Prognostic Role of Preoperative Chemotherapy in Liver-Limited Metastasis from Gastric Cancer.

BACKGROUND: We investigated the prognostic role of preoperative chemotherapy in patients who underwent hepatectomy for liver-limited metastasis (LLM) from gastric cancer (GC). METHODS: A retrospective analysis was conducted for 52 consecutive patients who underwent macroscopically complete (R0 or R1) resection for synchronous or metachronous LLM from GC. RESULTS: Of the 52 patients, 18 (35%) received preoperative chemotherapy (PC group), while 34 (65%) underwent upfront surgery (US group). The PC group had a significantly longer overall survival than the US group (cumulative 5-year OS rate: 47.6% vs. 24.8%, p = 0.041). Multivariate analysis of OS revealed that preoperative chemotherapy was an independent favorable prognostic factor (hazard ratio: 0.445, p = 0.036). Patients showing a partial response to preoperative chemotherapy on RECIST had an improved OS compared with those exhibiting stable or progressive disease after preoperative chemotherapy and with US (p = 0.025), even among those with solitary LLM (p = 0.062) and multiple LLM (p = 0.026). At recurrence after hepatectomy for LLM, the PC group had a significantly higher incidence of solitary tumors than the US group (p = 0.043) and had a higher chance to undergo surgical resection for recurrent sites (p = 0.006). CONCLUSIONS: Preoperative chemotherapy can be recommended for patients with LLM from GC. The evaluation of the efficacy of preoperative chemotherapy offers additional information to determine the surgical indication for LLM.

Outcome of radical surgery for gallbladder carcinoma according to TNM stage: implications for adjuvant therapeutic strategies.

PURPOSE: Outcomes following surgery for advanced gallbladder carcinoma remain unsatisfactory. This study aimed to determine the surgical outcome and effectiveness of adjuvant chemotherapy according to TNM stage in patients with gallbladder carcinoma. METHODS: A total of 200 patients undergoing surgery for gallbladder carcinoma were enrolled. Clinicopathological data were evaluated and surgical outcomes were compared between patients with and without adjuvant chemotherapy according to TNM stage. RESULTS: The 5-year overall survival (OS) after resection for patients with stage I (n = 27), IIA (n = 18), IIB (n = 28), IIIA (n = 25), IIIB (n = 43), IVA (n = 7), and IVB (n = 52) disease was 90.8%, 94.4%, 73.6%, 33.7%, 57.7%, 14.3%, and 11.8%, respectively (p < 0.001). R0 resection was performed in all patients with stage I or II disease, in 89.7% of those with stage III disease, and 69.5% of those with stage IV disease. For patients with stage III disease, adjuvant chemotherapy was associated with improved OS (5-year OS, 60.9% vs. 41.1%; p = 0.028) and was an independent prognostic factor (hazard ratio, 2.045; p = 0.039). For patients with stage IV disease, adjuvant chemotherapy appeared to affect OS (5-year OS, 25.1% vs. 5.3%; p = 0.041); R0 resection (hazard ratio, 1.882; p = 0.040) was the only independent prognostic factor. CONCLUSION: TNM stage clearly predicts survival after resection of gallbladder carcinoma. R0 resection with adjuvant chemotherapy is recommended for long-term survival in the multimodal management of patients with stage III or IV gallbladder carcinoma.

Long-term outcomes of surgical resection for T1b gallbladder cancer: an institutional evaluation.

