared with the late­onset group. The present study demonstrated that upregulation of CD200, which belongs to the immunoglobulin superfamily and is recognized as a molecule that acts in immune tolerance via inhibition of classical macrophage activation, may be associated with early­onset preeclampsia, although it remains unknown whether upregulation of CD200 expression is a cause or effect of the development of early­onset preeclampsia. Early­onset preeclampsia might have a different mechanism from that of late­onset; thus, further studies are needed to clarify the mechanism of these conditions for adequate treatment.