Embodied, visible, and courteous: exploring robotic social touch with virtual idols.

In recent years, virtual idols have garnered considerable attention because they can perform activities similar to real idols. However, as they are fictitious idols with nonphysical presence, they cannot perform physical interactions such as handshake. Combining a robotic hand with a display showing virtual idols is the one of the methods to solve this problem. Nonetheless a physical handshake is possible, the form of handshake that can effectively induce the desirable behavior is unclear. In this study, we adopted a robotic hand as an interface and aimed to imitate the behavior of real idols. To test the effects of this behavior, we conducted step-wise experiments. The series of experiments revealed that the handshake by the robotic hand increased the feeling of intimacy toward the virtual idol, and it became more enjoyable to respond to a request from the virtual idol. In addition, viewing the virtual idols during the handshake increased the feeling of intimacy with the virtual idol. Moreover, the method of the hand-shake peculiar to idols, which tried to keep holding the user's hand after the conversation, increased the feeling of intimacy to the virtual idol.

Metastatic prostate cancer with low PSA levels diagnosed after holmium laser enucleation of the prostate.

Holmium laser enucleation of the prostate is a widely accepted surgical treatment method for benign prostate hyperplasia, but its effect on prostate cancer remains unclear. In this study, we report the cases of two patients with metastatic prostate cancer diagnosed during follow-up after holmium laser enucleation of the prostate. Case 1 was a 74 year-old man who underwent holmium laser enucleation of the prostate. Prostate-specific antigen levels declined from 4.3 to 1.5 ng/mL at 1 month after surgery, but after 19 months, they increased to 6.6 ng/mL. Based on pathological and radiological findings, he was diagnosed as having prostate cancer, with Gleason score 5 + 4 with neuroendocrine differentiation, cT3bN1M1a. Case 2 was a 70 year-old man who also underwent holmium laser enucleation of the prostate. Prostate-specific antigen levels declined from 7.2 to 2.9 ng/mL at 6 months after surgery, but after 12 months, they increased to 12 ng/mL. Based on pathological and radiological findings, he was diagnosed as having prostate cancer, with Gleason score 4 + 5 with intraductal carcinoma of the prostate, cT3bN1M1a. This report suggests that advanced prostate cancer may be newly diagnosed after holmium laser enucleation of the prostate. Even if prostate cancer had not been demonstrated in the enucleated specimen, and postoperative PSA levels were below the standard values, physicians should regularly monitor prostate-specific antigen levels after holmium laser enucleation of the prostate, and further examination should be considered keeping in mind prostate cancer progression.

RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer.

The invasiveness of pancreatic cancer and its resistance to anticancer drugs define its malignant potential, and are considered to affect the peritumoral microenvironment. Cancer cells with resistance to gemcitabine exposed to external signals induced by anticancer drugs may enhance their malignant transformation. Ribonucleotide reductase large subunit M1 (RRM1), an enzyme in the DNA synthesis pathway, is upregulated during gemcitabine resistance, and its expression is associated with worse prognosis for pancreatic cancer. However, the biological function of RRM1 is unclear. In the present study, it was demonstrated that histone acetylation is involved in the regulatory mechanism related to the acquisition of gemcitabine resistance and subsequent RRM1 upregulation. The current in vitro study indicated that RRM1 expression is critical for the migratory and invasive potential of pancreatic cancer cells. Furthermore, a comprehensive RNA sequencing analysis showed that activated RRM1 induced marked changes in the expression levels of extracellular matrix­related genes, including N­cadherin, tenascin­C and COL11A. RRM1 activation also promoted extracellular matrix remodeling and mesenchymal features, which enhanced the migratory invasiveness and malignant potential of pancreatic cancer cells. The present results demonstrated that RRM1 has a critical role in the biological gene program that regulates the extracellular matrix, which promotes the aggressive malignant phenotype of pancreatic cancer.

Identification of a novel target of SETD1A histone methyltransferase and the clinical significance in pancreatic cancer.

