Radiogenomics for predicting p53 status, PD-L1 expression, and prognosis with machine learning in pancreatic cancer.

BACKGROUND: Radiogenomics is an emerging field that integrates "Radiomics" and "Genomics". In the current study, we aimed to predict the genetic information of pancreatic tumours in a simple, inexpensive, and non-invasive manner, using cancer imaging analysis and radiogenomics. We focused on p53 mutations, which are highly implicated in pancreatic ductal adenocarcinoma (PDAC), and PD-L1, a biomarker for immune checkpoint inhibitor-based therapies. METHODS: Overall, 107 patients diagnosed with PDAC were retrospectively examined. The relationship between p53 mutations as well as PD-L1 abnormal expression and clinicopathological factors was investigated using immunohistochemistry. Imaging features (IFs) were extracted from CT scans and were used to create prediction models of p53 and PD-L1 status. RESULTS: We found that p53 and PD-L1 are significant independent prognostic factors (P = 0.008, 0.013, respectively). The area under the curve for p53 and PD-L1 predictive models was 0.795 and 0.683, respectively. Radiogenomics-predicted p53 mutations were significantly associated with poor prognosis (P = 0.015), whereas the predicted abnormal expression of PD-L1 was not significant (P = 0.096). CONCLUSIONS: Radiogenomics could predict p53 mutations and in turn the prognosis of PDAC patients. Hence, prediction of genetic information using radiogenomic analysis may aid in the development of precision medicine.

Quantitative Assessment of the Blood Perfusion of the Gastric Conduit by Indocyanine Green Imaging.

BACKGROUND: Indocyanine green (ICG) fluorescence imaging has been used to assess the blood perfusion of the gastrointestinal tract in surgery. Especially, it was used to determine the best anastomotic site. However, in previous studies, ICG fluorescence was judged subjectively based on the visual appearance. This study evaluated the usefulness of our novel method to quantitatively assess the blood perfusion of the gastric conduit in esophagectomy based on ICG fluorescence. MATERIALS AND METHODS: Twenty patients who underwent esophagectomy with gastric conduit reconstruction were prospectively investigated. Using a camera in contact with the surface of the stomach, ICG images were quantitatively evaluated using "ROIs", a software program that quantified the fluorescence intensity and created a time-fluorescence intensity curve to assess the blood perfusion three times intraoperatively. RESULTS: No postoperative esophago-gastrostomy leakage developed. However, after preparing the gastric conduit and just before anastomosis, the maximum increase in fluorescence intensity (FImax) significantly decreased (48.8 ± 26.0 and 31.5 ± 14.9 versus 84.9 ± 28.2; P < 0.001 and P < 0.001, respectively), and the time to reach FImax was significantly extended (60 ± 35.4 and 58.3 ± 34.9 versus 18.9 ± 6.5; P < 0.001 and P < 0.002, respectively), in comparison to the control value. Just before anastomosis, 18 cases (90%) showed an identical pattern characterized by an obtuse and low arterial inflow peak and a slow rise of fluorescence intensity over time, indicating a decreased blood flow. CONCLUSIONS: The quantitative analysis of ICG fluorescence imaging could objectively prove a decrease in blood perfusion-which could not be determined macroscopically-in the gastric conduit before esophageal reconstruction. The results from the present and further studies may indicate its clinical value.

Hepatectomy for oligo-recurrence of non-small cell lung cancer in the liver.

