Utility of Machine Learning in the Prediction of Post-Hepatectomy Liver Failure in Liver Cancer.

Background: Posthepatectomy liver failure (PHLF) is a serious complication associated with high mortality rates. Machine learning (ML) has rapidly developed and may outperform traditional models in predicting PHLF in patients who have undergone hepatectomy. This study aimed to predict PHLF using ML and compare its performance with that of traditional scoring systems. Methods: The clinicopathological data of 334 patients who underwent liver resection were retrospectively collected. The Pycaret library, a simple, open-source machine learning library, was used to compare multiple classification models for PHLF prediction. The predictive performance of 15 ML algorithms was compared using the mean area under the receiver operating characteristic curve (AUROC) and accuracy, and the best-fit model was selected among 15 ML algorithms. Next, the predictive performance of the selected ML-PHLF model was compared with that of routine scoring systems, the albumin-bilirubin score (ALBI) and the fibrosis-4 (FIB-4) index, using AUROC. Results: The best model was extreme gradient boosting (accuracy:93.1%; AUROC:0.863) among the 15 ML algorithms. As compared with ALBI and FIB-4, the ML PHLF model had higher AUROC for predicting PHLF. Conclusion: The novel ML model for predicting PHLF outperformed routine scoring systems.

Determinants of job continuity among older workers: a mixed-methods research in Japan.

This study aims to determine the factors that encourage older workers to continue working. This study had an exploratory sequential design using a mixed-methods approach, including interviews and questionnaire surveys. In the interview survey, we targeted 30 workers aged between 60-65 across three manufacturing companies. After using the results of the content analysis in the interviews, we conducted an online questionnaire survey with 1,500 workers aged between 60-89 across the country. We analyzed whether the 15 factors were related to intention to continue working using logistic regression analysis. We identified factors affecting job continuity from three perspectives: individual, company, and life. We determined several factors: health condition, job performance, self-esteem, conservatism, employment system, workload, medical insurance and welfare programs, monetary and non-monetary rewards, relationships, attachment to the organization, distance between living and work, social support, economic situation, and employment policy. In the questionnaire survey, some factors had no relationship with job continuity, including conservatism, employment systems, monetary rewards, and the distance between living and work. Employers and policymakers can use the findings to consider appropriate ways of supporting older workers.

The Individual and Work-Related Factors Associated with the Occupational Future Time Perspective: A Cross-Sectional Study of Older Workers in Japan.

OBJECTIVES: Occupational future time perspective (OFTP) is important concept for the successful career in older workers. The purpose of this study was to examine the associations between individual and work-related factors and OFTP. METHODS: We conducted a cross-sectional study via an online questionnaire survey. Respondents were stratified sampled according to the distribution of workers across Japan. To assess OFTP, we used the Japanese version of the OFTP scale. We included the factors such as sex, age, education, marital status, subjective health status, personal income, length of employment, industry, size of company, employment status, working days per week, and night shift. Multiple regression analysis was employed to calculate the regression coefficients for each factor, with OFTP serving as the dependent variable. RESULTS: We totally included 1,484 respondents. Our findings indicated that higher OFTP was associated with higher education, better subjective health status, higher personal income, and smaller size of company. Compared to the manufacturing, certain industries such as agriculture and forestry, transportation and postal services, and healthcare showed lower OFTP. In contrast to permanent workers, contract and part-time workers demonstrated lower OFTP, whereas owners of non-family businesses exhibited higher OFTP. Furthermore, individuals working 1-4 days per week showed lower OFTP compared to those working 5 days per week. CONCLUSIONS: Older workers facing limitations in resources, such as educational background, personal income, precarious employment, and health status, tend to have lower OFTP. Such individuals should be given priority for support and assistance.

Surgical resection of double advanced pancreatic neuroendocrine tumors with multiple renal cell carcinoma associated with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46 year-old man with a 35 mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55 mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36 mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6 months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22 months after primary surgery. The patient remains alive 41 months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL.

Endo-reduplication in mouse liver after conditional mutation of ORC2 and combined mutation of ORC1 and ORC2.