BACKGROUND: There is no comprehensive agreement concerning the overall performance of radical resection for T1b gallbladder cancer (GBC). This research focused on addressing whether T1b GBC may spread loco-regionally and whether radical resection is necessary. METHODS: A retrospective analysis was conducted of 1032 patients with GBC who underwent surgical resection at our centre and its affiliated institutions between January 1982 and December 2018. A total of 47 patients with T1b GBC, 29 (62%) of whom underwent simple cholecystectomy and 18 (38%) of whom underwent radical resection with regional lymph node dissection, were enrolled in the study. RESULTS: GBC was diagnosed pre-operatively in 16 patients (34%), whereas 31 patients (66%) had incidental GBC. There was no blood venous or perineural invasion in any patient on histology evaluation, except for lymphatic vessel invasion in a single patient. There were no metastases in any analysed lymph nodes. The open surgical approach was more prevalent among the 18 patients who underwent radical resection (open in all 18 patients) than among the 29 patients who underwent simple cholecystectomy (open in 21; laparoscopic in 8) (P = 0.017). The cumulative 10- and 20-year overall survival rates were 65 and 25%, respectively. The outcome following simple cholecystectomy (10-year overall survival rate of 66%) was akin to that following radical resection (64%, P = 0.618). The cumulative 10- and 20-year disease-specific survival rates were 93 and 93%, respectively. The outcome following simple cholecystectomy (10-year disease-specific survival rate of 100%) was equivalent to that following radical resection (that of 86%, P = 0.151). While age (> 70 years, hazard ratio 5.285, P = 0.003) and gender (female, hazard ratio 0.272, P = 0.007) had a strong effect on patient overall survival, surgical procedure (simple cholecystectomy vs. radical resection) and surgical approach (open vs. laparoscopic) did not. CONCLUSIONS: Most T1b GBCs represent local disease. As pre-operative diagnosis, including tumour penetration of T1b GBC, is difficult, the decision of radical resection is justified. Additional radical resection is not required following simple cholecystectomy provided that the penetration depth is restricted towards the muscular layer and that surgical margins are uninvolved.

Clinicopathological Characteristics and Surgical Outcomes of Primary Cystic Duct Carcinoma: A Multi-institutional Study.

BACKGROUND: The role of surgery in the management of primary cystic duct carcinoma (CDC) remains unclear especially in advanced disease. This study aimed to evaluate long-term outcomes in patients undergoing surgery for primary CDC. METHODS: From a multi-institutional database, we identified 41 patients who underwent surgery for primary CDC, defined as a part of gallbladder carcinoma with the tumor centre located in the cystic duct. RESULTS: Of the 41 patients, 31 (75.6%) underwent preoperative biliary drainage for jaundice. Twenty-eight (68.3%) patients underwent extensive resection including major hepatectomy (n = 21), pancreaticoduodenectomy (n = 4), or both procedures (n = 3). Thirty-four (82.9%) patients had ≥ pT3 tumor, while 31 (75.6%) patients had involvement of contiguous organs/structures. Nodal and distant metastasis was found in 26 (63.4%) and 7 (17.1%) patients, respectively. Most patients (90.2%) had perineural invasion. Median overall survival was 23.7 months in all 41 patients. Factors independently associated with both overall and disease-specific survival were pN (P = 0.003 and P = 0.007, respectively) and pM (P = 0.003 and P = 0.013, respectively) classification. Median survival was 75.3, 17.7, and 5.2 months for patients with pN0M0 (n = 14), pN1/2pM0 or pN0pM1 (n = 21), and pN1/2pM1 (n = 6) disease, respectively (P < 0.001). CONCLUSIONS: Primary CDC is characterized by locally advanced disease with aggressive histopathological characteristics at surgery, leading to extensive resection during treatment. Surgery provides potential benefits for patients with pN0pM0 disease, whereas pN1/2 and/or pM1 status appear to have strong adverse effects on survival.

[Long-Term Survival after Surgery with Postoperative Chemotherapy for Perihilar Cholangiocarcinoma with Residual Invasive Carcinoma at Ductal Resection Margins-A Case Report].

A 64-year-old man with liver dysfunction was given a diagnosis of perihilar cholangiocarcinoma(Bismuth type Ⅳ). The tumor was predominantly right-sided and invaded to the bifurcation of the right and left portal veins. After confirming sufficient liver functional reserve and future liver remnant, the patient underwent extended right hepatectomy, extrahepatic bile duct resection, and portal vein resection and reconstruction. Intraoperative examination of frozen sections revealed the presence of residual invasive carcinoma on both the hepatic and duodenal sides of the ductal resection margins. However, we did not perform pancreaticoduodenectomy or additional resection of the margin-positive proximal bile duct considering the curability and invasiveness of these procedures. He received postoperative chemotherapy with biweekly gemcitabine plus cisplatin for 1 year, followed by gemcitabine monotherapy for 1 year, and S-1 monotherapy has been performed since then. He remains alive and well with no evidence of disease 63 months after surgery.