Although histone H3K4 methyltransferase SETD1A is overexpressed in various cancer types, the molecular mechanism underlying its overexpression and its target genes in pancreatic ductal adenocarcinoma (PDAC) remain unclarified. We conducted immunohistochemical staining for SETD1A in 105 human PDAC specimens to assess the relationship between SETD1A overexpression and clinicopathological features. The function and target genes of SETD1A were investigated using human pancreatic cancer cell lines. SETD1A expression was upregulated in 51.4% of patients with PDAC and was an independent prognostic factor associated with shorter disease-free survival after resection (p < 0.05). Knockdown and overexpression of SETD1A showed that SETD1A plays a crucial role in increasing the proliferation and motility of PDAC cells. SETD1A overexpression increased tumorigenicity. RNA sequencing of SETD1A-knockdown cells revealed downregulation of RUVBL1, an oncogenic protein ATP-dependent DNA helicase gene. ChIP analysis revealed that SETD1A binds to the RUVBL1 promoter region, resulting in increased H3K4me3 levels. Knockdown of RUVBL1 showed inhibition of cell proliferation, migration, and invasion of PDAC cells, which are similar biological effects to SETD1A knockdown. High expression of both SETD1A and RUVBL1 was an independent prognostic factor not only for disease-free survival but also for overall survival (p < 0.05). In conclusion, we identified RUVBL1 as a novel downstream target gene of the SETD1A-H3K4me3 pathway. Co-expression of SETD1A and RUVBL1 is an important factor for predicting the prognosis of patients with PDAC.

[Re-Administration of Pembrolizumab for Urothelial Carcinoma after immune-Related Myasthenia Gravis : A Case Report].

Immune checkpoint inhibitors (ICIs) provide excellent benefits to the treatment of various cancer types, including urothelial carcinoma. Conversely, they can cause immune-related adverse events (irAEs), and some of them are severe or fatal. Furthermore, evidence on the safety and effectiveness of the readministration of ICIs after the occurrence of irAEs is limited. In this case report, a 78-year-old man who suffered from metastatic right renal pelvic cancer was treated with pembrolizumab. He had a partial response to pembrolizumab, but he developed grade 3 myasthenia gravis. The myasthenia gravis symptoms were immediately relieved by corticosteroids and intravenous immunoglobulin therapy. When the disease rapidly progressed, he was treated again with pembrolizumab. After 5 days, a chest radiograph showed shrinkage of pulmonary metastases. Unfortunately, he died of multiple brain infarctions 7 days after the readministration. We report this case with a literature review on the efficacy and safety of the readministration of ICIs after the occurrence irAEs including myasthenia gravis.

Clinical practice pattern in patients with advanced urothelial cancer who had progressed on pembrolizumab in the pre-enfortumab vedotin era.

OBJECTIVES: Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment for advanced urothelial carcinoma. However, the standard treatment for patients after disease progression with pembrolizumab had not been established until the recent approval of enfortumab vedotin. We analyzed the treatment of these patients in the real world, and the patient background and outcomes. METHODS: We extracted data from 543 patients who experienced progressive disease after pembrolizumab initiation from a Japanese nation-wide cohort of platinum-refractory, metastatic urothelial carcinoma. RESULTS: The median overall survival of the 543 patients was 3.5 months (95% confidence interval 3.0-4.1). Of these, only 20.6% (n = 112) received chemotherapy as a subsequent systemic treatment after progressive disease. The regimen of chemotherapy was very diverse. The median overall survival was 11.9 months (95% confidence interval 9.2-14.7) for patients who received chemotherapy, compared to 2.4 months for those who did not receive chemotherapy (95% confidence interval 2.1-2.9; P < 0.0001). Patients who received subsequent chemotherapy were more likely to have better performance status, neutrophil-to-lymphocyte ratio <3, hemoglobin >11 mg/dL, and history of a single chemotherapeutic regimen at pembrolizumab initiation. CONCLUSIONS: This report highlights the real-world practice of the management after pembrolizumab treatment failure in the pre-enfortumab vedotin era, characterized by infrequent use of subsequent anticancer therapy comprising various regimens, reflecting the lack of a standard treatment. Clinical introduction of enfortumab vedotin is expected to improve treatment outcomes in this setting. The present study will provide important baseline data for evaluating the influence of enfortumab vedotin on clinical practices and outcomes.

