Evaluation in real-time use of artificial intelligence during colonoscopy to predict relapse of ulcerative colitis: a prospective study.

BACKGROUND AND AIMS: The use of artificial intelligence (AI) during colonoscopy is attracting attention as an endoscopist-independent tool to predict histologic disease activity of ulcerative colitis (UC). However, no study has evaluated the real-time use of AI to directly predict clinical relapse of UC. Hence, it is unclear whether the real-time use of AI during colonoscopy helps clinicians make real-time decisions regarding treatment interventions for patients with UC. This study aimed to establish the role of real-time AI in stratifying the relapse risk of patients with UC in clinical remission. METHODS: This open-label, prospective, cohort study was conducted in a referral center. The cohort comprised 145 consecutive patients with UC in clinical remission who underwent AI-assisted colonoscopy with a contact-microscopy function. We classified patients into either the Healing group or Active group based on the AI outputs during colonoscopy. The primary outcome measure was clinical relapse of UC (defined as a partial Mayo score >2) during 12 months of follow-up after colonoscopy. RESULTS: Overall, 135 patients completed the 12-month follow-up after AI-assisted colonoscopy. AI-assisted colonoscopy classified 61 patients as the Healing group and 74 as the Active group. The relapse rate was significantly higher in the AI-Active group (28.4% [21/74]; 95% confidence interval, 18.5%-40.1%) than in the AI-Healing group (4.9% [3/61]; 95% confidence interval, 1.0%-13.7%; P < .001). CONCLUSIONS: Real-time use of AI predicts the risk of clinical relapse in patients with UC in clinical remission, which helps clinicians make real-time decisions regarding treatment interventions. (Clinical trial registration number: UMIN000036650.).

Beyond complete endoscopic healing: Goblet appearance using an endocytoscope to predict future sustained clinical remission in ulcerative colitis.

OBJECTIVES: Complete endoscopic healing, defined as Mayo endoscopic score (MES) = 0, is an optimal target in the treatment of ulcerative colitis (UC). However, some patients with MES = 0 show clinical relapse within 12 months. Histologic goblet mucin depletion has emerged as a predictor of clinical relapse in patients with MES = 0. We observed goblet depletion in vivo using an endocytoscope, and analyzed the association between goblet appearance and future prognosis in UC patients. METHODS: In this retrospective cohort study, all enrolled UC patients had MES = 0 and confirmed clinical remission between October 2016 and March 2020. We classified the patients into two groups according to the goblet appearance status: preserved-goblet and depleted-goblet groups. We followed the patients until March 2021 and evaluated the difference in cumulative clinical relapse rates between the two groups. RESULTS: We identified 125 patients with MES = 0 as the study subjects. Five patients were subsequently excluded. Thus, we analyzed the data for 120 patients, of whom 39 were classified as the preserved-goblet group and 81 as the depleted-goblet group. The patients were followed-up for a median of 549 days. During follow-up, the depleted-goblet group had a significantly higher cumulative clinical relapse rate than the preserved-goblet group (19% [15/81] vs. 5% [2/39], respectively; P = 0.02). CONCLUSIONS: Observing goblet appearance in vivo allowed us to better predict the future prognosis of UC patients with MES = 0. This approach may assist clinicians with onsite decision-making regarding treatment interventions without a biopsy.

Endocytoscopic intramucosal capillary network changes and crypt architecture abnormalities can predict relapse in patients with an ulcerative colitis Mayo endoscopic score of 1.

OBJECTIVES: Recent studies have suggested the necessity of therapeutic intervention for patients with ulcerative colitis at high risk of clinical relapse with a Mayo endoscopic score (MES) of 1. The aim of this retrospective cohort study was to demonstrate the impact of intramucosal capillary network changes and crypt architecture abnormalities to stratify the risk of relapse in patients with an MES of 1. METHODS: All included patients had an MES of ≤1 and confirmed sustained clinical remission between October 2016 and April 2019. We classified patients with an MES of 1 as "intramucosal capillary/crypt (ICC)-active" or "ICC-inactive" using endocytoscopic evaluation. We followed patients until October 2019 or until relapse; the main outcome measure was the difference in clinical relapse-free rates between ICC-active and ICC-inactive patients with an MES of 1. RESULTS: We included 224 patients and analyzed data for 218 (82 ICC-active and 54 ICC-active with an MES of 1 and 82 with an MES of 0). During follow-up, among the patients with an MES of 1, 30.5% (95% confidence interval 20.8-41.6; 25/82) of the patients relapsed in the ICC-active group and 5.6% (95% confidence interval 1.2-15.4; 3/54) of the patients relapsed in the ICC-inactive group. The ICC-inactive group had a significantly higher clinical relapse-free rate compared with the ICC-active group (P < 0.01). CONCLUSIONS: In vivo intramucosal capillary network and crypt architecture patterns stratified the risk of clinical relapse in patients with an MES of 1 (UMIN 000032580; UMIN 000036359).