[A Case of Umbilical Metastasis from Pancreatic Cancer after Surgery].

The patient was a 63-year-old woman with diagnosis of pancreatic cancer. Abdominal CT showed pancreatic head tumor and paraaortic lymph node metastasis. We performed chemotherapy with nab-paclitaxel plus gemcitabine. After 5 courses of chemotherapy, the tumor reduced in size. Pancreaticoduodenectomy followed by adjuvant chemotherapy with S-1 was performed. Fourteen months after surgery, umbilical metastasis(Sister Mary Joseph's nodule: SMJN)was found in the umbilicus near the abdominal incisional hernia. There was no evidence of metastasis except in the umbilicus, we performed the umbilical tumor resection and abdominal incisional hernia repair. Pathological diagnosis was pancreatic cancer metastasis. Although following chemotherapy, multiple skin metastases was found in the lower abdomen 3 months after umbilical resection. We performed skin metastases resection to relieve pain and symptoms of bleeding. But she died 29 months after the initial therapy(7 months after umbilical resection).

Early-stage T1b adenocarcinoma arising in the remnant cystic duct after laparoscopic cholecystectomy: a case report and literature review.

BACKGROUND: The cystic duct has been included in the staging classification scheme for gallbladder cancer since the 2010 publication of the AJCC Cancer Staging Manual (7th edition). To our knowledge, only seven other cases of adenocarcinoma arising in the remnant cystic duct following cholecystectomy have been reported in the English-language literature, and none has been reported as primary early-stage T1b remnant cystic duct cancer (CDC). We report, herein, a case of primary adenocarcinoma arising in the remnant cystic duct in a patient with history of laparoscopic cholecystectomy for gallstone disease. CASE PRESENTATION: An 81-year-old female presented with abdominal pain. Her medical history included a laparoscopic cholecystectomy for cholecystolithiasis two years prior. Jaundice was observed; imaging studies suggested that this was caused by choledocholithiasis. Blood chemistry findings showed severe liver dysfunction. Endoscopic retrograde cholangiography revealed haemobilia from the common bile duct with no evidence of choledocholithiasis. A bile sample showed Papanicolaou class IV cytology. As the extent of tumour spread was undetermined by abdominal ultrasonography and endoscopic ultrasonography, peroral cholangioscopy (POCS) was performed, which revealed tiny papillary lesions within the confluence of cystic duct, and fine granular lesions in the centre of bile ducts, signifying early-stage remnant CDC. Extrahepatic bile duct resection with regional lymphadenectomy was done. Histopathological findings revealed a 42-mm tubular adenocarcinoma originating from the remnant cystic duct with the considerable shallow spread across the extrahepatic bile ducts. It invaded the fibromuscular layer, with no lymphovascular or perineural invasion, no lymph node metastasis (13 nodes examined), and uninvolved surgical resection margin (R0 resection), and was staged as pT1bN0M0, Stage I. CONCLUSIONS: Primary early-stage T1b remnant CDC is an uncommon condition for which early diagnosis is challenging; if intraoperatively recognized, it can complicate surgery. Our experience of this case and an overview of the English literature suggest that POCS is an efficient tool to diagnosis this tumour and assess its spread along the extrahepatic bile ducts.

[A Case of Peritoneal Metastases after Radiofrequency Ablation for Liver Metastasis from a Pancreatic Neuroendocrine Tumor].

A 77-year-old woman presented with peritoneal metastases from a pancreatic neuroendocrine tumor(p-NET). At the age of 56 years, she underwent distal pancreatectomy for p-NET, which was pathologically diagnosed as G2. She underwent right hemihepatectomy for liver metastasis(S6)from the p-NET 10 years post-pancreatectomy. Eight years post-hepatectomy, radiofrequency ablation(RFA)was attempted for liver metastasis(S4)from the p-NET. However, RFA was not completed because of hematoma development along the needle tract of RFA. She underwent partial hepatectomy for this lesion 6 months post-RFA. Two years post-RFA, localized peritoneal metastases on the right diaphragm were detected. She underwent en bloc tumor resection with partial resection of the diaphragm. She remains alive and well with no evidence of disease 2 years post-resection of the peritoneal metastases from the p-NET.