BACKGROUND: The prognosis of metastatic recurrent non-small cell lung cancer (NSCLC) is poor, and chemotherapy improves survival by only a few months. The concept of oligo-recurrence, defined as a small number of new lesions at a distant site theoretically curable by local therapy, has recently been proposed for several cancers. To evaluate the possible benefits of surgical resection for oligo-recurrence, we report the outcomes of seven patients who underwent hepatic resection for oligo-recurrence of NSCLC in the liver. METHODS: Among the 2038 patients who underwent resection for NSCLC between January 1997 and December 2015 at the Department of Chest Surgery, Chiba Cancer Center, 7 (0.34%) with oligo-recurrence in the liver underwent hepatectomy. Perioperative data were retrospectively reviewed, including recurrence-free and overall survival. RESULTS: Primary tumor histopathological types included five cases of squamous cell carcinoma, one case of adenocarcinoma, and one case of large-cell carcinoma. All patients underwent complete tumor resection without complication. The median survival duration following hepatectomy was 24.0 (range 15.2-30.2) months. Four patients were alive at the end of follow-up (23.4-30.2 months), whereas three died between 15.2 and 24.5 months. There was no evidence of second recurrence in two patients. CONCLUSIONS: Hepatectomy may be equally effective as multidisciplinary therapy for oligo-recurrence of NSCLC in the liver.

[A Case of Locally Advanced Rectal Cancer Invading Posteriorly Adjacent to Sacrum Resected by Laparoscopic Low Anterior Resection].

We report a case of locally advanced rectal cancer invading toward sacrum treated by laparoscopic low anterior resection. A man in his 60's was diagnosed with rectal cancer expanding near to sacrum. The circumferential resection margin was assessed to be scarce. After preoperative chemotherapy, we performed laparoscopic low anterior resection. In order to obtain surgical margin, we had to cut into presacral venous plexus. With prepared sufficient devices, hemostasis was safely acquired. Pathological findings revealed clear surgical margin. It is important to prepare appropriate hemostasis devices in managing cases with high risks of intraoperative hemorrhage. Laparoscopic approach may contribute to these cases, making hemostasis easier than laparotomy with the magnified view, pneumoperitoneum and Trendelenburg position.

Solid variant type of serous cystadenocarcinoma of the pancreas: a case report and review of the literature.

Serous cystic neoplasms (SCN) of the pancreas are typically honeycombed microcystic masses, which are believed to be benign entity. This report describes a case of a 69-year-old man with a rare solid type of serous cystadenocarcinoma of the pancreas with liver metastases. A 6-cm well enhanced pancreatic tumor and multiple liver nodules were depicted with contrast medium on computed tomography scan. Distal pancreatectomy was performed at first operation. The cut surface of the tumor was solid and glossy appearance. Second operation of liver resection for all metastatic nodules was performed 27 months after the initial operation. The tumor cells in both the pancreas and the liver had cytoplasmic periodic acid-Schiff positive granules, which were completely digested by diastase. Eleven cases of serous cystadenocarcinoma of the pancreas have been reported in the literature. To our knowledge, this is the first case of a solid type serous cystadenocarcinoma.

[Long-term survival and effective treatment of synchronous liver metastases in a case of primary gastric choriocarcinoma by using hepatic arterial infusion chemotherapy, irinotecan, and cisplatin].

A 62-year-old man was admitted to our hospital because of appetite loss. Computed tomography(CT)revealed thickness of the gastric wall, multiple liver tumors, and lung nodes. Upper gastrointestinal endoscopy revealed an easy bleeding type 2 tumor at the gastric antrum. We performed distal gastrectomy to control bleeding from the gastric tumor. Histological findings from the gastric lesion indicated primary gastric choriocarcinoma(PCG). Combination chemotherapy using hepatic arterial infusion chemotherapy for synchronous liver metastases and S-1 was administered for 5 months after the operation. CT revealed that the liver metastases decreased remarkably. On the other hand, lung metastases increased. Irinotecan and cisplatin were administered. Liver metastases did not increase, as observed using imaging studies. The patient died 17 months after the operation for cachexia. PCG is a highly aggressive tumor that is often associated with liver metastasis. It is important to control liver metastasis from PCG.

[A Case of Sigmoid Colon Cancer with Metastasis to the Uterus].