Blockade of EGFR Activation Promotes TNF-Induced Lung Epithelial Cell Apoptosis and Pulmonary Injury.

Pneumonitis is the leading cause of death associated with the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) against non-small cell lung cancer (NSCLC). However, the risk factors and the mechanism underlying this toxicity have not been elucidated. Tumor necrosis factor (TNF) has been reported to transactivate EGFR in pulmonary epithelial cells. Hence, we aimed to test the hypothesis that EGFR tyrosine kinase activity regulates TNF-mediated bronchial epithelial cell survival, and that inhibition of EGFR activity increases TNF-induced lung epithelial cell apoptosis. We used surfactant protein C (SPC)-TNF transgenic (tg) mice which overexpress TNF in the lungs. In this model, gefitinib, an EGFR-TKI, enhanced lung epithelial cell apoptosis and lymphocytic inflammation, indicating that EGFR tyrosine kinase prevents TNF-induced lung injury. Furthermore, IL-17A was significantly upregulated by gefitinib in SPC-TNF tg mice and p38MAPK activation was observed, indicative of a pathway involved in lung epithelial cell apoptosis. Moreover, in lung epithelial cells, BEAS-2B, TNF stimulated EGFR transactivation via the TNF-α-converting enzyme in a manner that requires heparin binding (HB)-EGF and transforming growth factor (TGF)-α. These novel findings have significant implications in understanding the role of EGFR in maintaining human bronchial epithelial cell homeostasis and in NSCLC treatment.

Case Report: Combined pembrolizumab, 5-fluorouracil, and cisplatin therapy were remarkably effective in p16-positive squamous cell carcinoma of unknown primary.

Background: Cancer of unknown primary (CUP) is a malignant tumor without a known primary lesion with a frequency of 3-5%. It can be divided into favorable and unfavorable prognosis subsets. While recommended treatments are available for the former group, there is no established treatment for the latter. Here, we report the effective treatment of a 32-year-old woman with p16-positive squamous cell CUP with pembrolizumab plus 5-fluorouracil and cisplatin therapy. Case presentation: A 32-year-old woman presented with metastatic lesions in the liver, lung, bone, cervical region, abdominal region, and pelvic lymph nodes. She was diagnosed with p16-positive squamous cell carcinoma of unknown primary origin. The patient received pembrolizumab plus 5-fluorouracil and cisplatin therapy, which markedly reduced the metastasis and improved her Eastern Cooperative Oncology Group performance status after two courses. Conclusion: This case report highlights the potential of pembrolizumab plus 5-fluorouracil and cisplatin therapy for treating CUP with an unfavorable prognosis. p16 positivity is worth examining for squamous cell carcinoma of unknown primary origin, and if present, this therapy should be considered a promising treatment option.

Monocyte subsets associated with the efficacy of anti­PD­1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.

CD20 gene deletion causes a CD20-negative relapse in diffuse large B-cell lymphoma.

In diffuse large B-cell lymphoma (DLBCL), a CD20-negative relapse is clinically significant because it is associated with chemo-refractory phenotypes and loss of a therapeutic target. The alteration of the CD20 gene is reported as infrequent in CD20-negative relapse in B-cell lymphoma. We established a DLBCL cell line with loss of CD20 expression (SD07) from a patient at CD20-negative relapse. She was initially diagnosed with CD20-positive DLBCL and received repeated immuno-chemotherapy that included rituximab. SD07, which has an immunoglobulin κ rearrangement identical to that of lymphoma cells at CD20-negative relapse, showed homozygous deletion of the CD20 gene with loss of the copy number of 11q12. SD07 is the first case in which it is proven that the loss of CD20 expression in relapsed DLBCL is the result of deletion of the CD20 gene. Deletion of the CD20 gene is a molecular mechanism of CD20-negative relapse in a subset of DLBCL.

Follicular tissue fragments in fine-needle aspiration cytology of lymph nodes: A useful clue in differential diagnosis of follicular lymphoma and reactive follicular hyperplasia.