Curative Surgery and Ki-67 Value Rather Than Tumor Differentiation Predict the Survival of Patients With High-grade Neuroendocrine Neoplasms.

OBJECTIVE: To elucidate the role of surgery in patients with high-grade neuroendocrine neoplasms (hg-NENs) and Ki-67 more than 20%. BACKGROUND: Although surgery is the first treatment choice in patients with low-grade NENs, whether it increases the survival of patients with hg-NENs is debatable. METHODS: Between 2005 and 2018, 63 patients pathologically diagnosed with hg-NENs treated at our institution were retrospectively analyzed. The risk factors for overall survival (OS) and recurrence-free survival were analyzed, and OS was compared between each treatment group. RESULTS: The median observation time was 21.2 months, and the median Ki-67 value was 52%. Patients with hg-NENs were classified into low Ki-67 (Ki-67 <52%) and high Ki-67 (Ki-67 ≥52%) groups. Multivariate analysis for OS identified surgery (P = 0.013) and low Ki-67 value (P = 0.007) as independent risk factors, whereas morphological differentiation defined by the WHO 2017 criteria showed no association with OS. Patients with low Ki-67 value subjected to R0/1, R2, and chemotherapy had a median survival time of 83.8, 16.6, and 28.1 months, respectively. The median survival time for R0/1 group was significantly longer than that for chemotherapy group ( P = 0.001). However, no difference in survival was reported between patients from R0/1 and chemotherapy groups with high Ki-67. Ki-67 value could determine recurrence-free survival ( P = 0.006) in patients who underwent R0/1 surgery for pancreatic hg-NENs. CONCLUSIONS: R0/1 surgery predicted prognoses in the low Ki-67 group. The indication of surgery for patients with hg-NENs did not depend on tumor differentiation.

Hormonal tumor mapping for liver metastases of gastroenteropancreatic neuroendocrine neoplasms: a novel therapeutic strategy.

PURPOSE: In patients with metastatic functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), it is unknown what degree of tumor reduction is required to eliminate hormonal symptoms. We aimed to reduce hormonal symptoms derived from advanced GEP-NENs by efficient minimal intervention, constructing a hormonal tumor map of liver metastases. METHODS: Between 2013 and 2019, we treated 12 insulinoma or gastrinoma patients with liver metastases. Liver segments containing hormone-producing tumors were identified by injecting calcium gluconate via the hepatic arteries and monitoring the change in serum hormone concentration in the three hepatic veins. A greater-than-twofold increase in hormone concentration indicated a tumor-feeding vessel. RESULTS: Cases included eight insulinomas and four gastrinomas. Primary lesions were functional in three patients and nonfunctional in 9. Nine patients showed hormonal step-up indicating the presence of functional lesions; eight showed step-up in tumor-bearing liver segments, while one with synchronous liver metastases showed step-up only in the pancreatic region. Five patients underwent surgery. Serum hormone concentration decreased markedly after removing the culprit lesions in 3; immediate improvement in hormonal symptoms was achieved in all patients. Three patients with previous surgical treatment who showed step-up underwent transcatheter arterial embolization, achieving temporary improvement of hormonal symptoms. Four patients showed unclear localization of the hormone-producing tumors; treatment options were limited, resulting in poor outcomes. CONCLUSION: Hormonal tumor mapping demonstrated heterogeneity in hormone production among primary and metastatic tumors of GEP-NENs. Minimally invasive treatment based on hormonal mapping may be a viable alternative to conventional cytoreduction.

A novel classification of portal venous tumor invasion to predict residual tumor status after surgery in patients with pancreatic neuroendocrine neoplasms.