The six subunit Origin Recognition Complex (ORC) is essential for loading MCM2-7 at origins of DNA replication to promote initiation of DNA replication in organisms ranging from S. cerevisiae to humans. In rare instances, as in cancer cell-lines in culture with mutations in ORC1 , ORC2 or ORC5 , or in endo-reduplicating mouse hepatocytes in vivo without ORC1 , DNA replication has been observed in the virtual absence of individual ORC subunits. Although ORC1 is dispensable in the mouse liver for endo-reduplication, because of the homology of ORC1 with CDC6, it could be argued that CDC6 was substituting for ORC1 to restore functional ORC. Here, we have created mice with a conditional deletion of ORC2 , to demonstrate that mouse embryo fibroblasts require ORC2 for proliferation, but that the mouse hepatocytes can carry out DNA synthesis in vitro and endo-reduplicate in vivo , despite the deletion of ORC2 . Combining the conditional mutation of ORC1 and ORC2 revealed that the mouse liver can still carry out endo-reduplication despite the deletion of the two genes, both during normal development and after partial hepatectomy. Since endo-reduplication, like normal S phase replication, requires the presence of MCM2-7 on the chromatin, these results suggest that in primary hepatocytes there is a mechanism to load sufficient MCM2-7 to carry out effective DNA replication despite the virtual absence of two subunits of ORC.

Integrative analysis of DNA replication origins and ORC-/MCM-binding sites in human cells reveals a lack of overlap.

Based on experimentally determined average inter-origin distances of ~100 kb, DNA replication initiates from ~50,000 origins on human chromosomes in each cell cycle. The origins are believed to be specified by binding of factors like the origin recognition complex (ORC) or CTCF or other features like G-quadruplexes. We have performed an integrative analysis of 113 genome-wide human origin profiles (from five different techniques) and five ORC-binding profiles to critically evaluate whether the most reproducible origins are specified by these features. Out of ~7.5 million union origins identified by all datasets, only 0.27% (20,250 shared origins) were reproducibly obtained in at least 20 independent SNS-seq datasets and contained in initiation zones identified by each of three other techniques, suggesting extensive variability in origin usage and identification. Also, 21% of the shared origins overlap with transcriptional promoters, posing a conundrum. Although the shared origins overlap more than union origins with constitutive CTCF-binding sites, G-quadruplex sites, and activating histone marks, these overlaps are comparable or less than that of known transcription start sites, so that these features could be enriched in origins because of the overlap of origins with epigenetically open, promoter-like sequences. Only 6.4% of the 20,250 shared origins were within 1 kb from any of the ~13,000 reproducible ORC-binding sites in human cancer cells, and only 4.5% were within 1 kb of the ~11,000 union MCM2-7-binding sites in contrast to the nearly 100% overlap in the two comparisons in the yeast, Saccharomyces cerevisiae. Thus, in human cancer cell lines, replication origins appear to be specified by highly variable stochastic events dependent on the high epigenetic accessibility around promoters, without extensive overlap between the most reproducible origins and currently known ORC- or MCM-binding sites.

High-grade pancreatic intraepithelial neoplasia diagnosed based on changes in magnetic resonance cholangiopancreatography findings: A case report.

BACKGROUND: High-grade pancreatic intraepithelial neoplasia (PanIN) exhibits no mass and is not detected by any examination modalities. However, it can be diagnosed by pancreatic juice cytology from indirect findings. Most previous cases were diagnosed based on findings of a focal stricture of the main pancreatic duct (MPD) and caudal MPD dilatation and subsequent pancreatic juice cytology using endoscopic retrograde cholangiopancreatography (ERCP). We experienced a case of high-grade PanIN with an unclear MPD over a 20-mm range, but without caudal MPD dilatation on magnetic resonance cholangiopancreatography (MRCP). CASE SUMMARY: A 60-year-old female patient underwent computed tomography for a follow-up of uterine cancer post-excision, which revealed pancreatic cysts. MRCP revealed an unclear MPD of the pancreatic body at a 20-mm length without caudal MPD dilatation. Thus, course observation was performed. After 24 mo, MRCP revealed an increased caudal MPD caliber and a larger pancreatic cyst. We performed ERCP and detected atypical cells suspected of adenocarcinoma by serial pancreatic juice aspiration cytology examination. We performed a distal pancreatectomy and obtained a histopathological diagnosis of high-grade PanIN. Pancreatic parenchyma invasion was not observed, and curative resection was achieved. CONCLUSION: High-grade Pan-IN may cause MPD narrowing in a long range without caudal MPD dilatation.