A 65-year-old woman complaining of fetor ex vagina was diagnosed with endometrial adenocarcinoma of the uterus based on the pathological findings of an endometrial biopsy. Sigmoid colon cancer was found on a pre-operative CT scan. Diagnosis of double cancer was made and we performed sigmoidectomy and panhysterectomy with associated resection of both adnexa. Histopathological examination found that the tumor accounted for almost all of the uterine mucosa and over half of the muscular layer. Immunostaining showed CK7 (-), CK20 (+), CDX2 (+), ER (-), and PgR (-), and we diagnosed it as a metastasis to the uterus of the sigmoid colon cancer. The pathological diagnosis was a moderately differentiated adenocarcinoma, pT4b (SI: urinary bladder), pN0 (0/12), H0, P1,M1a (uterus), pStage Ⅳ. As adjuvant chemotherapy, she was administered XELOX for 6 months. Although colorectal cancer rarely metastasizes to the uterus, due to the increase in the prevalence of colorectal cancer, it may be also increase. To choose the best treatment course, it is necessary to diagnose whether it is a primary uterine cancer or a metastatic uterine cancer.

[A Case of Anal Canal Carcinoma with Inguinal Lymph Node Metastasis Treated with Laparoscopic Abdominoperineal Resection].

We report a case of anal canal cancer with inguinal lymph node metastasis treated with laparoscopic abdominoperineal resection combined with inguinal lymph node dissection. A 52-year-old woman was diagnosed with anal squamous carcinoma after excision of an anal canal tumor. Further examination revealed right inguinal lymph node metastasis. Chemoradiotherapy was administered but was discontinued because of serious adverse events. We therefore performed laparoscopic abdominoperineal resection combined with inguinal lymph node dissection. The pathological findings revealed residual squamous cell carcinoma at the lymphatic vessels in the rectal wall and lymph nodes, including the right inguinal region. Therapeutic effect of Grade 1a was achieved in spite of interruption of the chemoradiotherapy. She was discharged 17 days after the operation, and no recurrence was observed for 11 months. Radical resection was performed for the anal canal squamous cell carcinoma with the metastasis to the right inguinal lymph node, even after interruption of the chemoradiotherapy.

[A Case of Early Recurrence after Esophagectomy for Cancer Following Neoadjuvant Chemotherapy Resulting in a Complete Response of the Primary Lesion].

A 78-year-old man presented with a chief complaint of dysphagia. He was diagnosed with an esophageal squamous cell carcinoma and referred to our hospital. A type 3 tumor was identified in the lower thoracic esophagus on endoscopy. A CT scan revealed lymph node metastases at the No. 3 station. The clinical stage of the tumor was T3N1M0, Stage III. The patient was treated with neoadjuvant chemotherapy consisting of2 courses of5 -FU and nedaplatin. He had a partial response and underwent a radical esophagectomy. Histopathological examination revealed a complete response of the primary lesion and viable cancer cells in only one lymph node at the No. 3 station. No adjuvant chemotherapy was administered. Three months after the operation, recurrences in the upper abdominal multiple para-aortic lymph nodes were detected. Although he was treated with chemotherapy, he died 7 months after the operation. Even after a complete response of the primary lesion was achieved using neoadjuvant chemotherapy, esophageal cancer with lymph node metastasis has the potential for an early recurrence. Therefore, we should consider adjuvant therapy in such cases.

[Intraperitoneal chemotherapy with CDDP for patients with peritoneal recurrent gastric cancer following surgical intervention].

We evaluated the efficacy of intraperitoneal chemotherapy with cisplatin (CDDP) for peritoneal recurrent gastric cancer following surgical intervention. Twelve patients were enrolled. The combination systemic chemotherapy was S-1 or S-1 plus paclitaxel (S-1+PTX). PTX was administered intravenously at 80 mg/m² on day S-1 and 15. S-1 was administered at 80 mg/ m²/ day for 7 consecutive days, followed by 7 days of rest, and the cycle was repeated. CDDP was administered intraperitoneally at 40 mg/body on day 8. This treatment was repeated every 4 weeks until disease progression was diagnosed. The survival time(ST)and time to treatment failure(TTF)were estimated. The surgical interventions were gastrectomy in 3 patients, colostomy in 8 patients, and enterostomy in 1 patient. Overall, the median TTF and ST were 294 days and 455 days, respectively. When stratified by surgical method and combination chemotherapy, the median TTF and ST were not statistically significant. However, when stratified by performance status (PS), the median TTF was 352 days for patients with PS 0 and 218 days for those with PS 1, 2 (p=0.0029), whereas the median ST was 553 days for patients with PS 0 and 331 days for those with PS 1, 2 (p=0.0198). In conclusion, the data suggest that intraperitoneal CDDP chemotherapy with systemic chemotherapy is effective for the treatment of extensive peritoneal recurrent gastric cancer, especially in patients with good PS.

