Cost-effectiveness analysis of pembrolizumab in patients with treatment-refractory metastatic colorectal cancer in Japan.

OBJECTIVE: The immune checkpoint inhibitor pembrolizumab has recently been recognized as a standard treatment regimen for patients with metastatic colorectal cancer and the microsatellite-instability-high/mismatch repair-deficient mutation. However, its cost-effectiveness in late-line treatment remains unclear. The aim of this study was to assess the cost-effectiveness of pembrolizumab for patients with microsatellite-instability-high/mismatch repair-deficient metastatic colorectal cancer. METHODS: Markov decision modeling using treatment costs, disease-free survival and overall survival was performed to examine the cost-effectiveness of pembrolizumab monotherapy compared with chemotherapy, and best supportive care. The Japanese healthcare payer's perspective was adopted. The outcomes were modeled on the basis of published literature. The primary outcome was the incremental cost-effectiveness ratio between the strategies. Sensitivity analyses were performed and the effects of uncertainty on the model parameters were investigated. RESULTS: Pembrolizumab monotherapy had incremental cost-effectiveness ratios of $408204.3 per quality-adjusted life-year gained compared with best supportive care and $489123.4 per quality-adjusted life-year gained compared with chemotherapy. Given a Japanese willingness-to-pay threshold of $69560.38 per quality-adjusted life-year, the base case results suggested that pembrolizumab monotherapy was not cost-effective. The sensitivity analysis results were in line with the base case results. CONCLUSION: Pembrolizumab monotherapy is not a cost-effective option in late-line treatment for patients with metastatic colorectal cancer and microsatellite-instability-high/mismatch repair-deficient mutation in the Japanese healthcare system. Further studies on its cost-effectiveness in first-line treatment are warranted.

Short- and long-term outcomes of laparoscopic radical gallbladder resection for gallbladder carcinoma: A multi-institutional retrospective study in Japan.

BACKGROUND/PURPOSE: Laparoscopic resection of gallbladder carcinomas remains controversial. This study aimed to evaluate the surgical and oncological outcomes of laparoscopic procedures for suspected gallbladder carcinoma (GBC). METHODS: In this retrospective study, data regarding suspected GBC treated with laparoscopic radical cholecystectomy before 2020 in Japan, was included. Patient characteristics, surgical procedure details, surgical outcomes, and long-term outcomes were analyzed. RESULTS: Data of 129 patients with suspected GBC who underwent laparoscopic radical cholecystectomy were retrospectively collected from 11 institutions in Japan. Among them, 82 patients with pathological GBC were included in the study. Laparoscopic gallbladder bed resection was performed in 114 patients and laparoscopic resection of segments IVb and V was performed in 15 patients. The median operation time was 269 min (range: 83-725 min), and the median intraoperative blood loss was 30 mL (range: 0-950 mL). The conversion and postoperative complication rates were 8% and 2%, respectively. During the follow-up period, the 5-year overall survival rate was 79% and the 5-year disease-free survival rate was 87%. Recurrence was detected in the liver, lymph nodes, and other local tissues. CONCLUSION: Laparoscopic radical cholecystectomy is a treatment option with potential favorable outcomes in selected patients with suspected GBC.

Anal tuberculosis presenting as refractory perianal abscess.

Although most cases occur in immunocompromised individuals, anal tuberculosis can occur in the absence of HIV infection. Anal tuberculosis should be considered in the differential diagnosis of chronic or recurrent anal fistulas.

Fecalith in the Proximal Area of the Appendix is a Predictor of Failure of Nonoperative Treatment for Complicated Appendicitis in Adults.

