Multicenter Prospective Cohort Study of Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer (YPB-001).

OBJECTIVES: The present multicenter prospective observational study investigated the effectiveness and safety of neoadjuvant chemotherapy (NAC) for patients with borderline resectable pancreatic cancer (BRPC) and those with RPC contacting major vessels, with respect to a historical control of upfront surgery. MATERIALS AND METHODS: Patients with BRPC and RPC contacting major vessels were prospectively registered and administered NAC with durations and regimens determined by the corresponding treating physician. Our primary aim was to assess the R0 resection rate, and secondary aim was to evaluate safety, resection rate, time to treatment failure, overall survival, and response rate. RESULTS: Fifty of 52 enrolled patients were analyzed; 2 with serious comorbidities died during treatment. Thirty-one patients underwent resection, with R0 resection being achieved in 26 (52% of total and 84% of all resected cases). Univariate and multivariate analyses indicated age (≥75 years) as the only independent predictor of nonresection. Median progression-free survival and median survival time were longer in the prospective cohort than in the historical cohort. CONCLUSIONS: Overall, NAC for BRPC in real-world setting might yield R0 resection rates similar to those reported in previous clinical studies. Development of safe regimens and management strategies that can maintain treatment intensity in geriatric patients is warranted.

[A Case of Medullary Carcinoma of the Colon].

The patient is a 79-year-old woman who visited her local doctor with a chief complaint of abdominal pain. A lower gastrointestinal endoscopy revealed a circumferential type 3 mass in the transverse colon. The patient was diagnosed with transverse colon cancer (cT3N0M0, cStage Ⅱa)and underwent laparoscopic transverse colectomy(D3). The postoperative course was good, and she was discharged on POD 9. Pathological results showed a diagnosis of medullary carcinoma(pT3N0M0, pStage Ⅱa)with MSI-high. The patient was treated with UFT/UZEL for 6 months as postoperative adjuvant chemotherapy. The patient has been recurrence-free for 1 year and 6 months postoperatively and is under outpatient follow-up. Medullary carcinoma is a rare histologic type that is estimated to account for 2-3% of all colorectal cancers. Medullary carcinoma of the colon is more common in elderly patients, women, and the right side of the colon, with a relatively favorable prognosis. We report a case of medullary carcinoma of the transverse colon in which the patient had a relatively long survival, with some discussion of the literature.

[A Case of Resection of Primary Hepatic Neuroendocrine Tumor].

Neuroendocrine tumors(NET)often occur in the digestive tract, pancreas, and lungs. Primary hepatic neuroendocrine tumor(PHNET)is extremely rare and has a high malignancy and poor prognosis. Diagnosis is extremely difficult only by imaging findings, and in majority of the cases, definitive diagnosis is produced by an excisional biopsy. We report a case of PHNET diagnosed by preoperative liver tumor biopsy and underwent surgical resection. A 60's man was admitted with the main complaint of weight loss. Image examination(abdominal echo, CT, MRI)revealed continuous tumors of 6 cm and 5 cm in the liver S4 to S8 area, respectively, and a tumor of <1 cm in the S5 and S7 areas. When liver biopsy was performed, immunostaining revealed that it was chromogranin A-positive. Therefore, it was diagnosed as NET. No other lesions were observed in PET-CT, and the patient was diagnosed with PHNET. Extended left hepatectomy and partial S5/S7 liver resections were performed. The pathological diagnosis was NET and Ki-67 index was 7%, which was equivalent to NET G2 in the WHO classification.

[A Case of Tumor Embolization to the Internal Iliac Vein Four Years after the Surgery for Rectal Cancer].

