Subgroup analysis of the AFTER I-O study: a retrospective study on the efficacy and safety of subsequent molecular targeted therapy after immune-oncology therapy in Japanese patients with metastatic renal cell carcinoma.

BACKGROUND: We performed subgroup analyses of the AFTER I-O study to clarify the association of time-to-treatment failure (TTF) and discontinuation reason of prior immune-oncology (I-O) therapy, and molecular targeted therapy (TT) regimen with the outcomes of TT after I-O. METHODS: The data of Japanese metastatic renal cell carcinoma patients treated with TT after nivolumab (NIVO) (CheckMate 025) or NIVO + ipilimumab (IPI) (CheckMate 214) were retrospectively analyzed. The objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) of TT after I-O were analyzed by subgroups: TTF (<6 or ≥6 months) and discontinuation reason of prior I-O (progression or adverse events), and TT regimen (sunitinib or axitinib). We also analyzed PFS2 of prior I-O and OS from first-line therapy. RESULTS: The ORR and median PFS of TT after NIVO and NIVO+IPI among the subgroups was 17-36% and 20-44%, and 7.1-11.6 months and 16.3-not reached (NR), respectively. The median OS of TT after NIVO was longer in patients with longer TTF of NIVO and treated with axitinib. Conversely, median OS of TT after NIVO+IPI was similar among subgroups. The median PFS2 of NIVO and NIVO+IPI was 36.7 and 32.0 months, respectively. The median OS from first-line therapy was 70.5 months for patients treated with NIVO and NR with NIVO+IPI. The safety profile of each TT after each I-O was similar to previous reports. CONCLUSIONS: The efficacy of TT after NIVO or NIVO+IPI was favorable regardless of the TTF and discontinuation reason of prior I-O, and TT regimen.

Re-challenge of Platinum-based Chemotherapy for Platinum-refractory Patients with Recurrent or Metastatic Head and Neck Cancer: Claims Data Analysis in Japan.

BACKGROUND: The role of platinum rechallenge in head and neck cancer (HNC) has not yet been fully evaluated. OBJECTIVES: It is our goal to assess the real-world treatment patterns and usefulness of platinum rechallenge in patients with platinum-refractory recurrent or metastatic HNC receiving platinum rechallenge. METHODS: This is a retrospective study using data from a Japanese hospital claims database stored in electronic hospital information systems. Patients with HNC or undefined histology with an HNC diagnosis using the disease code, between January 1, 2013 and September 30, 2016, were included. Patients diagnosed with other malignancies on or before the initial diagnosis of HNC and those without cancer stage information in the database were excluded from the study. RESULTS: A total of 43 994 patients were identified from the database as HNC patients. Of those, in patients who had cancer progression within 6 months after platinum-based chemotherapy administered for primary or recurrent disease (N=842), the median treatment duration of platinum rechallenge for platinum refractory patients was only 1 cycle. The second-line treatment continuation rate at 6 months was 20.1% for patients who received platinum rechallenges and 32.8% for those who received non-platinum-based regimens. CONCLUSIONS: The findings from this study of data from routine clinical practice suggest that the benefit of platinum rechallenge in a platinum-refractory setting would be limited.

A multicenter retrospective study of nivolumab monotherapy in previously treated metastatic renal cell carcinoma patients: interim analysis of Japanese real-world data.

BACKGROUND: In a phase III clinical trial, CheckMate 025, treatment of metastatic renal cell carcinoma (mRCC) with nivolumab demonstrated superior efficacy over everolimus. However, as the clinical trial excluded patients with specific complications and poor performance status (PS), the effectiveness and safety of nivolumab in clinical practice, in which patients with various clinical complications are treated, is unclear. This study explored real-world nivolumab treatment in Japanese mRCC patients. METHODS: This is an interim analysis of a multicenter, non-interventional, medical record review study (minimum follow-up: 9 months). All eligible Japanese mRCC patients who first received nivolumab between February and October 2017 were included; data cut-off was April 2019. We analyzed nivolumab treatment patterns, efficacy (including overall survival, progression-free survival, objective response rate, and duration of response) and safety (including immune-related adverse events). RESULTS: Of 208 evaluable patients, 31.7% received nivolumab as fourth- or later line of treatment. At data cut-off, 26.9% of patients were continuing nivolumab treatment. The major reason for discontinuation was disease progression (n = 100, 65.8%). Median overall survival was not reached; the 12-month survival rate was 75.6%. Median progression-free survival was 7.1 months, the objective response rate was 22.6%, and median duration of response was 13.3 months. Patients who were excluded or limited in number in CheckMate 025, such as those with non-clear cell RCC or poor PS, also received benefits from nivolumab treatment. Immune-related adverse events occurred in 27.4% of patients (grade ≥ 3, 10.1%). CONCLUSION: Nivolumab was effective and well-tolerated in real-world Japanese mRCC patients. TRIAL REGISTRATION: UMIN000033312.