BACKGROUND: In Fine-needle aspiration cytology (FNAC) of lymph nodes, tissue fragments derived from follicular structures may be observed in specimens. We defined such tissue fragments as follicular tissue fragments (FTF), and investigated differences in cytological findings for FTFs of each histological type. METHOD: A total of 41 cases with FNAC of lymph nodes were examined. In these cases, the histopathological diagnoses were reactive lymphoid hyperplasia (RLH) (n = 17), follicular lymphoma (FL) (n = 13), diffuse large B-cell lymphoma (DLBCL) (n = 18), and Burkitt lymphoma (n = 1). Specimens were analyzed for the presence of FTFs, and for tingible-body macrophages (TBMs) and monomorphism of lymphocytes in FTFs. FTFs with a maximum diameter of >500 µm were defined as large-FTFs. RESULTS: FTFs were identified in RLH (14/17, 82.4%), FL (13/13, 100%), and DLBCL (3/18, 16.7%). In the RLH subtypes, FTFs were present only in follicular hyperplasia (FH) (14/15, 93.3%) and not in paracortical hyperplasia (0/2). The number of cases with large FTFs among those with FTFs were as follows: RLH (10/14, 71.4%), FL (11/13, 84.6%), and DLBCL (0/3). Similarly, those with TBMs in FTFs were as follows: RLH (13/14, 92.9%), FL (0/13) and DLBCL (2/3, 66.7%). Monomorphism was observed in RLH (1/14, 7.1%) and FL (11/13, 84.6%), but not in DLBCL (0/3). CONCLUSIONS: Distinction between FL and FH is possible by identifying large-FTFs. In FL, TBMs are absent in FTFs and lymphocytes often show monomorphism. Therefore, recognizing FTFs and observing details inside the FTFs are useful for identification and differential diagnosis of FL and FH in FNAC of lymph nodes.

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

Over-expression of CCL3 MIP-1alpha in a blastoid mantle cell lymphoma with hypercalcemia.

We analyzed a case with the blastoid variant of mantle cell lymphoma (MCL-BV), a rare subtype of B-cell lymphoma, presenting with marked hypercalcemia at diagnosis. Enzyme-linked immunosorbent assay (ELISA) showed elevated serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), and type I collagen telopeptide, but not parathyroid hormone, calcitriol or parathyroid hormone-related peptide at diagnosis, suggesting local osteoclastic hypercalcemia in this case. By reverse transcription polymerase chain reaction (RT-PCR) analysis, we found predominant expression of mRNA for MIP-1alpha in addition to those for receptor-activator of nuclear-factor kappa B ligand (RANKL), TNF-alpha, and IL-6 in lymphoma cells obtained from the patient. Furthermore, recombinant MIP-1alpha significantly stimulated (3)H-thymidine uptake by isolated MCL cells in vitro. Treatment with intravenous fluids, bisphosphonate, and methylprednisolone followed by combination chemotherapy promptly corrects the hypercalcemia and successfully induced complete remission, which was accompanied by a decrease of these cytokines in the serum, including MIP-1alpha. In the present case, MIP-1alpha, an osteoclast-activating factor produced by mantle lymphoma cells, may contribute to the development of hypercalcemia. It likely acts through RANKL expression in tumor cells and/or stroma cells, as indicated in multiple myeloma (MM) and adult T-cell leukemia/lymphoma (ATLL). Furthermore, MIP-1alpha is also involved in the development of an aggressive phenotype on MCL by stimulating proliferation of these lymphoma cells. In summary, the present study demonstrated that MIP-1alpha is an important factor in the development of both hypercalcemia and an aggressive phenotype in some types of B-cell lymphoma.

t(3;14)(p14.1;q32)/FOXP1-IGH translocation in thyroid extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).