[Surgical Resection after Transarterial Chemoembolization for Hepatocellular Carcinoma with Bile Duct Tumor Thrombus-Report of a Long-Term Survivor].

A 78-year-old woman with jaundice was referred to our hospital. On admission, serological testing for viral hepatitis was negative and serum levels of AFP and PIVKA-Ⅱ were elevated(925 ng/mL and 6,820 mAU/mL, respectively). Computed tomography revealed a main tumor measuring 3 cm in size at segment 1 of the liver and bile duct tumor thrombus extending to the right hepatic duct. A diagnosis of hepatocellular carcinoma with a bile duct tumor thrombus was made. After endoscopic biliary drainage for obstructive jaundice and transarterial chemoembolization for the lesions, she underwent left hepatectomy, resection of the caudate lobe, extrahepatic bile duct resection, and cholecystectomy. The hepatic side of the extrahepatic bile duct was transected at the confluence of the right anterior and posterior ducts because invasion of the tumor thrombus to the right hepatic duct was suspected on cholangioscopy. Histological examination revealed the tumor to be a moderately differentiated hepatocellular carcinoma with bile duct tumor thrombus. Surgical margins were negative, and vascular invasion was not found. She remains alive and well with no evidence of disease 64 months after hepatectomy.

[A Case of Peritoneal Recurrence of Invasive Ductal Carcinoma Derived from Intraductal Papillary Mucinous Neoplasm after Surgery Treated with Palliative Radiation Therapy and Chemotherapy].

An 82-year-old man with a diagnosis ofintraductal papillary mucinous carcinoma(IPMC)underwent pancreaticoduodenectomy followed by adjuvant chemotherapy with S-1. Six months after surgery, he had upper abdominal pain, and CT demonstrated a recurrent intraabdominal tumor located at the surgical incision scar. It was diagnosed as a solitary peritoneal recurrence, and palliative radiation therapy at a dose of 30 Gy was performed for the relief of abdominal pain after administration ofoxycodone. He was free ofpain without pharmacological therapy and received subsequent chemotherapy with nabpaclitaxel plus gemcitabine(GnP). He remains free ofpain and alive without progression ofthe disease 24 months after recurrence. Hypofractionated-accelerated radiotherapy is feasible and results in pain relief for local recurrence of IPMC.

Upregulation of phosphorylated sphingosine kinase 1 expression in colitis-associated cancer.

BACKGROUND: Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that is generated by sphingosine kinase 1 (SphK1) and is known to play an important role in inflammation and cancer progression. Moreover, SphK1 and S1P act as upstream mediators of proinflammatory cytokine interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT3). We hypothesized that the expression levels of phosphorylated SphK1 (pSphK1), phosphorylated STAT3 (pSTAT3), and IL-6 are universally higher in CAC patients than in sporadic colorectal cancer (CRC) patients because all of these factors are associated with inflammation. In this study, we determined the expression levels of pSphK1 in patients with sporadic CRC and CAC and clarified the importance of S1P in CAC patients. MATERIALS AND METHODS: We randomly selected 10 sporadic CRC patients and 10 CAC patients who underwent curative resection, and we examined their surgical specimens by immunohistochemistry. We determined the expression levels of pSphK1, pSTAT3, and IL-6 in these samples. RESULTS: We found pSphK1 expression to be more prevalent in CAC patients (P = 0.019) and to have a higher immunohistochemistry score (P = 0.005) than in sporadic CRC patients. However, the expression of pSTAT3 and IL-6 did not differ between the patient groups. CONCLUSIONS: To our knowledge, this is the first report comparing pSphK1 expression levels in CAC with those in sporadic CRC. The high levels of pSphK1 expression in CAC suggest an important role of S1P in the disease process of CAC.

Different Roles of Sphingosine Kinase 1 and 2 in Pancreatic Cancer Progression.