Effects of transmembrane serine protease 4 on the survival in patients with pancreatic ductal adenocarcinoma undergoing surgery followed by adjuvant chemotherapy.

PURPOSE: The transmembrane serine protease 4 (TMPRSS4) gene is upregulated in various human cancers. However, its biological functions in pancreatic ductal adenocarcinoma remain unclear. We examined the expression of TMPRSS4 in pancreatic ductal adenocarcinoma tissues and its correlation with clinicopathological parameters in patients with pancreatic ductal adenocarcinoma who underwent surgery. METHODS: The TMPRSS4 expression was immunohistochemically examined in 81 PDAC patients with pancreatic ductal adenocarcinoma. We analyzed the association between the TMPRSS4 expression and clinicopathological factors, the recurrence-free survival (RFS), and the overall survival (OS) and examined the effect of TMPRSS4 expression on cell migration and sensitivity to 5-fluorouracil. RESULTS: The expression rate of TMPRSS4 in the samples was 62.9% (51/81). The TMPRSS4 expression was not correlated with any clinicopathological feature. The five-year overall and recurrence-free survival rates were significantly lower in the TMPRSS4-positive group than in the TMPRSS4-negative group. On a multivariate analysis, TMPRSS4 positivity, poorly differentiated histology, and non-adjuvant chemotherapy predicted a poor OS, while TMPRSS4 positivity and poorly differentiated histology predicted a poor RFS. TMPRSS4-silenced pancreatic ductal adenocarcinoma cells showed higher sensitivity to 5- fluorouracil than did the control siRNA-transfected cells. CONCLUSIONS: TMPRSS4 can be considered a prognostic factor and therapeutic target for pancreatic ductal adenocarcinoma.

Effect of body fat mass loss on prognosis of radical resection for pancreatic ductal adenocarcinoma based on bioelectrical impedance analysis.

BACKGROUND: Few reports have performed a prognostic analysis based on bioelectrical impedance analysis in patients with radical resection of pancreatic ductal adenocarcinoma (PDAC), and its usefulness in prognostic analysis remains unclear. This study aimed to evaluate body composition changes in patients undergoing radical resection for PDAC and analyze its impact on prognosis. METHODS: The medical records of radical resection for patients with PDAC were retrospectively reviewed, and the parameters of body composition, including body weight, skeletal muscle mass, body fat mass (BFM), and extracellular water-total body water ratio, from preoperatively to 12 months postoperatively, for each surgical procedure were measured based on direct segmental multifrequency bioelectrical impedance analysis with an InBody 770 (InBody Inc., Tokyo, Japan) device. The clinicopathological and prognostic factors were analyzed. RESULTS: Among 79 patients who underwent radical resection for PDAC, 36 (46%), 7 (8%), and 36 (46%) underwent pancreatoduodenectomy, total pancreatectomy, and distal pancreatectomy, respectively. The multivariate overall survival analysis demonstrated that BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021), lymph node metastasis (p = 0.014), and non-adjuvant chemotherapy (p <  0.001) were independent poor prognostic factors. Multivariate analysis revealed that preoperative BFM < 12 kg and preoperative albumin < 3.5 g/dL were independently associated with BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021 and p = 0.047, respectively). CONCLUSIONS: Loss of BFM in the early postoperative period may have a poor prognosis in radical resection of PDAC.

Integrative analysis of DNA replication origins and ORC/MCM binding sites in human cells reveals a lack of overlap.