OBJECTIVES: MALT lymphoma occurs in various organs and has several characteristic genetic aberrations. Thyroid MALT lymphoma has been reported to include t(3;14)(p14.1;q32)/FOXP1-IGH as a specific genetic aberration, but the number of studies is limited. METHOD AND RESULTS: We examined 86 thyroid lymphoma cases using fluorescence in situ hybridization (FISH) for the detection of t(3;14)/FOXP1-IGH in formalin fixed paraffin-embedded tissue (FFPE). Histopathological diagnoses of the analyzed specimen were as follows: thyroid MALT lymphoma (n = 59), DLBCL (n = 23), follicular lymphoma (n = 4), and benign lesions (n = 14) included Hashimoto's thyroiditis (n = 13) and other (n = 1). Of the 100 analyzed cases, thirty-six (36 %) thyroid lymphoma cases were positive for t(3;14)/FOXP1-IGH. Thirty-three (55.9 %) of the 59 MALT lymphoma cases were positive for t(3;14)/FOXP1-IGH. Three (13.0 %) of the 23 DLBCL cases were positive for t(3;14)/FOXP1-IGH. All 4 follicular lymphomas examined were negative for t(3;14)/FOXP1-IGH. None of the benign cases was positive for t(3;14)/FOXP1-IGH, including Hashimoto's thyroiditis (0/13) and benign tissue (0/1). CONCLUSIONS: Our study found that t(3;14)/FOXP1-IGH was frequently found in thyroid MALT lymphoma. A detection of t(3;14)/FOXP1-IGH is extremely useful for the differential diagnosis between primary MALT lymphoma of the thyroid and other thyroid disorders.

Impact of CD123 expression, analyzed by immunohistochemistry, on clinical outcomes in patients with acute myeloid leukemia.

Aberrant expression of the interleukin-3 receptor alpha chain (IL3RA or CD123) is frequently observed in patients with a subset of leukemic disorders, including acute myeloid leukemia (AML), particularly in leukemia stem cells. We analyzed the relationships between immunohistochemical (IHC) expression, including that of CD123, and clinical outcomes. This study involved a retrospective analysis of 48 patients diagnosed with de novo AML (M0-M5, n = 48) at our hospital between February 2008 and September 2015. Among patients with de novo AML, CD123 expression was associated with a failure to achieve complete response (CR) to initial induction chemotherapy (P = 0.044) and poor overall survival (OS) (P = 0.036). This is the first study using IHC to demonstrate that CD123 expression is associated with a poor CR rate and poor OS in de novo AML patients. These results support previous reports using flow cytometry (FCM). CD123 expression may thus be useful for assessing AML patients' prognoses. At the time of diagnosis, CD123 expression analysis using IHC may represent a clinically useful assessment for de novo AML patients.

Systematic review and two new cases of primary upper urinary tract neuroendocrine carcinomas.

BACKGROUND: Upper urinary tract neuroendocrine carcinoma (UUT-NEC) is extremely rare and has a poor prognosis. Although a few cases of successful treatment have been reported, no treatment has shown established efficacy. PATIENTS AND METHODS: We analyzed 70 UUT-NEC patients, including 68 with small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) reported between 1985 and 2017 and 2 treated at our hospital. RESULTS: Median patient age was 66 years, 58.6% were men, and 60% were of Asian descent. Most UUT-NECs were SCNEC (68; 95.7%), whereas LCNEC was very rare (2; 2.9%). More than half of the patients had accompanying other histological components, the most common being urothelial carcinoma (51.5%), whereas 41.4% had NEC alone. Of the 70 patients, 27 underwent additional therapy (e.g., chemotherapy and radiotherapy) along with surgery. Median survival was 15 months. In univariate analysis, stages T1-2 disease showed better prognosis than stages T3-4 (P < 0.001). Additional treatment (e.g., chemotherapy and radiotherapy) significantly improved prognosis (P = 0.014). Moreover, platinum-based chemotherapy also was associated with improved prognosis (P = 0.017). For platinum-based chemotherapy, multicollinearity with additional treatments was strong, and, thus, these data were not included in the analysis. Multivariate analysis revealed pathological stage (T1-2 vs. T3-4; P = 0.003) and additional treatment (P = 0.028) to be independent predictors of improved prognosis. CONCLUSION: Although UUT-NEC has a poor prognosis, additional treatment along with surgery and therapeutic intervention and stage T1-2 disease are independent factors to improve prognosis.

Increased expression of interleukin-17 is associated with macrophages in chronic immune thrombocytopenia.

Objectives: Interleukin-(IL-)17-mediated cells contribute to the imbalance of cellular immunity in the pathogenesis of immune thrombocytopenia (ITP). We examined samples of bone marrow (BM) clots to determine if IL-17-mediated immunological changes involve the BM and to identify clinical predictors of treatment response. Methods: We enrolled 33 patients with chronic ITP. BM clots were obtained before treatment and stained with the following markers: CD3, CD4, CD8, CD20, CD25, CD68, CD163, and IL-17. Pathological findings and clinical information, including laboratory data, were compared between the patients and 11 control subjects and between IL-17-high and -low-expression groups. Results: Univariate analysis revealed increased cells expressing CD68, CD163, and IL-17 in the patients with ITP than in the control subjects (P = 0.02, 0.001, and 0.001, respectively). The expression of both CD68 and CD163 showed correlation with IL-17 expression (r = 0.60 and 0.48, respectively). Responses to Eltrombopag were better in the IL-17-low-expression group than in the IL-17-high-expression group (P = 0.056). Conclusions: Macrophages and monocytes were associated with IL-17 expression in patients with ITP. We demonstrated that ITP is associated with IL-17-expressing monocytes/macrophages and might be more difficult to treat.