60-year-old man was admitted to our hospital with a chief complaint of melena. Lower gastrointestinal endoscopy revealed a type 2 tumor on the anterior wall of the rectum(Rb). He was referred to our department, and he underwent abdominoperineal rectal resection with D3 dissection and right lateral node dissection for Rb, cT2, N0, M0 intestinal cancer. Pathological diagnosis was a tub2, pT2, N0, Ly0, V0, pDM0(30 mm), pPM0(160 mm), pR0, pStage Ⅰ cancer. Therefore, postoperative adjuvant chemotherapy was not performed. Subsequent follow-up examinations were conducted on a regular basis to confirm no recurrence. However, 4 years after the surgery, high levels of tumor markers, such as CEA(59.2 ng/mL) and CA19-9(75.5 U/mL), were detected. CT showed tumor embolism to the internal iliac vein and multiple lung metastases. After IVC filter placement, chemoradiotherapy was performed. Although the tumor embolism disappeared, multiple lung metastases increased. Additionally, brain metastasis appeared 6 years after the operation. After that, according to the policy of BSC, he died 7 years after the surgery.

[A Case of Laparoscopic Gastric Local Resection for Simultaneous Multiple Gastric GIST Discovered Owing to Gastrointestinal Bleeding].

An 80-year-old woman with anemia presented to our hospital. Upper gastrointestinal endoscopy revealed a 4 cm submucosal tumor(SMT)with a delle and 2 cm SMT in the upper part of the stomach. CT revealed sustained enhancement of both tumors. The posterior tumor was an intraductal growth, and the anterior tumor was an extravascular growth. We performed a laparoscopic gastric local excision for the multiple SMTs. The anterior tumor was resected with an automatic suture instrument. However, the posterior tumor could not be identified from within the abdominal cavity because it was resected while confirming using an endoscope, and all layers were sutured. On histopathological examination, the posterior tumor was 40mm in size, with spindle-shaped atypical cells growing in the submucosal layer. Immunostaining was c-kit(+), CD34(+), S-100(-), and desmin(-). The Ki-67 level was<1%. The anterior wall tumors showed similar findings, but some showed smooth muscle differentiation. From the results, a diagnosis of simultaneous multiple gastric GIST(low risk)was made.

A new prognostic model for hepatocellular carcinoma recurrence after curative hepatectomy.

We previously reported the effectiveness of the product of tumor number and size (NxS factor) for the prognosis of hepatocellular carcinoma (HCC) in patients following hepatectomy. The present study aimed to propose a new score based on the NxS factor to predict HCC recurrence following hepatectomy. A total of 406 patients who underwent hepatectomy for HCC at Osaka University Graduate School of Medicine were retrospectively analyzed to develop the new score. Among clinicopathological factors, including the NxS factor, the marker subset that achieved the best performance for prediction of early recurrence was assessed, and a prognostic model for HCC recurrence after curative hepatectomy (REACH) was developed. As the validation set, 425 patients who underwent hepatectomy for HCC at Yamaguchi University Graduate School of Medicine and Shimonoseki Medical Center were analyzed, and the prognostic ability of the REACH score was compared with that of well-known staging systems. Following analysis, the REACH score was constructed using six covariates (NxS factor, microscopic hepatic vein invasion, differentiation, serum albumin, platelet count and indocyanine green retention rate at 15 min). In the validation set, the REACH score predicted early recurrence in 73 of 81 samples, with a sensitivity of 89% and a specificity of 58%. The area under the curve (AUC) of the receiver operating characteristic curve of the REACH score was 0.78 and 0.74, respectively, for 1- and 2-year recurrence after hepatectomy; each AUC was higher than that of any of the other staging systems. Survival analysis indicated the REACH score had the best predictive value in disease-free and overall survival. The present findings demonstrated that the REACH score may be used to classify patients with HCC into high- and low-risk of recurrence, and to predict subsequent survival following hepatic resection.

[A Case of Metastasis of Ascending Colon Cancer to the Small Intestine That Was Diagnosed Based on Ileus].

A 69-year-old man was administered an ileus tube for ileus by ascending colon cancer. The next day, he underwent right hemicolectomy with D3 lymph node dissection for perforative peritonitis due to ascending colon cancer. The pathological diagnosis was A, type 2, muc>tub1, pT3, pN0. M0, pStageⅡ. He received 5 courses of UFT/Leucovorin(LV)chemotherapy. Two years later, he was hospitalized for ileus. He underwent surgery. The peritoneal dissemination was absent in the surgical findings. We resected a small intestinal tumor from the oral side of anastomosis. Because the tumor appearance and pathological findings were similar to those of ascending colon cancer, the patient was diagnosed with metastasis of ascending colon cancer to the small intestine. We report our rare encounter with metastases of colorectal cancer to the small intestine.