Based on experimentally determined average inter-origin distances of ∼100 kb, DNA replication initiates from ∼50,000 origins on human chromosomes in each cell cycle. The origins are believed to be specified by binding of factors like the Origin Recognition Complex (ORC) or CTCF or other features like G-quadruplexes. We have performed an integrative analysis of 113 genome-wide human origin profiles (from five different techniques) and 5 ORC-binding profiles to critically evaluate whether the most reproducible origins are specified by these features. Out of ∼7.5 million union origins identified by all datasets, only 0.27% were reproducibly obtained in at least 20 independent SNS-seq datasets and contained in initiation zones identified by each of three other techniques (20,250 shared origins), suggesting extensive variability in origin usage and identification. 21% of the shared origins overlap with transcriptional promoters, posing a conundrum. Although the shared origins overlap more than union origins with constitutive CTCF binding sites, G-quadruplex sites and activating histone marks, these overlaps are comparable or less than that of known Transcription Start Sites, so that these features could be enriched in origins because of the overlap of origins with epigenetically open, promoter-like sequences. Only 6.4% of the 20,250 shared origins were within 1 kb from any of the ∼13,000 reproducible ORC binding sites in human cancer cells, and only 4.5% were within 1 kb of the ∼11,000 union MCM2-7 binding sites in contrast to the nearly 100% overlap in the two comparisons in the yeast, S. cerevisiae . Thus, in human cancer cell lines, replication origins appear to be specified by highly variable stochastic events dependent on the high epigenetic accessibility around promoters, without extensive overlap between the most reproducible origins and currently known ORC- or MCM-binding sites.

Surgical resection for liver recurrence after curative resection of pancreatic ductal adenocarcinoma.

PURPOSE: This study aimed to evaluate the clinical significance of surgical resection for liver recurrence in patients with curatively resected pancreatic ductal adenocarcinoma. METHODS: The medical records of patients with a liver recurrence after undergoing curative pancreatectomy for pancreatic ductal adenocarcinoma were retrospectively reviewed. Clinicopathological and prognostic factors were analyzed, as was the clinical impact of surgical resection for liver recurrence. RESULTS: Overall, 502 patients underwent curative pancreatic ductal adenocarcinoma resection. Of the 311 patients with recurrence after curative pancreatectomy, 71 (23%) had an initial recurrence in the liver, with 35 having solitary recurrence (11%). Patients with solitary, two or three, or more than four recurrences had median overall survival times of 28.5, 18.0, and 12.2 months, respectively (p < 0.001). Surgical indications for liver recurrence in our institution included solitary tumor, good disease control under chemotherapy after recurrence for > 6 months, and sufficient remnant liver function. Ten patients who met our institutional policy inclusion criteria underwent liver resection. Among 35 patients with initially solitary liver recurrence, those who underwent liver resection outlived those who did not (57.6 months vs. 20.1 months, p < 0.001). In multivariate analysis of overall survival, solitary liver recurrence and liver resection were independent favorable prognostic factors in patients with initial liver recurrence. CONCLUSION: In selected patients with solitary liver recurrence after curatively resected pancreatic ductal adenocarcinoma, liver resection may be a treatment option.

Analysis of Acquisition of COVID-2019 Neutralizing Antibodies in Organ Transplant Recipients.

BACKGROUND: This study confirmed the kinetics of antibodies acquired by SARS-CoV-2 vaccination in solid-organ transplant recipients and examined their association with the development of COVID-19 and immunosuppressive status in organ transplant recipients. METHODS: We measured COVID-19 neutralizing antibody titer in 21 organ transplant recipients vaccinated with the COVID-19 vaccine and 14 nontransplant recipients (control group) 3 times before and at 1 and 6 months after the third dose of vaccine. By confirming the kinetics of the acquired antibodies, we examined the relevance of the background characteristics of organ transplant recipients, such as the development of infectious diseases and immunosuppressive status. RESULTS: The proportion of patients with neutralizing antibodies was significantly higher in the nontransplant group than in the transplant group. Neutralizing antibody titers were significantly lower in transplant recipients when they were compared before the third dose and 1 month later. In the transplant recipient group, 11 patients were positive, and 10 were negative for neutralizing antibodies. When the causal relationship between the neutralizing antibody titer and background was examined, a positive correlation was found between the antibody titer and the number of years since transplantation, and a negative correlation was found between the tacrolimus trough values, amount of mycophenolate mofetil or steroids taken internally, and antibody titer. CONCLUSION: This study suggests that the effectiveness of vaccination in transplant recipients is associated with the post-transplant period before vaccination and the dose of immunosuppressive agents.