BACKGROUND: Pancreatic cancer is a disease with poor prognosis, and development of new treatments is necessary. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays a critical role in progression of many types of cancer. However, little is known about the role of sphingosine kinases in pancreatic cancer. This study investigated the roles of sphingosine kinases in pancreatic cancer progression. MATERIALS AND METHODS: S1P levels in pancreatic cancer and noncancerous pancreatic tissue were measured in 10 patients. We generated PAN02 murine pancreatic cancer cell lines with a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system genes 9 (Cas9)-mediated deletion of SphK1 or SphK2 and assessed cell growth and migration. In an animal model, we assessed the survival of mice injected with PAN02 cells intraperitoneally. RESULTS: S1P levels in the pancreatic cancer tissue were significantly higher than those in noncancerous tissue. SphK1 knockout (KO) cells showed greater proliferation and migration than wild type (WT) cells, and SphK2 KO cells showed less proliferation and migration than WT cells. Animal experiments showed that the survival of mice injected with SphK1 KO cells was significantly shorter than those injected with WT cells, and the survival of mice injected with SphK2 KO cells was longer than those injected with WT cells. Surprisingly, cytotoxic assay using gemcitabine showed that SphK1 KO cells survived less than WT cells, and SphK2 KO cells survived more than WT cells. CONCLUSIONS: S1P produced by SphK1 and SphK2 may have different functions in pancreatic cancer cells. Targeting both SphK1 and SphK2 may be a potential strategy for pancreatic cancer treatment.

Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma.

BACKGROUND: Recent progress in genomic analysis using next-generation sequencing technology has enabled the comprehensive detection of mutations and tumor mutation burden (TMB) in patients. A high TMB (TMB-H) tumor is defined as one with high somatic mutational rates, which correlates with clinical responses to certain treatments such as immunotherapies. We determined TMB in lung adenocarcinoma and clarified the characteristics of patients with TMB-H in relation to common driver mutations and smoking history. MATERIALS AND METHODS: Genomic aberrations and TMB were determined in Japanese patients with lung adenocarcinoma (n = 100) using next-generation sequencing of 415 known cancer genes. TMB-H was defined as > 20 mutations per megabase (Mb) of sequenced DNA. RESULTS: The median TMB was 13.5 (5-33) mutations/Mb. Ten of 100 (10%) patients showed TMB-H, and the others showed low TMB (TMB-L). Only two of 10 (20%) patients with TMB-H had one of the common driver mutations (ALK and ERBB2 mutation), whereas 57 of 90 (63%) patients with TMB-L had one of the driver mutations, including ALK, EGFR, ERBB2, ROS, RET, and MET (P < 0.05). Notably, no EGFR mutation was observed in patients with TMB-H. Eight of 10 (80%) patients with TMB-H had recent smoking history, whereas only 17 of 90 (19%) patients with TMB-L had recent smoking history (P < 0.001). CONCLUSIONS: We found that TMB-H is associated with smoking history, whereas TMB-L is associated with the common driver mutations in lung adenocarcinoma, which may impact treatment strategies for these patients.

[Pancreaticoduodenectomy for Recurrent Retroperitoneal Liposarcoma].

A 56-year-old woman was referred to our hospital with complaints of appetite loss and abdominal distension. Enhanced abdominal computed tomography revealed a giant retroperitoneal tumor. We performed en bloc tumor resection. The histological diagnosis was of a dedifferentiated liposarcoma. One year after the initial surgery, 2 tumors were detected around the pancreas using computed tomography. We made a diagnosis of recurrent retroperitoneal liposarcoma and attempted surgical removal of the tumors. However, 1 of the tumors firmly adhered to the pancreas and duodenum; thus, we performed subtotal stomach-preserving pancreaticoduodenectomy to remove the tumors. The histological diagnosis was the same as that obtained during the initial surgery: a dedifferentiated liposarcoma. The patient remains alive and well with no evidence of disease 2 years after the initial surgery.

[Surgical Resection for Peritoneal Metastasis in Hepatocellular Carcinoma-A Report of Three Cases].