[A Case of Rectal Neuroendocrine Carcinoma That Showed a Sharp Turning Point after Neoadjuvant Radiochemotherapy and Conversion Surgery].

A 45-year-old man presented with the chief complaint of anal discomfort to a previous doctor. The symptoms remained after undergoing seton surgery following the diagnosis of intermuscular anal fistula. CT showed a tumor that was 3 cm in diameter on the right wall of the rectum, and he received a diagnosis of neuroendocrine carcinoma(NEC)based on a biopsy. Subsequently, he was admitted to our hospital. Liver metastasis accompanied NEC, and chemotherapy was performed for stage Ⅳ diagnosis. We detected tumor disappearance after administering 8 courses of CDDP plus CPT-11. However, after 3 months, a 1 cm nodule appeared at the primary lesion, which was considered as recurrence. We selected reintroduction of CDDP plus CPT-11 treatment, but the tumor progressed. CDDP plus VP-16 plus radiation therapy was introduced, and tumor shrinkage was observed without distant metastasis. We judged that radical resection was possible, and performed Miles' operation, total prostate gland resection, and urethra reconstruction. He was discharged on the 28th day after surgery. The pathological findings indicated neuroendocrine small cell carcinoma, and the CRT effect was judged as Grade 2 and curability A. However, he was admitted to the emergency room following convulsions on the 46th day after surgery was performed. CT revealed multiple cerebral metastasis, meningeal dissemination, and liver metastasis. He underwent cyber knife surgery for brain metastasis. Drainage was required for cerebral hypertension due to meningeal dissemination. He died on the 115th postoperative day.

[Effect of Pegfilgrastim Primary Prophylactic Administration on Relative Dose Intensity(RDI)in Postoperative Adjuvant Chemotherapy(TC Therapy)for Breast Cancer - A Single-Center, Retrospective Study].

This study assessed the effect of pegfilgrastim in patients with early stage breast cancer who were receiving docetaxel and cyclophosphamide(TC)therapy(75mg/m / 2 docetaxel plus 600 mg/m2 cyclophosphamide). In total, 17 patients who were to receive 4 planned cycles of TC therapy every 3 weeks were included in this study. Of the 17 patients, 10 who received pegfilgrastim after January 2016 formed the Peg-G group and 7 who did not receive pegfilgrastim until December 2015 formed the control group. We observed a high successful execution rate and relative dose intensity(RDI)with docetaxel in both groups. The successful execution rates were 100% in the Peg-G group and 42.8% in the control group. The RDI was 86.5%(65.4-100%)in the Peg-G group and 52.5%(48.0-58.0%)in the control group. This study showed that the use of pegfilgrastim results in a high successful execution rate and RDI in patients with early stage breast cancer undergoing TC therapy.

[A Case of Small Bowel Adenocarcinoma That Was Diagnosed and Treated using Laparoscopic Surgery].

A 40-year-old man presented to our department with chief complaints of nausea and abdominal pain, and was diagnosed with small intestine ileus. After hospitalization, he underwent intestinal tract decompression using an ileus tube. A small bowel tumor was suspected as the cause of the intestinal obstruction. We then performed laparoscopic surgery for diagnosis and resection. In the intraoperative findings, stenosis near the small intestine tumor could be confirmed. The patient therefore underwent laparoscopic resection of a segment of the small intestine. Following rapid intraoperative pathological examination, the tumor was identified as well-differentiated adenocarcinoma with metastasis of the intermediate mesenteric lymph nodes. We then performed dissection of the main lymph nodes using small laparotomy incisions. Adjuvant chemotherapy with XELOX(130mg/m2 L-OHP on day 1 and 2,000 mg/m2 capecitabine on days 1-14)was administered for 6 months. Currently the patient is in relapse-free survival.

Risk Factors and Managements of Bile Leakage After Hepatectomy.

