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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Enteral immuno-enhanced diets with arginine are safe and beneficial for patients early after esophageal cancer surgery.

We previously reported that provision of immediate enteral nutrition (EN) with a certain amount of omega (omega)-3 fatty acids (FAs) in patients after esophageal cancer surgery resulted in reduced platelet aggregation, coagulation activity, and cytokine production. We investigated whether EN using immuno-enhanced diet (IED) containing a large amount of omega-3 FAs as well as arginine and RNA affected the above-described responses. We also attempted to reveal whether arginine in the IED can potentially harm patients who undergo esophageal cancer surgery. Twenty-nine patients with esophageal cancer who underwent similar surgical procedures were selected. All patients received EN starting immediately after surgery. Fourteen patients received the formula with fewer omega-3 FAs, and fifteen patients received the IED. Administration of the IED tended to inhibit postoperative decrease in platelet count. Prothrombin activity and thrombin-antithrombin III complex levels were significantly reduced in the IED group. Plasma IL-8 levels were significantly lower (P < 0.05) in patients without the IED on the fifth postoperative day (POD). The proportion of T-cells was significantly higher (P < 0.05) in the IED group on PODs 1 and 7. Nitrate/nitrite levels did not differ significantly between the two groups. Early EN with an IED may enhance the inhibitory effects on postoperative platelet aggregation and hypercoagulation, and appeared to be advantageous to T-cell proliferation. These effects are expected to be beneficial in patients at risk of developing infectious complications. This study also showed that the IED could be safely used without any adverse effects for patients early after a radical surgery for the esophageal cancer.

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.

[A case of primary leiomyosarcoma of the ureter].

A 60-year-old woman was admitted to our hospital with pain in the left flank. Retrograde pyelography, computed tomographic scan, and magnetic resonance imaging demonstrated left hydronephrosis due to a 7 cm retroperitoneal mass involving the left ureter. Left nephroureterectomy and partial resection of the mesentery revealed a primary ureteral leiomyosarcoma. Three months postoperatively, the patient received systemic chemotherapy (CYVADIC; cyclophosphamide, vincristine, adriamycin and DTIC) for a recurrent tumor. Two courses of chemotherapy reduced the tumor by nearly 60%. Then we performed surgery in an attempt to resect the residual disease. However, the tumor continued to progress and the patient died approximately one year after diagnosis.

[A case of gastric cancer with peritoneal dissemination who achieved five-year survival by successive treatments with TS-1 alone and in combination with other drugs].

The patient was a 65-year-old male with gastric cancer. Peritoneal disseminations were detected during distal gastrectomy. CDDP and mitomycin C were administered into the peritoneal cavity. Administration of TS-1 was begun and continued without adverse effects. After 33 months, a high dose of CDDP was administered twice in combination with TS-1, because elevation of serum CEA levels and paraortic lymphnode swelling were observed for the first time. A partial response was obtained, but an elevation of CEA was seen again in three months. We then tried weekly administration of paclitaxel, and a complete response was achieved in three months. After three months'rest from chemotherapy, a third regrowth of the tumor was observed. Paclitaxel was ineffective, and so we opted for weekly administration of low-dose CDDP combined with TS-1, which led to the third recovery. Biweekly administration of CPT-11 combined with TS-1 followed the low-dose CDDP and was successfully continued five years after the surgery. The treatment course in this patient was fully suggestive for patients with advanced or recurrent gastric cancer because the use of newly available chemotherapeutic agents in turn was effective at each recurrence of the tumor and achieved five-year survival with minimal hospitalization.

The effects of immediate enteral feeding with a formula containing high levels of omega-3 fatty acids in patients after surgery for esophageal cancer.

BACKGROUND: We investigated whether supplementation of enteral nutrition (EN) with omega-3 polyunsaturated acids (PUFAs) affected platelet aggregation, coagulation activity, and inflammatory response in the early stages after esophageal cancer surgery. METHODS: Twenty-eight patients with esophageal cancer who underwent the same surgical procedure were selected for this study. All patients received EN, which was started immediately after the operation and was increased to a maximum volume of 1500 ml/day by the third postoperative day (POD). Eleven patients received a conventional EN formula (Ensure Liquid), while the remaining 17 patients received a different formula rich in omega-3 PUFAs (Racol [RAC]). Several markers of coagulation and fibrinolysis were determined in POD 2, while the concentrations of interleukin (IL)-6, IL-8, 6-keto-PGF1alpha and thromboxane B2 were determined on PODs 1, 3, and 5. RESULTS: A total of 27 patients completed the study, 11 in the Ensure Liquid group and 16 in the RAC group. Administration of RAC significantly inhibited the postoperative decrease in platelet count. The level of D-dimer was attenuated significantly in the RAC group. Plasma IL-8 levels were decreased significantly in the RAC group on PODs 1 and 3. The anti-inflammatory effects of omega-3 PUFAs were confirmed by the clinical findings of lower body temperature. The plasma concentration of 6-keto-PFG1alpha also tended to decrease in the RAC group with a significant difference on POD 5. CONCLUSIONS: Early EN with a large amount of omega-3 PUFAs in reduced platelet aggregation, coagulation activity, and cytokine production. All these effects would be expected to be beneficial in patients following esophageal cancer surgery. The clinical significance of the changes in eicosanoid production remains to be established.

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.

Influences of thoracic duct blockage on early enteral nutrition for patients who underwent esophageal cancer surgery.

OBJECTIVES: We have previously reported the beneficial effects of immediate enteral nutrition (EN) after esophageal cancer surgery. This randomized control study was conducted to determine whether immediate EN is beneficial or not for patients whose thoracic ducts were ligated, as well as those whose thoracic ducts were preserved. PATIENTS AND METHODS: Thirty-nine patients who underwent radical resection of the esophageal cancer entered this trial. After stratifying into two groups--patients whose thoracic ducts were preserved [D(+)] and those whose thoracic ducts were ligated [D(-)], they were randomly divided into two groups--the patients who received early EN and those who received parenteral nutrition (PN) followed by delayed enteral feeding. Thus, the number of patients in the D(+)-EN group, D(+)-PN group, D(-)-EN group and D(-)-PN group were 13, 12, 7 and 7, respectively. The mortality and morbidity rates, and several blood chemistries were compared between the EN groups and the PN groups. RESULTS: Total lymphocyte count showed a significant early increase and serum c-reactive protein (CRP) was significantly decreased in the D(+)-EN group compared to the D(+)-PN group. However those differences were not observed between the D(-) groups. Serum total bilirubin was significantly decreased in the both EN groups compared to the PN groups. The mortality and morbidity rates were not different between the EN group and the PN group in the D(+) patients and also in the D(-) patients. CONCLUSIONS: Patients whose thoracic ducts were ligated did not obtain any other benefit from early enteral feeding except for bilirubin metabolism. Early enteral feeding is not recommended for patients whose thoracic ducts are ligated during radical resection of a cancer in the thoracic esophagus.