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.

[A Case of Mucinous Adenocarcinoma of the Appendix with Peritoneal Dissemination Diagnosed by Laparoscopic Abdominal Exploration and Appendectomy].

We report a case of mucinous adenocarcinoma of the appendix with peritoneal dissemination diagnosed by laparoscopic abdominal exploration and appendectomy. A man in his 60's was diagnosed with peritoneal dissemination of mucinous adenocarcinoma incidentally during an operation for an inguinal hernia. Carcinoma of the appendix was suspected as the primary lesion after further examination. We performed laparoscopic abdominal exploration and appendectomy. The purpose of the operation was to detect the primary lesion, make a pathological diagnosis, and to evaluate the extent of peritoneal dissemination. Laparoscopic findings revealed wide spread peritoneal dissemination and the pathological findings confirmed mucinous adenocarcinoma of the appendix. These laparoscopic procedures lead to a precise diagnosis and allowed for adequate treatment selection.

[The Present Status of Surgical and Endoscopic Treatment for Gastric Cancer Patients Aged 85 Years or Older].

This study aimed to survey treatment ofgastric cancer via gastrectomy or endoscopic submucosal dissection(ESD)in patients aged 85 years or older and to clarify the risks and benefits of gastrectomy in terms of postoperative complications and prognosis. The analysis included 40 patients who were treated via gastrectomy and 41 who were treated via ESD. All patients were aged 85 years or older. Although most ofthe patients who had gastrectomy had good performance status(PS), comorbidities were found in 72.5%, and limited operation was often performed. In the gastrectomy group, R0 tumor-free resection margins were achieved in 75%, and postoperative complications occurred in 45%. Despite R0 surgery, the 2-year overall survival rate was 61.7% and the 3-year overall survival was 42.9%. Seven patients(17.1%)in the ESD group were diagnosed with T1b tumors, and no patients were shifted to surgery. Treatment decisions for super-elderly gastric cancer patients are made with regard to age, PS, and comorbidities. There is a limit to survival time after radical gastrectomy. It is necessary to examine the negative effect of gastrectomy on survival time. Selected patients aged 85 years or older with T1b gastric cancer should be given the option of ESD.

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.

Evaluation of Preoperative Chemotherapy with Modified OPTIMOX-1 Plus Bevacizumab in Patients with Advanced Rectal Cancer with Factors Contraindicative of Curative Surgery.

BACKGROUND/AIMS: The efficacy and safety of neoadjuvant chemotherapy in patients with highly advanced rectal cancer for whom radical surgery was considered difficult were evaluated. METHODOLOGY: From June 2007 to February 2011, 10 advanced lower rectal cancer patients with factors contraindicative of curative surgery with total mesenteric excision were eligible for this study. Neoadjuvant chemotherapy consisting of modified OPTIMOX1 (mFOLFOX6 and sLV5FU2 alternating administration) plus bevacizumab was administered. RESULTS: Adverse events seen with chemotherapy consisted of grade 2 leukopenia in 1 patient, but there were no cases of delayed administration or dosage reduction due to grade 2 neurotoxicity. The surgical procedures were anus-preserving resection in 8 patients, total pelvic exenteration in 1 patient, and posterior pelvic exenteration in 1 patient. A positive radial margin was confirmed in 3 patients, but radical surgery was performed, histologically as well, in the other patients. Upon comparing the clinical and postoperative histological stages, primary tumor and node downstaging was achieved in 20.0% and 70.0% of the patients, respectively. CONCLUSIONS: These findings suggest the potential utility of neoadjuvant chemotherapy consisting of modified OPTIMOX1 plus bevacizumab prior to permitting radical resection or anus-preserving surgery in patients with highly advanced rectal cancer.

[A Case of Double Cancers of the Stomach and Endometrium with Peritoneal Metastasis].