Development of an abdominal wall abscess caused by fish bone ingestion: a case report.

BACKGROUND: A small percentage of patients with foreign body ingestion develop complications, which have a variety of clinical presentations. Less than 1% of cases require surgical intervention. We present a patient with an abdominal wall abscess resulting from a fish bone that pierced the cecum. The patient was treated laparoscopically. CASE PRESENTATION: A 55-year-old Japanese man presented to our hospital with a complaint of right lower abdominal pain. A physical examination revealed tenderness, swelling, and redness at the right iliac fossa. Computed tomography showed a low-density area with rim enhancement in his right internal oblique muscle and a hyperdense 20 mm-long pointed object in the wall of the adjacent cecum. Based on the findings we suspected an abdominal wall abscess resulting from a migrating ingested fish bone. He was administered antibiotics as conservative treatment, and the abscess was not seen on subsequent computed tomography. Two months after the initial treatment, he presented with the same symptoms, and a computed tomography scan showed the foreign body in the same location as before with the same low-density area. We diagnosed the low-density area as recurrence of the abdominal wall abscess. He underwent laparoscopic surgery to remove the foreign body. His appendix, and part of his cecum and the parietal peritoneum that included the foreign body, were resected. He had an uneventful postoperative course, and at 1 year after the surgery, the abdominal wall abscess had not recurred. CONCLUSIONS: An abdominal wall abscess developed in association with the migration of an ingested fish bone. We suggest that a laparoscopic surgical resection of the portion of the bowel that includes the foreign body is a useful option for selected cases.

Feasibility and Safety of Laparoscopic Appendectomy Performed by Residents with No Experience in Open Appendectomy.

INTRODUCTION: Open appendectomy for acute appendicitis is a common procedure for surgical residents to perform at the beginning of their training. Recently, many programs have moved to laparoscopic appendectomy as the initial training procedure. However, the feasibility and safety of laparoscopic appendectomy for acute appendicitis performed by surgical residents without any experience of open appendectomy remains controversial. METHODS: The records of patients who underwent laparoscopic appendectomy for acute appendicitis between August 2006 and March 2017 were retrospectively reviewed. Patients were assigned to two groups according to whether their procedure was performed by a surgical resident, with no experience of open appendectomy, or a surgical fellow, with adequate open appendectomy experience but no experience with laparoscopic appendectomy. RESULTS: A total of 130 patients were included. Five residents performed 104 procedures, and three fellows performed 26 procedures. The baseline patient characteristics were comparable between groups. The median operative time was comparable (77.0 min vs. 65.5 min; p = 0.771). There were no significant differences in overall complications; with 14 patients (13%) in the resident group and five patients (19%) in the fellow group experienced complications (p = 0.535). No patient required reoperation, and there were no fatalities. The median length of stay was similar (5.0 days vs. 5.5 days; p = 0.430). CONCLUSIONS: Laparoscopic appendectomy for acute appendicitis is feasible and safe when performed by surgical residents with no prior open appendectomy experience. It may be performed as the first procedure during surgical training with no adverse effect on patients.

Chylothorax after hepatectomy: a case report.