PURPOSE: To elucidate whether portal venous tumor invasion (PVTI) is a prognostic factor for patients with pancreatic neuroendocrine neoplasms (Pan-NENs). METHODS: From 2002 to 2019, 240 patients with Pan-NEN were included to examine prognostic factors. PVTI based on computed tomography (CT) images are classified into four types: no PVTI (Vp0/1), PVTI not invading the superior mesenteric vein (Vp2), PVTI invading the superior mesenteric vein or portal vein (Vp3), and PVTI invading the portal bifurcation (Vp4). RESULTS: Simultaneous liver metastases (SLM) determined the overall survival (OS) in 240 patients. The 5-year OS rates with and without SLM were 46% and 92%, respectively (P < 0.001). PVTIs were observed in 56 of the 240 patients (23%). Among such patients, 39, 11, and 6 had Vp2, Vp3, and Vp4, respectively. The 5-year OS rates with and without PVTI were 62% and 82%, respectively (P < 0.001). Severity of PVTI did not decide PFS and OS after R0/1 resection. There was significant difference in the prognoses between Vp0/1 and Vp2-4. In 161 patients without SLM, 21 had PVTI (13%). According to a multivariate analysis, PVTI and Ki-67 index were independent prognostic factors for progression-free survival (PFS) in patients without SLM. The 5-year PFS rates with and without PVTI were 18% and 77%, respectively (P < 0.001). The 5-year OS rates with and without PVTI were 76% and 95%, respectively (P = 0.02). PVTI was associated with tumor functionality, high serum NSE, and high Ki-67 index. CONCLUSIONS: PVTI may be a predictor for postoperative recurrence.

Inhibitor library screening identifies ispinesib as a new potential chemotherapeutic agent for pancreatic cancers.

Screening custom-made libraries of inhibitors may reveal novel drugs for treating pancreatic cancer. In this manner, we identified ispinesib as a candidate and attempted to determine its clinical efficacy and the biological significance of its functional target Eg5 in pancreatic cancer. One hundred compounds in our library were screened for candidate drugs using cell cytotoxicity assays. Ispinesib was found to mediate effective antitumor effects in pancreatic cancer. The clinical significance of the expression of the ispinesib target Eg5 was investigated in 165 pancreatic cancer patients by immunohistochemical staining and in Eg5-positive pancreatic cancer patient-derived xenograft (PDX) mouse models. Patients with Eg5-positive tumors experienced significantly poorer clinical outcomes than those not expressing Eg5 (overall survival; P < .01, recurrence-free survival; P < .01). Ispinesib or Eg5 inhibition with specific siRNA significantly suppressed cell proliferation and induced apoptosis in pancreatic cancer cell lines. Mechanistically, ispinesib acted by inducing incomplete mitosis with nuclear disruption, resulting in multinucleated monoastral spindle cells. In the PDX mouse model, ispinesib dramatically reduced tumor growth relative to vehicle control (652.2 mm3 vs 18.1 mm3 in mean tumor volume, P < .01 by ANOVA; 545 mg vs 28 mg in tumor weight, P < .01, by ANOVA). Ispinesib, identified by inhibitor library screening, could be a promising novel therapeutic agent for pancreatic cancer. The expression of its target Eg5 is associated with poorer postoperative prognosis and is important for the clinical efficacy of ispinesib in pancreatic cancer.

Surgery after sunitinib administration to improve survival of patients with advanced pancreatic neuroendocrine neoplasms.