BACKGROUND: The purpose of this study was to retrospectively determine the risk factors and evaluate the management of bile leakage. METHODS: Three hundred and thirty-four patients who underwent hepatectomy for Child classification grade A liver disease, without biliary reconstruction and laparoscopic procedures, between 2003 and 2013 were included. Risk factors were identified using multivariate analysis. RESULTS: Bile leakage was observed in 30 (9.0%) patients. Multivariate analysis demonstrated that type of hepatectomy (segmentectomy 1, medial sectionectomy, anterior sectionectomy, or central bisectionectomy) and operating time was independent risk factors for bile leakage. Among 30 patients with confirmed bile leakage, central type leakage that was in communication with the biliary tree occurred in 23 (76.7%) patients and peripheral type, which was not in communication with the biliary tree, in 7 (23.3%) patients. Ten patients were treated with only drainage. Endoscopic or percutaneous transhepatic procedures were performed in 15 cases with central type leakage. Ablation treatment using ethanol or minocycline was mainly performed for peripheral type leakage. Four cases with central type leakage had strictures of the right hepatic duct. Two of them were treated with ablation treatment, portal vein embolization, or fistulojejunostomy. Median duration from diagnosis to end of therapy was 77 days (11-323) in central type and 44 days (6-123) in peripheral type leakage, respectively. CONCLUSIONS: Complex hepatectomy and operating time are independent risk factors for postoperative bile leakage. Biliary exploration should be performed as soon as possible after diagnosis, because most bile leakage is the central type. Central type of bile leakage is sometimes refractory to therapy, needing various treatments and requiring a long time for recovery.

Perioperative Microbiologic Monitoring of Sputum on Postoperative Day One as a Predictor of Pneumonia After Hepatectomy.

BACKGROUND: The purpose of this study was to retrospectively evaluate microbial examination of sputum on postoperative day one (POD1) and to determine risk factors for postoperative pneumonia (POP) after hepatectomy. METHODS: Two hundred ninety-four patients who expectorated sputum on POD1 after hepatectomy between 2003 and 2014 were investigated. Sputum samples were submitted for microbial examination. Risk factors for POP were identified using multivariable analysis. RESULTS: One hundred fifty-eight (53.7%) of 294 patients had bacteria in their sputum on POD1. POP was observed in 24 (8.2%) patients, with increased mortality in the patients with POP (0.74 vs 12.5%, p < 0.01). Multivariate analysis demonstrated that a Brinkman index of >400 and bacteria in sputum on POD1 were independent risk factors for POP. Bacterial homology in sputum obtained on POD1 and onset day of POP was found in 13 of the 24 (54.2%) patients with POP. In particular, in 13 patients with POP caused by methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa, homology was confirmed in 9 patients (69.2%). CONCLUSION: A Brinkman index ≥400 and bacteria in sputum on POD1 increased the risk of POP. Presence of bacteria in sputum on POD1 may be useful in determining early treatment against POP after hepatectomy.

Dendritic cells transfected with heat-shock protein 70 messenger RNA for patients with hepatitis C virus-related hepatocellular carcinoma: a phase 1 dose escalation clinical trial.

BACKGROUND: We previously reported overexpression of heat-shock protein (HSP) 70 in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) using proteomic profiling and immunohistochemical staining (IHS). This suggested that HSP70 could be a molecular target for treatment of HCC. METHODS: Twelve patients with HCV-related HCC were enrolled in a phase 1 clinical trial. Dendritic cells (DCs) transfected with HSP70 mRNA (HSP70-DCs) induced by electroporation were injected intradermally. Patients were treated three times every 3 weeks. The number of HSP70-DCs injected was 1 × 10(7) as the lowest dose, then 2 × 10(7) as the medium dose, and then 3 × 10(7) as the highest dose. Immunological analyses were performed. FINDINGS: No adverse effects of grade III/IV, except one grade III liver abscess at the 3 × 10(7) dose, were observed. Thus, we added three more patients to confirm whether 3 × 10(7) is an appropriate dose. Eventually, we chose 3 × 10(7) as the recommended dose of DCs. Complete response (CR) without any recurrence occurred in two patients, stable disease in five, and progression of disease in five. The two patients with CR have had no recurrence for 44 and 33 months, respectively. IHS in one patient who underwent partial hepatectomy showed infiltration of CD8+ T cells and granzyme B in tumors, indicating that the dominant immune effector cells were cytotoxic T lymphocytes with tumor-killing activity. INTERPRETATION: This study demonstrated that HSP70-DCs therapy is both safe and feasible in patients with HCV-related HCC. Further clinical trials should be considered.