[A case of rectal gastrointestinal stromal tumor (GIST) locally resected after long-term chemotherapy with imatinib mesylate].

We report a case of gastrointestinal stromal tumor (GIST) locally resected after long-term chemotherapy with imatinib mesylate. A 78-year-old woman was diagnosed with GIST in the lower rectum on screening colonoscopy for anemia. The tumor was 7 cm in diameter, and the anal sphincter was considered to be difficult to preserve due to the extent of the tumor. The patient refused surgery, so she was administered imatinib mesylate chemotherapy. The medication was continued for 5 years without any major adverse events, and the status of the tumor was stable. Five years later, she underwent transanal local resection for anal prolapse and incarceration of the tumor. Pathological findings revealed a 7 cm sized high-risk GIST. The long-term stable status of the tumor was maintained, and the anal function was preserved by the local resection.

A Randomized Trial of Ionic Silver Dressing to Reduce Surgical Site Infection After Gastrointestinal Surgery.

Objective: To determine whether Aquacel Ag Hydrofiber dressings containing ionic silver are superior to film dressings for preventing superficial surgical site infections (SSI) in patients undergoing elective gastrointestinal surgery. Background: Multiple clinical trials have assessed the effectiveness of silver-containing wound dressings; however, systematic reviews failed to find any advantages of these dressings and concluded that there was insufficient evidence to indicate that they prevented wound infections. This study aimed to evaluate the efficacy of Aquacel Ag Hydrofiber dressings for preventing superficial SSIs in patients undergoing gastrointestinal surgery. Methods: Patients undergoing elective gastrointestinal surgery were randomly assigned to receive either Aquacel Ag Hydrofiber (study group) or film dressings (control group). The primary end point was superficial SSI within 30 days after surgery (UMIN Clinical Trials Registry ID: 000043081). Results: A total of 865 patients (427 study group, 438 control group) were qualified for primary end-point analysis. The overall rate of superficial SSIs was significantly lower in the study group than in the control group (6.8% vs 11.4%, P = 0.019). There was no significant difference in superficial SSI rates between the groups in patients undergoing upper gastrointestinal surgery; however, the rate was significantly lower in the study group in patients undergoing lower gastrointestinal surgery (P = 0.042). Multivariate analysis identified Aquacel Ag Hydrofiber dressings as an independent factor for reducing superficial SSIs (odds ratio, 0.602; 95% confidence interval, 0.367-0.986; P = 0.044). Conclusions: Aquacel Ag Hydrofiber dressings can reduce superficial SSIs compared to film dressings in patients undergoing elective gastrointestinal surgery, especially lower gastrointestinal surgery.

Totally laparoscopic pancreas-sparing duodenectomy.

Pancreas-sparing duodenectomy (PSD) is a practical surgical procedure for patients with duodenal adenoma, which is difficult to resect endoscopically. We describe how we performed a totally laparoscopic PSD to resect a duodenal adenoma in a 64-year-old woman, who had been referred for treatment of a 50-mm villous polypoid mass in the second portion of the duodenum. We performed end-to-side anastomosis between the common duct of the bile and pancreatic ducts and the jejunal limb intracorporeally following the duodenal resection. A biliary leak developed, but resolved spontaneously and the patient was discharged on postoperative day (POD) 32. The surgical margin was free of neoplastic change. Although there is limited experience and appropriate indications must await future studies, this case demonstrates that laparoscopic PSD is feasible, safe, and effective for selected patients.