Peritoneal metastasis is relatively rare in patients with hepatocellular carcinoma(HCC). No consensus has been reached regarding the treatment of this type of metastasis. Herein, we report 3 patients who underwent resection of peritoneal metastasis due to HCC. Case 1: A 48-year-old man underwent hepatectomy twice and radiofrequency ablation(RFA)once for HCC. Eight years after the initial resection, he underwent resection of peritoneal metastasis in the pelvic floor. He is alive with disease 17 months after the last operation. Case 2: A 71-year-old man with a history of percutaneous ablation therapy for HCC 3 times underwent hepatectomy for recurrent HCC. During the laparotomy, a peritoneal metastatic tumor was found near the live tumor, and simultaneous resection of both the tumors was performed. The patient died of recurrent disease 20 months after the last resection. Case 3: A 58-year-old man underwent hepatectomy for HCC and RFA for its recurrence. Peritoneal metastasis that invaded the duodenum was detected 8 years after the hepatectomy. Although the metastatic tumor was resected, he died of the carcinoma 2 months after the resection. We concluded that resection of peritoneal metastasis provides a survival benefit for selected patients with HCC.

[A Case of Long-Term Survival after Reoperation for Neck Lymph Node Metastasis Occurring Seven Years after Pancreaticoduodenectomy for Pancreatic Adenocarcinoma].

A 59-year-old woman with pancreatic cancer underwent pancreaticoduodenectomy. The tumor was histologically diagnosed as a well-differentiated tubular adenocarcinoma with a small amount of mucinous component. After resection, the patient underwent hepatic perfusion therapy using 5-FU and gemcitabine chemotherapy for 1 year. 7 years after the initial surgery, CT and PET-CT revealed an isolated enlarged lymph node in the left neck. As the patient had no other metastasis, lymphadenectomy was performed. A diagnosis of lymph node metastasis originating from pancreatic cancer was confirmed on the basis of histological and immunohistopathological assessments. After the second resection, chemotherapy with S-1 was administered for 1 year. The patient has been alive without tumor relapse for 11 years. In patients with late recurrence after pancreatectomy, aggressive isolated lymph node resection and maintained chemotherapy may contribute to the improvement in prognosis.

[Mixed Type Liposarcoma with Intra-Abdominal Bleeding - Report of a Case].

A 71-year-old man presented with sudden abdominal pain. He had past history of atrial fibrillation, cerebral infarction and heart-valve replacement and received anticoagulant therapy with warfarin. Computed tomography of the abdomen revealed bloody ascites and a huge mass in contact with the third portion of the duodenum. The mass was encapsulated and consisted of a solid component with calcification and hematoma. Under the preoperative diagnosis of gastrointestinal stromal tumor with intra-abdominal bleeding, laparotomy was performed. Intraoperative findings revealed the tumor arising from the right mesocolon and excision of the tumor with right hemicolectomy was performed. Histologic examination confirmed a diagnosis of mixed type liposarcoma. No postoperative complication was observed and he was discharged home on the 8th postoperative day. He remains alive and well with no evidence of disease 52 months after resection.

[A Case of Hepatocellular Carcinoma with Lymph Node Metastasis Successfully Treated by Multidisciplinary Treatment].

Lymph node metastasis has a poor prognosis in patients with hepatocellular carcinoma(HCC). We report a case of HCC with lymph node metastasis successfully treated by multidisciplinary treatment. An 81-year-old woman who was followed up for liver cirrhosis received a diagnosis of HCC, which was detected by CT as a solitary tumor 20mm in diameter in the couinaud segment 7 of the liver. She underwent transcatheter arterial chemoembolization(TACE)twice for HCC because of her advanced age and no intention to undergo hepatectomy. Some 12 months later, local recurrence was managed by repeat TACE and paraaortic lymph node metastasis by surgical resection. The patient received radiotherapy for mediastinal nodal disease 6 months after the resection. She remains alive and well without no evidence of disease 84 months after the initial treatment. This case and a review of the literature suggest that multidisciplinary treatment with TACE, surgical resection and radiotherapy may provide a survival benefit for selected patients with HCC with isolated lymph node metastasis.