BACKGROUND: Little research is available regarding the treatments combining surgical resection with systemic chemotherapy for advanced pancreatic neuroendocrine neoplasm patients. We retrospectively elucidated whether sunitinib administration before surgery in advanced pancreatic neuroendocrine neoplasm (Pan-NEN) patients increases survival. METHODS: This study included 106 of 326 Pan-NEN patients with distant metastases and/or unresectable locally advanced tumors who visited our department to receive sunitinib for more than 1 mo during April 2002 to December 2019. Risk factors for overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: The median duration of preoperative sunitinib administration and observation time after sunitinib were 6 and 26.5 mo, respectively. Of 106 patients, 31 (29.2%) underwent surgery following sunitinib administration. Hepatectomy, synchronous hepatopancreatectomy, pancreatectomy, and lymphadenectomy were performed for 13, 12, 5, and 1 patient, respectively. The 5-y OS rates in the resected and nonresected groups were 88.9% and 14.1%, respectively (P < .001). In the multivariate analysis, the absence of surgical resection following sunitinib (hazard ratio [HR], 13.1; P = .001), poor differentiation (HR, 5.5; P = .007), and bilateral liver metastases (HR, 3.7; P = .048) were independent risk factors for OS, although large liver tumor volumes were more evident in the nonresected group, as patient characteristics. The median DFS was 16.1 mo in 22 patients who underwent R0/1 resections, and risk factors for postoperative recurrence were Ki-67 index >7.8% (HR, 7.4; P = .02) and R1 resection (HR, 4.4; P = .04). CONCLUSION: Surgical resection after sunitinib administration improved OS in advanced Pan-NENs.

Impact of the objective response to and number of cycles of platinum-based first-line chemotherapy for metastatic urothelial carcinoma on overall survival of patients treated with pembrolizumab.

OBJECTIVES: To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab. METHODS: This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis. RESULTS: Overall, 391 patients received standard first-line chemotherapy and pembrolizumab as a second-line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first-line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy. CONCLUSIONS: Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum-based first-line chemotherapy.

Pancreatic metastasis from renal cell carcinoma presenting as gastrointestinal hemorrhage: a case report.

In some patients with metastatic renal cell carcinoma to the pancreas, gastrointestinal hemorrhages occur, but because of the rarity of this condition, treatment strategies have not been established. A 71-year-old man who had undergone a nephrectomy for renal cell carcinoma (RCC) went to a hospital in a state of shock. Computed tomography revealed a hypervascularized tumor in the head of the pancreas, suggesting metastatic RCC. Upper endoscopy revealed bleeding in the duodenum due to tumor invasion. An emergency angiogram showed that the tumor received its blood supply mainly from the gastroduodenal artery. Transarterial embolization (TAE) of the gastroduodenal artery was performed and bleeding was controlled. Two months after TAE, elective pancreaticoduodenectomy was performed. The patient currently continues to undergo outpatient follow-up 2 years later without recurrence. TAE was very effective in controlling the acute phase of severe gastrointestinal hemorrhage from pancreatic metastasis of RCC.

Multi-organ metastasis as destination for breast cancer cells guided by biomechanical architecture.

A majority of breast cancer patients die of widespread aggressive multidrug-resistant tumors. Aspartate ß-hydroxylase (ASPH) is an α-ketoglutarate-dependent dioxygenase and oncofetal antigen involved in embryogenesis. To illustrate if ASPH could be targeted for metastatic breast cancer, embedded and on-top three-dimensional (3-D) cultures, 3-D invasion, mammosphere formation, immunofluorescence, immunohistochemistry, Western blot, co-IP and microarray were conducted. In vitro metastasis was developed to imitate how cancer cells invade basement membrane at the primary site, transendothelially migrate, consequently colonize and outgrow at distant sites. Orthotopic and experimental pulmonary metastatic (tail vein injection) murine models were established using stable breast cancer cell lines. Cox proportional hazards regression models and Kaplan-Meier plots were applied to assess clinical outcome of breast cancer patients. In adult non-cancerous breast tissue, ASPH is undetectable. Pathologically, ASPH expression re-emerged at ductal carcinoma in situ (DCIS), and enhanced with disease progression, from early-stage invasive ductal carcinoma (IDC) to late-stage carcinoma. ASPH at moderate to high levels contribute to aggressive molecular subtypes, early relapse or more frequent progression and metastases, whereas substantially shortened overall survival and disease-free survival of breast cancer patients. Through direct physical interactions with A disintegrin and metalloproteinase domain-containing protein (ADAM)-12/ADAM-15, ASPH could activate SRC cascade, thus upregulating downstream components attributed to multifaceted metastasis. ASPH-SRC axis initiated pro-invasive invadopodium formation causing breakdown/disorganization of extracellular matrix (ECM), simultaneously potentiated epithelial-mesenchymal transition (EMT), induced cancer stem cell markers (CD44 and EpCAM), enhanced mammosphere formation and intensified 3-dimentional invasion. Oncogenic SRC upregulated matrix metallopeptidases (MMPs) were assembled by invadopodia, acting as executive effectors for multi-step metastasis. ASPH-SRC signal guided multi-organ metastases (to lungs, liver, bone, spleen, lymph nodes, mesentery or colon) in immunocompromised mice. Malignant phenotypes induced by ASPH-SRC axis were reversed by the third-generation small molecule inhibitor (SMI) specifically against ß-hydroxylase activity of ASPH in pre-clinical models of metastatic breast cancer. Collectively, ASPH could activate ADAMs-SRC-MMPs cascades to promote breast cancer tumor progression and metastasis. ASPH could direct invadopodium construction as a biomechanical sensor and pro-metastatic outlet. ASPH-mediated cancer progression could be specifically/efficiently subverted by SMIs of ß-hydroxylase activity. Therefore, ASPH emerges as a therapeutic target for breast cancer.