[Competencies expected of labor and social security attorneys in harmonizing work with diseases treatment].

OBJECTIVES: Labor and social security attorneys (LSSAs) are involved in various positions in harmonizing work with disease treatment; however, their qualification requirements do not include knowledge about the same. Expectations of their involvement in harmonizing work with disease treatment are insufficient. This study aimed to identify the competencies expected of the labor and social security LSSAs in harmonizing work with disease treatment. METHODS: In step 1, semi-structured interviews were conducted with LSSAs in this field. In step 2, a draft competency list was created based on the interview results. In step 3, the Delphi method was used to conduct a questionnaire survey among LSSAs who had over 10 consultation cases on harmonizing work with disease treatment, and they were asked about the level of importance (how important they thought it was to promote harmonizing work with disease treatment) and level of achievement (how much they had achieved). We also asked them about the competencies they considered necessary and added them as additional items in the draft. In step 4, the results of the previous step were presented to the participants who had given valid answers in step 3, and they were asked whether they would adopt the items as competencies. Items with an agreement rate of 80% or higher were considered competency items. Additionally, we asked them about the level of importance and level of achievement of the additional items created in step 3. RESULTS: In step 1, 24 LSSAs participated, and in step 2, a draft competency list of six major items, 18 medium items, and 71 minor items was created. In step 3, 49 LSSAs participated and 41 cooperated (response rate: 83.6%). Five items were selected for the draft competency list to be newly added. In step 4, 30 LSSAs cooperated (response rate: 73.1%). None of the items had an agreement rate of less than 80%, and over 40% of the items had an agreement rate of 100%. As a result, six major items, 18 medium items, and 76 minor items were selected for the competency list. CONCLUSIONS: This study identified the competencies expected of labor and social security LSSAs in harmonizing work with disease treatment. The results of this study can be used as a reference for developing a systematic training curriculum for LSSAs in this field in the future.

Micro-lymph node metastasis in intrahepatic cholangiocarcinoma showing pathological complete response to primary tumor and intrahepatic metastasis treated by gemcitabine plus cisplatin chemotherapy and radical surgery.

Surgical resection is the only curative treatment option for achieving long-term survival in biliary tract cancer patients. However, regional lymph node dissection in intrahepatic cholangiocarcinoma (ICC) is controversial. Herein, we document our experience with a 76-year-old man who had a 70 mm mass in liver segments 6 and 7 and a 10 mm mass in liver segment 3, which were diagnosed as poorly differentiated adenocarcinomas by needle biopsy. Lymphadenopathy was not evident on multidetector computed tomography scanning. Twenty courses of gemcitabine plus cisplatin chemotherapy were administered to the patient. The tumor masses shrunk and exhibited a partial response to chemotherapy as per the Response Evaluation Criteria in Solid Tumors version 1.1. Although tumor markers were all within normal limits, renal function parameters showed deterioration due to systemic chemotherapy. Therefore, continuing systemic chemotherapy was deemed unfeasible and we decided to perform a radical resection using extended posterior segmentectomy and partial liver resection with regional lymph node dissection. Postoperative histopathological examination revealed complete response of primary tumor and intrahepatic metastases; however, a micro-lymph node metastasis was found. The patient is still alive, without recurrence, more than 30 months after treatment initiation and 15 months after surgery. Even if remarkably effective pathological findings may be observed in the primary tumor, there are cases in which a micro-lymph node metastasis remains that are not identified on imaging examinations. Thus, regional lymphadenectomy may be useful in obtaining the exact state of disease progression and evaluation of chemotherapeutic effect in radical surgery.