BACKGROUND: Chylothorax is the accumulation of chyle within the pleural space. Chylothorax can occur as a complication after multiple different types of surgery, most frequently after thoracic surgery, albeit with an incidence rate of less than 1%. Chylothorax after abdominal surgery is extremely rare, and there are only a few case reports. CASE PRESENTATION: A 74-year-old Japanese woman presented with jaundice. She was diagnosed as having hilar cholangiocarcinoma and underwent right hepatectomy, caudate lobectomy, extrahepatic bile duct resection, and lymph node dissection after preoperative percutaneous transhepatic portal vein embolization. Postoperative liver function was normal. She developed chylous ascites on postoperative day 5, for which conservative treatment was initially effective. Dyspnea developed suddenly on postoperative day 42, and she had a massive right pleural effusion and a small amount of ascites. Management with pleural drainage, total parenteral nutrition, and octreotide injections decreased the chylothorax. However, the chylous effusion reaccumulated on postoperative day 57. As conservative treatments ultimately failed, lymphangiography was performed on postoperative day 62. Lymphangiography with Lipiodol (ethiodized oil) revealed extravasation into the pleural space, but the location of the leak was not identified. There was neither obstruction nor dilation of the thoracic duct. A lymphatic leak in her abdominal cavity was not demonstrated. A chest tube was placed after lymphangiography, and the chylothorax was diminished by postoperative day 71. She was discharged on postoperative day 72. Two and a half years after surgery, she is doing well with no evidence of recurrence of either chylothorax or cancer. CONCLUSIONS: Chylothorax can occur after hepatectomy and pleural effusion should raise suspicion for chylothorax. Lymphangiography may be effective for both diagnosis and treatment in the case of chylothorax after hepatectomy.

Primary hepatic carcinosarcoma with multimodal treatment.

Hepatic carcinosarcoma (HCS) generally presents in advanced stages, demonstrates aggressive behavior, and has a poor prognosis. Other than curative primary resection, no effective treatment options exist. We present a case of resected HCS with four repeat resections for solitary lymph node recurrence followed by chemoradiotherapy with doxorubicin and ifosfamide. A 67-year-old Japanese man was admitted to our hospital for evaluation of an asymptomatic hepatic tumor. The patient underwent right hepatectomy with a presumptive preoperative diagnosis of atypical hepatocellular carcinoma. Based on histopathological and immunohistochemical findings, the tumor was diagnosed as HCS containing osteosarcoma and chondrosarcoma components. After the initial surgery, the patient underwent four additional resections for solitary lymph node HCS recurrence, and then underwent chemoradiotherapy with doxorubicin and ifosfamide for an unresectable lymph node recurrence. Chemotherapy was stopped after two cycles because of severe adverse events, although chemoradiotherapy markedly reduced the size of the lymph node recurrence and provided a progression-free survival of 12 months. Thirty-seven months after the initial surgery, the patient died of cardiac invasion of multiple mediastinal lymph node metastases. The clinical course outlined in this case report suggests that chemoradiotherapy with doxorubicin and ifosfamide for metastatic HCS may prolong survival in patients with unresectable lesions.

Multiple mesenteric desmoid tumors after gastrectomy for gastric cancer: A case report and literature review.

INTRODUCTION: Many patients with desmoids have an antecedent trauma, particularly surgical intervention for familial adenomatous polyposis. However, cases of mesenteric desmoid after gastrectomy are extremely rare. We present a case of multiple mesenteric desmoids after total gastrectomy for gastric cancer. PRESENTATION OF CASE: A 70-year-old man had undergone a total gastrectomy for early stage gastric cancer. He had no other relevant medical history or family history. A year after gastrectomy, a computed tomography showed three mesenteric masses, and we performed careful observation. The 2-year postoperative examination indicated slowly growing masses. There were no other lesions except for the three masses. We decided to perform diagnostic surgery to evaluate the tumors. There were three mesenteric masses (1.5 cm, 4 cm and 1.5 cm in diameter). We performed partial small intestinal resections for each mass. Histological examination showed that the tumors were desmoids. A year after surgery, he was doing well with no evidence of recurrence of the desmoids or the gastric cancer. DISCUSSION: Diagnosing intra-abdominal desmoid tumors is often difficult. Especially if a patient has a history of malignancy, it may be extremely difficult to differentiate multiple mesenteric desmoids from a cancer recurrence. In the current case, surgical resection was a useful treatment option as diagnostic therapy. CONCLUSIONS: Multiple mesenteric desmoids could emerge after gastrectomy for gastric cancer, and surgical resection of the tumors is a useful option as a diagnostic therapy.