BACKGROUND: The management of complicated appendicitis remains controversial, since this disease has various clinical presentations and is associated with high rates of adverse events. Although initial nonoperative treatment is generally employed for complicated appendicitis, its clinical presentation and the predictors of nonoperative treatment failure are unclear. METHODS: Patients diagnosed with complicated appendicitis in our hospital between April 2015 and March 2020 were enrolled. In total, 113 patients were classified into three categories: emergency appendectomy, failure of nonoperative treatment and successful nonoperative treatment. The primary outcome was the rate of failure of nonoperative treatment, as assessed by logistic regression analysis. The secondary outcomes were the operative procedures and postoperative courses of the three groups. RESULTS: Of 113 patients, 45 (40%) underwent emergency appendectomy, 25 (22%) failed nonoperative treatment, and 43 (38%) had successful nonoperative treatment. Among these successful cases, 38 patients (88%) underwent interval appendectomy. In multivariate analyses, the presence of a fecalith in the proximal area of the appendix was an independent risk factor for failure of nonoperative treatment (odds ratio, 20.5; 95% confidence interval, 4.37-95.7, P < 0.001). Postoperative outcomes were more unfavorable in cases of failed nonoperative treatment than in cases of emergency and interval appendectomy. CONCLUSIONS: The presence of a fecalith in the proximal area of the appendix is an independent predictor for failure of nonoperative treatment for complicated appendicitis in adults. Patients with this risk factor should be considered candidates for surgical treatment.

The potentiality of laparoscopic partial liver excisional biopsy using analysis of the liver surface based on preoperative 3D simulation imaging: A case report.

INTRODUCTION: The imaging diagnostics of liver tumor are difficult. There are no effective biopsy examinations for liver tumors that cannot be detected even by ultrasonography (US) and computed tomography (CT). We report a remarkably useful biopsy method for such tumors. PRESENTATION OF CASE: A 67-year-old man with hepatitis C underwent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, and the images revealed multiple delayed enhanced masses that showed high signal intensity in the hepatobiliary phase. The possibility of malignancy could not be ruled out due to the trend towards increased size of the masses. Percutaneous liver biopsy was considered impossible because CT and US could not detect the masses. Laparoscopic liver biopsy with preoperative simulation using 3D imaging was performed. The 3D imaging provided accurate information of liver surface irregularities with cirrhosis change. The tumor location was confirmed, and adequate tumor excisional biopsy was performed. Histological assessment revealed the tumor to be a focal nodular hyperplasia-like nodule. DISCUSSION AND CONCLUSIONS: Laparoscopic liver biopsy has been widely used because of its safety and accuracy. It enables accurate resection of tumors that are undetectable with CT and US by employing preoperative 3D imaging while maintaining the less-invasiveness.

Harness Traction Technique (HARNESS): Novel Method for Controlling the Transection Plane During Laparoscopic Hepatectomy.

We present our experience using a novel method for controlling the transection plane, which we termed as the Harness Traction Technique (HARNESS) and evaluate its usefulness. From May 2009 to March 2012, laparoscopic hepatectomies using HARNESS were performed on 35 patients. After the superficial hepatic parenchyma on the line was transected at 1 to 2 cm depth, 5 mm tape was placed along the groove of the line and tied to prevent it from slipping off. Tape was tied and pulled using a forceps toward the best direction for minimizing the bleeding, moving the transection point to the appropriate position and creating good tension for parenchymal transection at the transection point. There were no conversions to laparotomy or intraoperative complications. HARNESS is useful for controlling the dissection line during laparoscopic hepatectomy, leading to precise and safe laparoscopic liver parenchymal dissection.

Novel strategy for laparoscopic treatment of pT2 gallbladder carcinoma.

BACKGROUND: This study evaluated our new strategy for treating suspected T2 gallbladder carcinoma (GBC) using a laparoscopic approach. METHODS: We examined 19 patients with suspected T2 GBC who were treated laparoscopically (LS group) between December 2007 and December 2013; these patients were compared with 14 patients who underwent open surgery (OS group). Laparoscopic staging was initially performed to exclude factors making the patients ineligible for curative resection. Intraoperative pathological examination of the surgical margin of the cystic duct was performed prior to laparoscopic gallbladder bed resection, and pathological examination was again performed to confirm the presence of carcinoma and the depth of tumor invasion. Surgery was completed when the pathological findings indicated that the patient was cancer free. Lymph node dissection was performed according to the depth of tumor invasion. RESULTS: None of the patients required conversion to laparotomy. For three patients with benign lesions, only gallbladder bed resection was required. Additional regional lymph node dissection was performed in 16 patients in the LS group. The mean operative time (309 vs. 324 min, p = 0.755) and mean number of dissected lymph nodes (12.6 vs. 10.2, p = 0.361) were not significantly different between the LS and OS groups. The intraoperative blood loss was significantly lower (104 vs. 584 mL, p = 0.002) and the postoperative hospital stay was significantly shorter (9.1 vs. 21.6 days, p = 0.002) for LS patients than for those in the OS group. In the LS group, one patient developed postoperative pneumonia, but all patients survived without recurrence after a mean follow-up of 37 months. CONCLUSION: Our strategy for suspected T2 gallbladder GBC is safe and useful, avoids unnecessary procedures, and is associated with similar oncologic outcomes as the open method.