Transcriptomic analysis reveals high ITGB1 expression as a predictor for poor prognosis of pancreatic cancer.

Transcriptomic analysis of cancer samples helps identify the mechanism and molecular markers of cancer. However, transcriptomic analyses of pancreatic cancer from the Japanese population are lacking. Hence, in this study, we performed RNA sequencing of fresh and frozen pancreatic cancer tissues from 12 Japanese patients to identify genes critical for the clinical pathology of pancreatic cancer among the Japanese population. Additionally, we performed immunostaining of 107 pancreatic cancer samples to verify the results of RNA sequencing. Bioinformatics analysis of RNA sequencing data identified ITGB1 (Integrin beta 1) as an important gene for pancreatic cancer metastasis, progression, and prognosis. ITGB1 expression was verified using immunostaining. The results of RNA sequencing and immunostaining showed a significant correlation (r = 0.552, p = 0.118) in ITGB1 expression. Moreover, the ITGB1 high-expression group was associated with a significantly worse prognosis (p = 0.035) and recurrence rate (p = 0.028). We believe that ITGB1 may be used as a drug target for pancreatic cancer in the future.

Machine learning with imaging features to predict the expression of ITGAV, which is a poor prognostic factor derived from transcriptome analysis in pancreatic cancer.

Radiogenomics has attracted attention for predicting the molecular biological characteristics of tumors from clinical images, which are originally a collection of numerical values, such as computed tomography (CT) scans. A prediction model using genetic information is constructed using thousands of image features extracted and calculated from these numerical values. In the present study, RNA sequencing of pancreatic ductal adenocarcinoma (PDAC) tissues from 12 patients was performed to identify genes useful in evaluating clinical pathology, and 107 PDAC samples were immunostained to verify the obtained findings. In addition, radiogenomics analysis of gene expression was performed by machine learning using CT images and constructed prediction models. Bioinformatics analysis of RNA sequencing data identified integrin αV (ITGAV) as being important for clinicopathological factors, such as metastasis and prognosis, and the results of sequencing and immunostaining demonstrated a significant correlation (r=0.625, P=0.039). Notably, the ITGAV high­expression group was associated with a significantly worse prognosis (P=0.005) and recurrence rate (P=0.003) compared with the low­expression group. The ITGAV prediction model showed some detectability (AUC=0.697), and the predicted ITGAV high­expression group was also associated with a worse prognosis (P=0.048). In conclusion, radiogenomics predicted the expression of ITGAV in pancreatic cancer, as well as the prognosis.

[Laparoscopic pancreatic resection of pancreatic cancer].

Laparoscopic pancreatic resection of pancreatic cancer is still not universally accepted as an alternative approach to open surgery because of technical difficulties and a lack of consensus regarding the adequacy of this approach for malignancy. Ten patients with pancreatic cancer underwent laparoscopic pancreatic resection, including pancreaticoduodenectomy and distal pancreatectomy in our institution. Eight of the 10 patients recovered without any complications and were discharged on the 10-29th postoperative day. The remaining 2 patients developed pancreatic fistula and were discharged on the 46 and 60th postoperative day, respectively. All lesions were well clear of surgical margins in 6 patients (R0). In the remaining 4 patients, microscopic neoplastic change was found at the surgical margin (R1). Those 4 patients developed tumor recurrence, including liver metastases or peritoneal dissemination, and 3 of the 4 died of the primary disease. Although experience is limited, laparoscopic pancreatic resection of pancreatic cancer can be feasible, safe, and effective in carefully selected patients. However, the benefit of this procedure has yet to be confirmed. Not only adequate experience in pancreatic surgery but also expertise in laparoscopy is mandatory, and careful selection of patients is essential for successful application of this procedure.

Prognostic significance of p16 protein in pancreatic ductal adenocarcinoma.