[Unresectable Esophageal Cancer on the Elderly Woman Which Was Treated Effectively with Ipilimumab plus Nivolumab-A Case Report].

Until now, the standard treatment regimen was cisplatin plus 5-FU as the chemotherapy for unresectable advanced esophageal cancer. Immune checkpoint inhibitors have brought about changes to the cancer treatment. Ipilimumab plus nivolumab was approved in June 2022 for unresectable advanced esophageal cancer. An 86-year-old woman who was normal ADL and cognitive function was diagnosed with unresectable esophageal cancer with multiple lymph node metastasis. We thought surgery or chemotherapy is impossible because of her age and health status, so we treated with ipilimumab plus nivolumab. After 2 cycles, tumor became reduced in size on endoscopic examination and accumulation in primary lesion and lymph node metastases was decreased considerably on positron emission tomography/computed tomography(PET-CT). Though the cycle after initiation of chemotherapy was uneventful, tumor regrowth on the examinations at 5 months. The patient's condition of the disease was improved temporarily after change chemotherapy to paclitaxel as the second-line therapy, but she died due to disease progression at 11.4 months from initiation of treatment. Ipilimumab plus nivolumab can become one of the effective treatments for patients who are impossible to treat with conventional chemotherapy.

[Surgical Resection and Adjuvant Chemotherapy for Early Multiple Peritoneal Recurrence after Rejection of Hepatocellular Carcinoma-A Case Report].

Thus far, no consensus has been reached regarding the treatment of peritoneal dissemination of hepatocellular carcinoma (HCC). Here, we report a case of surgical resection and postoperative adjuvant chemotherapy for early multiple peritoneal recurrences of HCC. A 74-year-old man was found to have hepatic mass of 80 mm in size in S7 and 57 mm in S8, and was diagnosed with HCC. The patient underwent an open anterior segmentectomy and S7 subsegmentectomy of the liver. Peritoneal washing cytology revealed the presence of malignant cells. The tumor strongly adhered to the diaphragm, necessitating partial resection of the diaphragm. Six months after surgery, multiple disseminated recurrences were found on the CT scan. Atezolizumab plus bevacizumab combination therapy was initiated, but tumor size enlargement and elevation of tumor markers were observed after 3 courses. Resection of the dissemination(2 on the surface of the lung right lower lobe, 1 on the right renal superior retroperitoneum, 1 on the omentum, and 1 invading the jejunum)was performed. Considering the high risk of recurrence, postoperative adjuvant chemotherapy with lenvatinib was administered for 1 year. No recurrence has been found for 16 months after the resection. Although more cases are needed to conclude, this case report suggests that surgical resection and postoperative administration of lenvatinib may be effective in the treatment of disseminated HCC lesions at a high risk of recurrence.

Mesenteric approach in pancreas-preserving partial duodenectomy for aortic graft-duodenal fistula: a case report.

An aortic graft-duodenal fistula commonly requires graft replacement and duodenectomy. However, the appropriate surgical approach to the duodenum with aortic graft fistula remains unclear. Herein, we describe the case of an 85-year-old male patient who underwent a pancreas-preserving partial duodenectomy using the mesenteric approach for aortic graft-duodenal fistula. The patient presented with hemorrhagic shock and duodenal bleeding 2 years after undergoing open aortic graft replacement. He first underwent emergent endovascular aortic repair with an artificial vascular graft to achieve hemostasis. Although his general condition stabilized following endovascular treatment, duodenal endoscopy revealed an aortic graft-duodenal fistula, exposing the artificial vascular graft via the third portion of the duodenum. As the radical treatment for aortic graft-duodenal fistula, open graft replacement and pancreas-preserving partial duodenectomy were performed using the mesenteric approach which helps to divide the pancreas and duodenum. The patient recovered without any major complications, such as postoperative pancreatic fistula, and was discharged. In conclusion, the mesenteric approach in partial duodenectomy for aortic graft-duodenal fistula could be safely performed. This procedure is useful to approach the duodenum fixed by fistula formation, which may help reduce intraoperative blood loss, operative time, and surgical invasiveness.