Preoperative serum methylation signature as prognostic tool after curative hepatectomy in patients with hepatocellular carcinoma.

AIM: This study aimed to investigate the relationship between prognosis after curative hepatectomy and serum methylation signature (SMS), defined by methylation levels of six specific genes (cyclin D2, Ras association (RalGDS/AF-6) domain family member 1, serine peptidase inhibitor Kunitz type 2, cystic fibrosis transmembrane conductance regulator, brain abundant membrane attached signal protein 1, and steroid-5-alpha-reductase alpha polypeptide 2). PATIENTS AND METHODS: Serum samples were collected preoperatively from 125 patients with hepatocellular carcinoma associated with hepatitis C virus infection who underwent curative hepatectomy. We measured the methylation levels of the preceding six genes. We defined the methylation of three genes or more in the serum as SMS-positive in this study. We investigated the prognosis of SMS-positive patients. RESULTS: SMS-positive patients exhibited significantly shorter disease-free survival (DFS) and overall survival (OS) than SMS-negative patients (p=0.0002 and p<0.0001, respectively). Multivariate analysis showed that SMS positivity was an independent risk factor for shorter DFS (hazard ratio (HR)=2.182; p<0.001) and OS (HR=4.198; p<0.001). CONCLUSION: SMS is useful as a prognostic predictor in patients with hepatocellular carcinoma after curative hepatectomy.

[A Case of Rectal Villous Tumor Detected with Heart Failure and Electrolyte Imbalance].

A 74-year-old woman presented to our emergency department with a chief complaint of appetite loss, and already diagnosed dehydration and heart failure. After hospitalization, the signs of heart failure were improved with liquid supplementation and electrolyte revision. At admission, computed tomography incidentally detected a rectal tumor. She underwent colonography, which revealed a huge villous tumor in the rectum. Based on the result of the initial biopsy, it was classified as a group 4 tumor, but additional biopsy of specimens obtained from 6 places led to a diagnosis of group 5 tumor. Then, we performed laparoscopic super-low anterior resection and made an ileal stoma. The electrolyte imbalance was improved and did not recur after the operation. In this case, the electrolyte imbalance caused by the huge villous tumor was electrolyte depletion syndrome (EDS).

An accurate prognostic staging system for hepatocellular carcinoma patients after curative hepatectomy.

The aim of this study was to develop an accurate predictive system for prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy. We pooled data of clinicopathological features of 234 HCC patients who underwent curative hepatectomy. On the basis of the pooled data, we established a simple predictive staging system (PS score) scored by the mathematical product of tumor number and size, and degree of liver function. We compared the prognostic abilities of the PS score (score 0-3) with those of six well-known clinical staging systems. Then, we found that there were significant differences (P<0.05) in both disease-free survival (DFS) and overall survival (OS) between patients with different PS scores (PS score 0 vs. 1; PS score 1 vs. 2), and there was a significant difference in DFS, but not OS, between patients with PS score 2 and those with PS score 3. Moreover, the PS score had smaller values of the Akaike information criterion for both DFS and OS than any of the six well-known clinical staging systems. These results suggest that the PS score serves as a simple, accurate predictor for the prognosis of HCC patients after hepatectomy.

Predictive biomarkers for the outcome of vaccination of five therapeutic epitope peptides for colorectal cancer.

BACKGROUND: We previously reported a phase I study of a cancer vaccine using five novel HLA-A*2402-restricted peptides, and demonstrated the safety and the promising potential of our five-peptide cocktail for advanced colorectal cancer. The objective of this analysis was to investigate predictive biomarkers for the prior selection of patients who are likely to have clinical benefit from such therapy. PATIENTS AND METHODS: Seventeen patients with colorectal cancer who were treated with the five peptides underwent a complete blood count, serum chemistry tests and enzyme-linked ImmunoSpot assay before the treatment as predictive markers of high reactivity to the peptides. RESULTS: Interleukin-6 level was a significant predictor for overall survival of patients treated with the peptide cocktail (p=0.017). A high neutrophil/lymphocyte ratio was likely to have some association with the poor induction of peptide-specific immune reaction. CONCLUSION: Interleukin-6 level might be a good predictive biomarker for clinical benefit of patients treated with this peptide vaccine.