The p16 gene, which is also known as CDKN2A, INK4A, or CDK4I, and its products that are known to be cell cycle inhibitors and tumor suppressors have been reported to be altered in various human tumor types. Altered p16 has been indicated to be correlated with negative p16 expression using immunohistochemistry (IHC). However, its association with the prognosis remains controversial because the findings of previous studies are inconsistent. The current study evaluated the relationship between the expression levels of p16 and the clinicopathological features associated with prognosis in patients with primary pancreatic ductal adenocarcinomas (PDACs). From January 2013 to December 2017, tissues of 103 PDAC patients who had undergone elective pancreatic resection were obtained and assessed for p16 expression by IHC. No correlation was observed between p16 status and clinicopathological factors (P>0.05). Notably, negative p16 expression on IHC was not significantly associated with poor prognosis using the Kaplan-Meier method.

MIR1246 in body fluids as a biomarker for pancreatic cancer.

Pancreatic cancer is an aggressive tumor associated with poor survival, and early detection is important to improve patient outcomes. In the present study, we examined MIR1246 expression as a biomarker of pancreatic cancer. Total RNA was extracted from serum, urine and saliva samples from healthy subjects (n = 30) and patients with pancreatic cancer (n = 41, stage 0-IV). The MIR1246 level in each fluid was analyzed by quantitative reverse transcription-polymerase chain reaction. Significantly higher MIR1246 expression in serum and urine was observed in patients with cancer than in healthy controls. A significant positive correlation was found between serum and urine MIR1246 expression (r = 0.34). Receiver operating characteristic curves were constructed for MIR1246 in all three body fluids. The area under the curve for serum MIR1246 was 0.87 (sensitivity, 92.3%; specificity, 73.3%), and that for urine MIR1246 was 0.90 (sensitivity, 90.2%; specificity, 83.3%). With a cut-off of the control group's mean plus twice the standard deviation, the sensitivities of MIR1246 in serum and urine for pancreatic cancer were 60.9 and 58.5%, respectively. Combining both serum and urine MIR1246 expression yielded a sensitivity of 85%. These results indicate that MIR246 may be a useful diagnostic biomarker for pancreatic cancer.

Laparoscopy in the management of hilar cholangiocarcinoma.

The use of minimally invasive surgery has become widely accepted in many gastrointestinal fields, even in patients with malignancy. However, performing laparoscopic resection for the treatment of hilar cholangiocarcinoma is still not universally accepted as an alternative approach to open surgery, and only a limited number of such procedures have been reported due to the difficulty of performing oncologic resection and the lack of consensus regarding the adequacy of this approach. Laparoscopy was initially limited to staging, biopsy and palliation. Recent technological developments and improvements in endoscopic procedures have greatly expanded the applications of laparoscopic liver resection and lymphadenectomy, and some reports have described the use of laparoscopic or robot-assisted laparoscopic resection for hilar cholangiocarcinoma as being feasible and safe in highly selected cases, with the ability to obtain an adequate surgical margin. However, the benefits of major laparoscopic surgery have yet to be conclusively proven, and carefully selecting patients is essential for successfully performing this procedure.

Arantius' ligament approach for the left extrahepatic Glissonean pedicle in pure laparoscopic left hemihepatectomy.

INTRODUCTION: Laparoscopic hemihepatectomy has not yet become widely accepted because of the technical difficulties in controlling each Glissonean pedicle laparoscopically. MATERIALS AND SURGICAL TECHNIQUE: The subjects in the present study included 12 patients who underwent laparoscopic left hemihepatectomy between August 2007 and June 2011. Arantius' ligament was divided. Retracting the caudal stump of the ligament revealed a space between the left Glissonean pedicle and the liver parenchyma. The left Glissonean pedicle could be easily encircled by using an Endo Retract Maxi. No Glissonean injuries, including bleeding or biliary leakage, occurred in any of the 12 patients. DISCUSSION: Therefore, the Arantius' ligament approach for the left extrahepatic Glissonean pedicle appears to be feasible and safe for successfully performing pure laparoscopic left hemihepatectomy.