Multidetector-computed tomography attenuation values between the tumor and aortic wall in response to induction therapy for esophageal cancer and its predictive value for aortic invasion.

The objective of this study was to evaluate the multidetector computed tomography (MDCT) attenuation value between the tumor and aorta in response to the induction therapy for esophageal cancer. In advanced esophageal cancer, the main reason for unresectability is the local invasion of the tumor into the aorta or trachea. Despite remarkable advances in diagnostic modalities, pre-operative assessment of pathological response and local tumor extent in esophageal cancer remains difficult. MDCT attenuation values between the tumor and aorta, and the contact angle of the tumor to the aorta (Picus' angle) were retrospectively evaluated in patients with esophageal cancer who underwent induction therapy in terms of predicting the pathological response, aortic invasion and prognosis of esophageal cancer. The induction therapy may increase the tumor-to-aorta distance and decrease the maximum tumor size and Picus' angle. When the tumor-to-aorta cut-off value was set at <1.3 mm, the accuracy of this distance for aortic invasion was 94.6%. In terms of this distance, 14 out of 19 patients with a tumor-to-aorta distance of <1.3 mm prior to the induction therapy had a distance of >1.3 mm following therapy and underwent curative resection. The assessment of the MDCT attenuation value between the esophageal tumor and the aorta is simple and objectively assesses the response to the induction therapy and aortic invasion in esophageal cancer. This method should be applied to predict the response to the induction therapy and to prevent unnecessary surgery in patients with tumors involving the aorta.

Systemic inflammatory response syndrome as a predictor of anastomotic leakage after esophagectomy.

PURPOSE: Esophageal anastomotic leakage is still a major cause of morbidity and mortality after esophagectomy. We conducted this study to elucidate how anastomotic leakage affects the systemic inflammatory response syndrome (SIRS) criteria. METHODS: The subjects of this retrospective study were 61 patients who underwent esophagectomy. We evaluated their preoperative status, the surgical procedures, and postoperative systemic response, including white blood cell count, heart rate, respiratory rate, body temperature, and laboratory data up to postoperative day (POD) 4. RESULTS: Anastomotic leakage developed in nine patients (14.8%) and was found on POD 7 on average. These patients had a significantly longer hospital stay than those without leakage. Although no difference was observed in postoperative changes of any of the SIRS criteria, the postoperative incidence of SIRS was significantly higher in the patients with anastomotic leakage on POD 4. The number of positive criteria for SIRS was also significantly higher in patients with anastomotic leakage than in those without leakage on PODs 3 and 4. CONCLUSIONS: The SIRS scoring system is valuable for evaluating the severity of systemic inflammatory response caused by anastomosis leakage, and may serve as an indicator for prompt management.

Duodenal gangliocytic paraganglioma with regional lymph node metastasis and a glandular component.

Gangliocytic paraganglioma (GP) is generally considered to be a benign periampullary lesion, although it is unclear whether it should be classified as a hamartoma or as a neoplasm. Here, we present a GP case with lymph node metastasis. A 16-year-old boy complained of exertional dyspnea. Upper endoscopy and imaging studies revealed a polypoid ampullary tumor. Pancreaticoduodenectomy with lymph node dissection was performed due to swelling of peripancreatic lymph nodes. Histologically, the tumor consisted of three cell types: epithelioid; spindle; and ganglion cells. In addition to these typical components of GP, a distinct glandular component was also present. There was substantial invasion of tumor cells into the lymphovascular vessels, associated with lymph node metastases. These lymph node metastases were histologically similar to the primary tumor. To judge from these findings GP may be a true neoplasm with metastatic capacity. Pre- and intraoperative investigations for lymph node or distant metastases are required for adequate resection of this kind of tumor.