Long-term survival after distal pancreatectomy with celiac axis resection and hepatic artery reconstruction in the setting of locally advanced unresectable pancreatic cancer.

The long-term survival of patients with locally advanced, unresectable pancreatic cancer is extremely poor. We present our experience with a 67-year-old woman who had a 40-mm mass in the body of the pancreas. Tumor infiltration reached the gastroduodenal artery, celiac artery, common hepatic artery, and splenic artery. After 10 courses of FOLFIRINOX, 2 courses of gemcitabine plus nab-paclitaxel, and 6 courses of gemcitabine alone, we performed distal pancreatectomy with celiac axis resection and hepatic artery reconstruction. The bifurcation of the gastroduodenal artery and the proper hepatic artery had to be resected, after which we created 2 anastomoses: proper hepatic-to-middle colic artery, and second jejunal-to-right gastroepiploic artery. Histopathologic examination revealed an Evans grade IIb histologic response to prior treatment and verified the R0 resection status. The patient was discharged on postoperative day 30 after treatment of a grade B pancreatic fistula and is still alive, without recurrence, more than 5 years after initiation of treatment. This patient with locally advanced, unresectable pancreatic cancer achieved long-term survival through perioperative multidisciplinary treatment, including distal pancreatectomy with celiac axis resection and hepatic artery reconstruction. This aggressive procedure could be a treatment option for patients with locally advanced, unresectable pancreatic cancer.

MicroDNA levels are dependent on MMEJ, repressed by c-NHEJ pathway, and stimulated by DNA damage.

Extrachromosomal circular DNA (eccDNA) are present within all eukaryotic organisms and actively contribute to gene expression changes. MicroDNA (200-1000bp) are the most abundant type of eccDNA and can amplify tRNA, microRNA, and novel si-like RNA sequences. Due to the heterogeneity of microDNA and the limited technology to directly quantify circular DNA molecules, the specific DNA repair pathways that contribute to microDNA formation have not been fully elucidated. Using a sensitive and quantitative assay that quantifies eight known abundant microDNA, we report that microDNA levels are dependent on resection after double-strand DNA break (DSB) and repair by Microhomology Mediated End Joining (MMEJ). Further, repair of DSB without resection by canonical Non-Homologous End Joining (c-NHEJ) diminishes microDNA formation. MicroDNA levels are induced locally even by a single site-directed DSB, suggesting that excision of genomic DNA by two closely spaced DSB is not necessary for microDNA formation. Consistent with all this, microDNA levels accumulate as cells undergo replication in S-phase, when DNA breaks and repair are elevated, and microDNA levels are decreased if DNA synthesis is prevented. Thus, formation of microDNA occurs during the repair of endogenous or induced DNA breaks by resection-based DNA repair pathways.

ATAC-seq identifies thousands of extrachromosomal circular DNA in cancer and cell lines.

Extrachromosomal circular DNAs (eccDNAs) are somatically mosaic and contribute to intercellular heterogeneity in normal and tumor cells. Because short eccDNAs are poorly chromatinized, we hypothesized that they are sequenced by tagmentation in ATAC-seq experiments without any enrichment of circular DNA. Indeed, ATAC-seq identified thousands of eccDNAs in cell lines that were validated by inverse PCR and by metaphase FISH. ATAC-seq in gliomas and glioblastomas identify hundreds of eccDNAs, including one containing the well-known EGFR gene amplicon from chr7. More than 18,000 eccDNAs, many carrying known cancer driver genes, are identified in a pan-cancer analysis of ATAC-seq libraries from 23 tumor types. Somatically mosaic eccDNAs are identified by ATAC-seq even before amplification is recognized by genome-wide copy number variation measurements. Thus, ATAC-seq is a sensitive method to detect eccDNA present in a tumor at the pre-amplification stage and can be used to predict resistance to therapy.