The patient was a 59-year-old woman with advanced double cancers of the stomach and endometrium with peritoneal metastasis. Abdominal computed tomography revealed that the endometrial cancer was more advanced than the gastric cancer; therefore, the peritoneal metastasis was diagnosed as arising from the endometrial cancer. Treatment of the endometrial cancer with cytoreductive surgery followed by adjuvant chemotherapy was performed first. She underwent total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Disseminated nodules were found throughout her abdomen. The histopathological findings indicated carcinosarcoma of the uterus, pT3bNXM1, Stage Ⅳb. One month after surgery, she received 6 courses of adjuvant chemotherapy with paclitaxel plus carboplatin. After the adjuvant chemotherapy, abdominal computed tomography revealed that both the ascites and the disseminated nodules had disappeared. Therefore, a second-look surgery for the endometrial cancer and definitive surgery for the gastric cancer were planned. At the laparotomy, no disseminated nodules were found, so distal gastrectomy and D2 lymphadenectomy were performed. The histopathological findings were pT4aN1M0P0Cy0, Stage ⅢA. She received adjuvant chemotherapy with S-1 for 1 year, and has been alive with no evidence of recurrence for 2 years and 7 months after the initial surgery.

[Treatment Strategy for Gastric Carcinoma with Lymphoid Stroma].

Gastric carcinoma with lymphoid stroma (GCLS) is a histological type with severe lymphocytic infiltration. GCLS is very rare and few cases have been reported. We examined the clinical features, problems of preoperative diagnosis, and treatment of 14 cases (1.8%) that were diagnosed as GCLS out of 790 gastric cancers surgically resected in our hospital. The mean age was 69 years. Six, 8, and 0 cases were located in the upper, middle, and lower fields of the stomach, respectively, and 8, 1, 4, and 1 cases were macroscopically 0-Ⅱc, 0-Ⅰ, type 2, and type 3, respectively. The depth of invasion was M, SM1, SM2, MP, and SS in 0, 0, 9, 3, and 2 cases, respectively. There were 12 cases(86%)with infection by Epstein-Barr virus, and just 1 case with lymph node metastasis. All cases have had no evidence of recurrence. There were no cases that were diagnosed as GCLS before surgery. GCLS is recognized as having a more favorable prognosis compared with other types of gastric carcinoma, so an aggressive surgery might achieve good outcomes. However, preoperative diagnosis is very difficult and there is a compelling need for new techniques or criteria for diagnosis of GCLS.

[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.

[The Different Indications and Treatment Effect between Preoperative Chemotherapy and Preoperative Radiotherapy for Advanced Rectal Cancer].

We evaluated the difference in effectiveness between preoperative radiotherapy (RT) and chemotherapy (C) as part of multimodal therapy for locally advanced rectal cancer. In the RT group, 43 patients were enrolled and preoperative radiotherapy was performed with 42.6 Gy for 4 weeks. In the C group, 16 patients were treated with preoperative chemotherapy consisting of mFOLFOX6/XELOX plus bevacizumab for 3 months. All 43 tumors in the RT group were located in the lower rectum. The C group was composed of 9 in the lower rectum and 7 in the middle or upper rectum. The C group was more advanced than the RT group in terms of depth of invasion, lymph node metastasis, and tumor diameter. The histological treatment response was better after RT (7 with little, 10 with a minor, 24 with a major, and 2 with a complete response) than after C (10 with little, 4 with a minor, 1 with a major, and 1 with a complete response). The tumor reduction ratio by colonography showed 36.5% after RT and 28.7% after C. CEA was reduced by 47.2% after RT and 45.2% after C. Though RT is more effective for local lesions than C, C is expected to be preferred as the local and systemic therapy for locally advanced rectal cancer with pelvic organ involvement or lateral lymph node metastases.

[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.

Performing simple and safe dunking pancreaticojejunostomy using mattress sutures in pure laparoscopic pancreaticoduodenectomy.

BACKGROUND: Although recent technological developments and improved endoscopic procedures have further spread the application of laparoscopic pancreatic resection, laparoscopic pancreaticoduodenectomy still presents major technical difficulties, such as when performing pancreatic-enteric anastomosis. METHODS: Laparoscopic dunking pancreaticojejunostomy using mattress sutures was performed in 15 consecutive patients with a soft pancreas and a nondilated pancreatic duct between October 2011 and December 2012. RESULTS: According to the International Study Group on Pancreatic Fistula criteria, 3 patients developed PF (grade A), whereas the remaining 12 patients did not. CONCLUSIONS: Dunking pancreaticojejunostomy using mattress sutures is considered to be a feasible and safe method for performing pure laparoscopic pancreaticoduodenectomy.

[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 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.

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.

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.