Sarcoidosis-associated hepatocellular carcinoma.

Sarcoidosis is a systemic granulomatous inflammation of unknown etiology, and seems to involve the liver parenchyma in most cases. However, sarcoidosis-associated hepatocellular carcinoma is rare. We report here a case in which a hepatocellular carcinoma occurred within the liver, which was probably involved as a result of systemic sarcoidosis. A 57-year-old Japanese man had been followed up for 2 years because of diabetic nephropathy and sarcoidosis. On admission for pneumonia, imaging studies revealed an unexpected hepatic tumor. Histology revealed a hepatocellular carcinoma accompanied by T-lymphocytic infiltration and marked granulomatous inflammation, which was surrounding some tumor nodules. The background liver parenchyma exhibited a moderate degree of fibrosis with granulomatous inflammation. The patient had no other apparent liver disease such as viral hepatitis, steatohepatitis, or primary biliary cirrhosis. Therefore, in the present case, sarcoidosis may be considered the probable background etiology for hepatocarcinogenesis.

[Syndrome of inappropriate antidiuretic hormone secretion following adjuvant CDDP and 5-FU administration in a patient with esophageal carcinoma].

A case of hyponatremia following the first course of systemic adjuvant chemotherapy with cisplatin (CDDP) and 5-FU in a previously treated patient with esophageal cancer is reported. A 61-year-old man was admitted to our hospital for adjuvant chemotherapy after transthoracic esophagectomy and 3-field lymphadenectomy for esophageal cancer. Six days following chemotherapy, his serum sodium concentration was found to be 118 mEq/L, without edema or dehydration. This hyponatremic state was diagnosed as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) induced by CDDP, based on the hypo-osmolality of his serum and urine, and an inappropriate level of plasma vasopressin.

Outcome after emergency surgery in patients with a free perforation caused by gastric cancer.

Perforation of gastric cancer is rare and it accounts for less than 1% of the incidences of an acute abdomen. In this study, we reviewed cases of benign or malignant gastric perforation in terms of the accuracy of diagnosis and investigated the clinical outcome after emergency surgery in patients with a free perforation caused by gastric cancer. On the basis of pathological examination, gastric cancer was diagnosed in 8 patients and benign ulcer perforation in 32 patients. The sensitivity, specificity and accuracy of intraoperative diagnosis by pathological examination were 50, 93.8 and 85%, respectively. Except for age, there were no differences in the other demographic characteristics between patients with gastric cancer and benign ulcer perforation. The median survival time of patients with perforated gastric cancer was 195 days after surgery. Patients with gastric cancer perforation had a poorer overall survival rate than those who had T3 tumors without perforation. In addition, in patients with perforation, recurrence of peritoneum occurred more frequently. In conclusion, to improve the survival rate of patients with perforated gastric cancer and to improve the accuracy of intraoperative diagnosis, endoscopic examination and/or pathological examination of the frozen section should be performed, if possible. A balanced surgical strategy using laparoscopic local repair as the first-step of surgery, followed by radical open gastrectomy with lymphadenectomy may be considered.

Minimally invasive surgery for resection of duodenal carcinoid tumors: endoscopic full-thickness resection under laparoscopic observation.

BACKGROUND: Carcinoid tumors of the duodenum are rare, and the most effective treatment for duodenal carcinoid tumors remains debatable. Because carcinoid tumors of the gastrointestinal tract tend to spread to the submucosal layer even during the early stages of the disease, the possibility of tumor seeding in the vertical margin of the tumor cannot be eliminated by conventional endoscopic mucosal resection (EMR). In addition, because the duodenal wall is thinner than the gastric wall, EMR performed for duodenal lesions may be associated with a high risk of accidental perforation. In this article, we introduce a minimally invasive endoscopic full-thickness resection technique after laparoscopic repair for the local resection of duodenal carcinoid tumors. METHODS: Under general anesthesia, after the duodenum was mobilized laparoscopically, the duodenal serosa at the site of the lesion was suctioned under laparoscopic observation, and full-thickness resection of the duodenum was performed using a cap-fitted endoscope, i.e., EMR-c, without injecting hypertonic saline-epinephrine. The sample was retrieved endoscopically after resection. After confirming that the full-thickness resection of the duodenal wall with enough surgical margins was achieved and that there was no active bleeding, the wound was sutured by the laparoscopic hand-suturing technique. RESULTS: We have performed this surgical procedure in two cases of duodenal carcinoid tumor. The mean operation time was 116 +/- 14 minutes, and the estimated blood loss was 2.5 +/- 0.5 ml. The postoperative courses were uneventful in both cases. CONCLUSIONS: The technique of endoscopic full-thickness resection of gastrointestinal tract under laparoscopic observation is a safe, simple, and can be radical surgical procedure for a small duodenal carcinoid tumor. This surgical procedure may be applicable in the case of other gastrointestinal tumors.