[A Case of Ureteral Metastasis from Prostate Cancer].

Ureteral metastasis from prostate cancer is rare. The present case report describes an 83-year-old patient with distant metastasis of prostate cancer to the right ureter that caused hydronephrosis. Upon initial examination at our hospital, he presented with a high prostate-specific antigen (PSA) level of 10.0 ng/ml. He was diagnosed with prostate adenocarcinoma, with Gleason score of 10 (5＋5) and clinical staging of cT2aN0M0. Intensity-modulated radiation therapy (IMRT) was performed after 1 year and 7 months of androgen depriation therapy. At 1 year and 4 months after IMRT, PSA increased to 3.068 ng/ml. Computed tomography scan revealed right hydronephrosis and thickening of the right ureter. We could not identify obvious malignant cells on ureteroscopic biopsy, and right nephroureterectomy was performed. Pathological examination revealed ureteral metastasis of prostate cancer. Six months after nephroureterectomy, PSA increased to 3.037 ng/ml. He was diagnosed with castration-resistant prostate cancer and has been treated with enzalutamide.

Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.

BACKGROUND: RRM1 is functionally associated with DNA replication and DNA damage repair. However, the biological activity of RRM1 in pancreatic cancer remains undetermined. METHODS: To determine relationships between RRM1 expression and the prognosis of pancreatic cancer, and to explore RRM1 function in cancer biology, we investigated RRM1 expression levels in 121 pancreatic cancer patients by immunohistochemical staining and performed in vitro experiments to analyze the functional consequences of RRM1 expression. RESULTS: Patients with high RRM1 expression had significantly poorer clinical outcomes (overall survival; p = 0.006, disease-free survival; p = 0.0491). In particular, high RRM1 expression was also associated with poorer overall survival on adjuvant chemotherapy (p = 0.008). We found that RRM1 expression was increased 24 hours after exposure to gemcitabine and could be suppressed by histone acetyltransferase inhibition. RRM1 activation in response to gemcitabine exposure was induced mainly in the cytoplasm and cytoplasmic RRM1 activation was related to cancer cell viability. In contrast, cancer cells lacking cytoplasmic RRM1 activation were confirmed to show severe DNA damage. RRM1 inhibition with specific siRNA or hydroxyurea enhanced the cytotoxic effects of gemcitabine for pancreatic cancer cells. CONCLUSIONS: Cytoplasmic RRM1 activation is involved in biological processes related to drug resistance in response to gemcitabine exposure and could be a potential target for pancreatic cancer treatment.

C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer.