Ki-67 expression of immunohistochemistry using computerized image analysis is a useful prognostic marker in follicular lymphomas.

Ki-67 is a useful proliferation marker in various tumors including lymphoma. In general, the number of Ki-67 positive cells in immunohistochemistry (IHC) is counted manually for routine pathological diagnosis. However, a manual count is subjective and time consuming. Currently, image analysis is often used for the quantification of positive cells in tissue in IHC. Thus, to determine the pathological prognostic factors for follicular lymphoma (FL), we studied the relationship between Ki-67 expression in IHC and the treatment effect and prognosis using image analysis software. We analyzed 82 newly-diagnosed patients with FL. All patients were treated with rituximab-containing regimens. The median Ki-67 expression was 17.0%. A high expression of Ki-67 tended to be associated with short overall survival (P = 0.058). Moreover, Ki-67 expression was significantly lower in patients with FL grade 1-2 than in those with FL grade 3a. This study suggests that image analysis provides an accurate, reproducible, and easy method of measuring Ki-67 expression in IHC in FL, and is possibly a useful marker for treatment selection or prognosis prediction in FL.

Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136 patients.

The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI-NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI-NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-γ and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD-1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy.

Expression of matrix metalloproteinase-7 correlates with the invasion of T1 colorectal carcinoma.

T1 colorectal carcinomas (CRCs) are an initial site of metastatic spread. Various risk factors for lymph node metastasis have been investigated in T1 CRCs. However, the major step in the entire process of metastasis remains unclear. In terms of carcinoma invasion and metastasis, matrix metalloproteinases (MMPs) have recently gained increasing attention. Notably, MMP-7 is frequently overexpressed in CRCs, but its implication has not been determined in T1 CRCs yet. The present study aimed to clarify the associations between the pathological risk factors of T1 CRCs and MMP-7. In the current study, 211 lesions of T1 CRC that were resected endoscopically or surgically at Showa University Northern Yokohama Hospital (Yokohama, Japan) between April 2008 and December 2009 were retrospectively analyzed. MMP-7 was immunostained and evaluated by its frequency of expression. Pathological factors of T1 CRCs were analyzed in association with MMP-7 expression. Furthermore, the ultrastructural alterations of carcinoma invasion were examined using low vacuum-scanning electron microscopy (LV-SEM). MMP-7 expression was associated with venous invasion (P=0.005), and LV-SEM revealed the disappearance of the normal structure of collagen and elastic fibers of veins invaded by tumor cells expressing MMP-7. At the invasive front, MMP-7 has a vital role in carcinoma invasion, correlating with venous invasion of T1 CRCs.

Early-onset primary peritoneal carcinoma from atypical cells after risk-reducing salpingo-oophorectomy for BRCA2 mutation carrier: a case report.

Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers is performed to reduce carcinogenesis. It decreases the ovarian, tubal, and peritoneal cancer risk to 3.5-4.3% and breast cancer risk to 30-40%. According to a previous study, despite RRSO, 3.4% of patients develop breast cancer and 0.8% develop peritoneal cancer. However, the long-term risk of recurrence and appropriate treatment for patients with unsuspected neoplasia after RRSO are unclear. Case: A 61-year-old woman who had a BRCA2 mutation underwent RRSO. Her pelvic washing cytology showed atypical cells, and similar atypical cells were identified on her fimbria. She underwent strict surveillance. Elevated CA125 levels and increased ascites in the pelvic cavity were detected by routine surveillance at 18 months after RRSO. She underwent staging laparotomy and was diagnosed with primary peritoneal carcinoma stage IIIC. It is helpful to perform surveillance by transvaginal ultrasound and serum CA125 analyses in cases that require strict management. The appropriate intervention should be considered for cases in which atypical cells or non-invasive carcinoma are detected after RRSO.

The role of microvessel density, lymph node metastasis, and tumor size as prognostic factors of distant metastasis in colorectal cancer.

Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per ×400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welch's t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.