Thromboangiitis obliterans with multiple large vessel involvement: case report and analysis of immunophenotypes.

Thromboangiitis obliterans (TAO, Buerger's disease) is an idiopathic, recurrent, segmental, nonatherosclerotic, inflammatory, occlusive vascular disease with a poorly understood pathogenesis. Intestinal or multi-organ involvement is rare. Recent immunohistochemical analyses of ordinary TAO have indicated an inflammatory and immunologic pathogenesis. We report a case of TAO involving multiple large vessels. By immunohistochemistry, CD3+ T cells were revealed around the recanalization sites within the abdominal aorta. CD4+ T cells were almost equal in number to CD8+ T cells. These findings indicate the participation of inflammatory and immunologic processes in TAO with multi-organ involvement (as in ordinary TAO).

Pancreatectomy for pancreatic cancer with reference to combined resection of the vessels, twenty nine year experience by a single surgeon.

Between 1978 and 2007 one hundred and seven patients consecutively underwent resection for primary pancreatic adenocarcinoma. There were 28 pN0 patients, 41 pN1 and 37 pN2 or more (one unknown). Combined resection of the portal vein was performed in 62 out of 107 patients (58%). The hepatic artery in 10 patients, superior mesenteric artery in 8 patients and celiac trunk in 7 patients were also resected additionally to the portal vein. The 5-year survival rate and 10-year survival rate of all 107 cases were 12.1% and 2.8% respectively. The 5-year survival rate of the pN0 group was 37%, significantly better than the 14% 5-year survival rate in the pN1 group (p=0.043). Of 69 patients with pN0 or pN1, 38 patients underwent combined resection of the portal vein. There was not significant difference between the 24% 5-year survival rate in the group without the portal vein resection and the 19% 5-year survival rate in the group with portal vein resection. The 20% 5-year survival rate of the portal vein only group and the 5-year survival rate of both the portal vein and hepatic artery group were the same. The groups of the further resection of the superior mesenteric artery and of the celiac trunk showed no long-term survival. It is concluded that aggressive combined resection of the portal vein or additional resection of the hepatic artery be feasible for a survival benefit in pN0 and pN1 diseases.

Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma.

Although we have identified two putative targets, ATF3 and CENPF, for a frequently gained/amplified region around 1q32-q41 in esophageal squamous cell carcinoma (ESCC), it is possible that other amplification targets remain to be identified. In this study, we tested whether SET and MYND domain-containing protein 2 (SMYD2), located between those two genes and encoding a lysine methyltransferase for histone H3K36 and p53K370 that regulates transcription and inhibits transactivation activity, respectively, acts as a cancer-promoting gene through activation/overexpression in ESCC. Frequent overexpression of SMYD2 messenger RNA and protein was observed in KYSE150 cells with remarkable amplification at 1q32-41.1 and other ESCC cell lines (11/43 lines, 25.6%). Overexpression of SMYD2 protein was frequently detected in primary tumor samples of ESCC (117/153 cases, 76.5%) as well and significantly correlated with gender, venous invasion, the pT category in the tumor-lymph node-metastases classification and status of recurrence. Patients with SMYD2-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and SMYD2 positivity was independently associated with a worse outcome in the multivariate analysis. Knockdown of SMYD2 expression inhibited and ectopic overexpression of SMYD2 promoted the proliferation of ESCC cells in a TP53 mutation-independent but SMYD2 expression-dependent manner. These findings suggest that SMYD2 plays an important role in tumor cell proliferation through its activation/overexpression and highlight its usefulness as a prognosticator and potential therapeutic target in ESCC.

ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis.

Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.