The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tumor progression. However, in pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. We identified that H3 acetylation was expressed in all pancreatic cancer patients, indicating that H3 acetylation may be essential in pancreatic cancer cells. We also found that the HAT inhibitor C646 augmented anti-tumor effects in vitro by inhibiting cell proliferation and cell cycle progression concomitantly with suppression of acetylated H3K9 and H3K27 expression. C646 or p300 and CBP (CREB-binding protein)-specific siRNA treatment inhibited the transcription of the G2/M cell cycle regulatory proteins cyclin B1 and CDK1 (cyclin-dependent kinase 1). C646 treatment also inhibited tumor growth in vivo in a xenograft mouse model. C646 could be an effective therapeutic agent for pancreatic cancer. The epigenetic status of pancreatic cancers based on their level of histone H3 acetylation may influence patient survival. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer.

Laparoscopic distal pancreatectomy in a patient with aberrant splenic artery originating from the superior mesenteric artery: A case report.

RATIONALE: Splenic artery originating from the superior mesenteric artery is extremely rare. Because of this, its significance in laparoscopic distal pancreatectomy has never been reported. Here, we present the first case of laparoscopic distal pancreatectomy in a patient with a splenic artery arising from the superior mesenteric artery. PATIENT CONCERNS: A 46-year-old Japanese woman with type 2 diabetes mellitus presented with worsening glycemic control. Abdominal ultrasonography revealed a pancreatic tail mass. DIAGNOSES: The patient was diagnosed with pancreatic neuroendocrine tumor by endoscopic ultrasound-guided fine needle aspiration. Preoperative computed tomography showed that the splenic artery with branches of dorsal pancreatic artery originated from the superior mesenteric artery. INTERVENTIONS: The patient underwent laparoscopic distal pancreatectomy. Prior to pancreatectomy, the splenic artery and its dorsal pancreatic branches were clamped using the superior and inferior approaches, respectively, to avoid bleeding and congestion. OUTCOMES: The postoperative course was uneventful. LESSONS: Preoperative evaluation of anatomical variants and development of strategies are important to avoid intraoperative complications in pancreatic surgery. Our results revealed that laparoscopic distal pancreatectomy can be performed safely by strategic approach even in a patient with a rare aberrant splenic artery.

Pembrolizumab for treating advanced urothelial carcinoma in patients with impaired performance status: Analysis of a Japanese nationwide cohort.

BACKGROUND: The benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum-refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug. METHODS: This retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0-1, 2, and 3-4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2. RESULTS: The numbers of patients with PS 0-1, 2, and 3-4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil-lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors. CONCLUSIONS: PS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR <3.5 and no liver metastasis may most greatly benefit from pembrolizumab therapy.

Prediction of early recurrence of pancreatic ductal adenocarcinoma after resection.

BACKGROUND: Even after curative resection, pancreatic ductal adenocarcinoma (PDAC) patients suffer a high rate of recurrence. There is an unmet need to predict which patients will experience early recurrence after resection in order to adjust treatment strategies. METHODS: Data of patients with resectable PDAC undergoing surgical resection between January 2005 and September 2018 were reviewed to stratify for early recurrence defined as occurring within 6 months of resection. Preoperative data including demographics, tumor markers, blood immune-inflammatory factors and clinicopathological data were examined. We employed Elastic Net, a sparse modeling method, to construct models predicting early recurrence using these multiple preoperative factors. As a result, seven preoperative factors were selected: age, duke pancreatic monoclonal antigen type 2 value, neutrophil:lymphocyte ratio, systemic immune-inflammation index, tumor size, lymph node metastasis and is peripancreatic invasion. Repeated 10-fold cross-validations were performed, and area under the receiver operating characteristic curve (AUC) and decision curve analysis were used to evaluate the usefulness of the models. RESULTS: A total of 136 patients was included in the final analysis, of which 35 (34%) experienced early recurrence. Using Elastic Net, we found that 7 of 14 preoperative factors were useful for the predictive model. The mean AUC of all models constructed in the repeated validation was superior to the standard marker CA 19-9 (0.718 vs 0.657), whereas the AUC of the model constructed from the entire patient cohort was 0.767. Decision curve analysis showed that the models had a higher mean net benefit across the majority of the range of reasonable threshold probabilities. CONCLUSION: A model using multiple preoperative factors can improve prediction of early resectable PDAC recurrence.