Adoptive immunotherapy with MUC1-mRNA transfected dendritic cells and cytotoxic lymphocytes plus gemcitabine for unresectable pancreatic cancer.

BACKGROUND: We previously reported the clinical efficacy of adoptive immunotherapy (AIT) with dendritic cells (DCs) pulsed with mucin 1 (MUC1) peptide and cytotoxic T lymphocytes (CTLs). We also reported that gemcitabine (GEM) enhances anti-tumor immunity by suppressing regulatory T cells. Therefore, in the present study, we performed combination therapy with AIT and GEM for patients with unresectable or recurrent pancreatic cancer. PATIENTS AND METHODS: Forty-two patients with unresectable or recurrent pancreatic cancer were treated. DCs were generated by culture with granulocyte macrophage colony-stimulating factor and interleukin-4 and then exposed to tumor necrosis factor-α. Mature DCs were transfected with MUC1-mRNA by electroporation (MUC1-DCs). MUC1-CTLs were induced by co-culture with YPK-1, a human pancreatic cancer cell line, and then with interleukin-2. Patients were treated with GEM, while MUC1-DCs were intradermally injected, and MUC1-CTLs were intravenously administered. RESULTS: Median survival time (MST) was 13.9 months, and the 1-year survival rate was 51.1%. Of 42 patients, one patient had complete response (2.4%), three patients had partial response (7.1%) and 22 patients had stable disease (52.4%). The disease control ratio was 61.9%. The MST and 1-year survival rate of 35 patients who received more than 1 × 10(7) MUC1-DCs per injection was 16.1 months and 60.3%, respectively. Liver metastasis occurred in only 5 patients among 35 patients without liver metastasis before treatment. There were no severe toxicities associated with AIT. CONCLUSION: AIT with MUC1-DCs and MUC1-CTLs plus GEM may be a feasible and effective treatment for pancreatic cancer.

[Clinical benefit of thoracoscopic approach for liver tumors located under the diaphragm].

UNLABELLED: It is important to ensure restricted operation fields and operation maneuvers in the surgical resection of liver tumors located under the diaphragm, especially those near the hepatic vein and IVC. Here we describe resection and ablation using thoracoscopy for tumors under the diaphragm after preoperative three-dimensional (3D) simulation. METHOD: Preoperative 3D images were reformatted preoperatively using a 3D software tool (Virtual Place; AZE, Japan). These images simulate the thoracoscopic view on the surface of the diaphragm, enabling us to confirm the tumor location and choose optimal port position. RESULT: We performed thoracoscopic surgery in 5 patients (4 with HCC and 1 with a metastatic tumor) after the simulation. In all cases, we were able to safely confirm the tumor locations and perform the surgeries. CONCLUSION: Preoperative 3D simulation makes it easy to determine the optimal port position for the thoracoscope and confirm the tumor location. The approach through the diaphragm using thoracoscpy is useful since it does not require liver mobilization.

[A resected case of hilar cholangiocarcinoma treated with neoadjuvant chemoradiation therapy].

The patient was a 69-year-old woman with elevated levels of hepatobiliary enzymes. An abdominal computed tomography (CT) scan revealed an enhanced mass in the liver hilum with dilatation of the intrahepatic bile duct. We diagnosed hilar cholangiocarcinoma and administered neoadjuvant chemoradiation therapy because of the possibility of tumor cells remaining at the surgical margins. Radical surgery was performed and pathological examination showed the tumor to be Grade 2b according to the Oboshi-Shimosato classification. Although postoperative bile leakage and intra-abdominal abscess were observed, the patient was discharged on day 82 after surgery. The patient is still alive without recurrence at 17 months after the surgery. Neoadjuvant chemoradiation therapy has the potential to obtain a negative surgical margin in patients with hilar cholangiocarcinoma, which is likely to be positive for cancer cells at the surgical margin in preoperative diagnosis.