Laparoscopic low anterior resection for rectal cancer with rectal prolapse: a case report.

BACKGROUND: Rectal cancer with rectal prolapse is rare, described by only a few case reports. Recently, laparoscopic surgery has become standard procedure for either rectal cancer or rectal prolapse. However, the use of laparoscopic low anterior resection for rectal cancer with rectal prolapse has not been reported. CASE PRESENTATION: A 63-year-old Japanese woman suffered from rectal prolapse, with a mass and rectal bleeding for 2 years. An examination revealed complete rectal prolapse and the presence of a soft tumor, 7 cm in diameter; the distance from the anal verge to the tumor was 5 cm. Colonoscopy demonstrated a large villous tumor in the lower rectum, which was diagnosed as adenocarcinoma on biopsy. We performed laparoscopic low anterior resection using the prolapsing technique without rectopexy. The distal surgical margin was more than 1.5 cm from the tumor. There were no major perioperative complications. Twelve months after surgery, our patient is doing well with no evidence of recurrence of either the rectal prolapse or the cancer, and she has not suffered from either fecal incontinence or constipation. CONCLUSIONS: Laparoscopic low anterior resection without rectopexy can be an appropriate surgical procedure for rectal cancer with rectal prolapse. The prolapsing technique is useful in selected patients.

Suboptimal Anticoagulant Management in Japanese Patients with Nonvalvular Atrial Fibrillation Receiving Warfarin for Stroke Prevention.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence in Japan. Although prothrombin time-international normalized ratio (PT-INR) targets for monitoring warfarin therapy in patients with nonvalvular AF (NVAF) are well defined, real-world patient characteristics and PT-INR levels remain unknown among Japanese patients with NVAF who initiate and continue warfarin (warfarin maintainers) versus those who switch from warfarin to direct oral anticoagulants (DOACs; warfarin switchers). METHODS: Patients with NVAF receiving oral anticoagulants between February 2013 and June 2015 were identified using a nationwide electronic medical record (EMR) database from 69 hospitals in Japan. Demographics and characteristics of patients, PT-INR, time in therapeutic range (TTR), and frequency in range (FIR) of PT-INR between warfarin maintainers and warfarin switchers were assessed. RESULTS: A total of 1705 patients met inclusion criteria and were examined (1501 warfarin maintainers versus 204 warfarin switchers). CHADS2, CHA2DS2-VASc, and HAS-BLED scores were comparable between groups. However, these scores were significantly higher among warfarin switchers at the time of switching than at the time of warfarin initiation. Furthermore, TTR and FIR of PT-INR were lower in warfarin switchers than in maintainers. Nevertheless, TTR and FIR were below 50% (PT-INR, 1.6-2.6) in both patient groups. CONCLUSIONS: In this EMR-based clinical study, patients who switched to DOACs had both poor or inadequate PT-INR control and higher risk factors of stroke. Many patients receiving warfarin did not achieve sufficient PT-INR therapeutic range. DOACs could be recommended in Japanese patients with NVAF with inadequate PT-INR control and increased risk of stroke.

Novel therapy for pancreatic fistula using adipose-derived stem cell sheets treated with mannose.

BACKGROUND: Given that no studies have reported the use of adipose-derived stem cell sheets for the prevention of pancreatic fistulas, it is unclear whether adipose-derived stem cell sheets are effective at preventing this complication. The aim of this study was to evaluate the efficacy of novel therapy for the prevention of pancreatic fistulas using adipose-derived stem cell sheets treated with mannose. METHODS: The rat pancreatic duct (splenic duct) and surrounding pancreatic parenchyma were transected to induce a pancreatic fistula. Adipose-derived stem cell sheets with or without mannose treatment were attached to the pancreatic transection stump. Amylase and lipase levels were measured in both the ascites and serum. The expression of 40 cytokines in human adipose-derived stem cells with and without mannose treatment was investigated using a multiplex assay. RESULTS: The adipose-derived stem cell sheets remained at the initial attachment site at 48 hours after operation. Macroscopically, more severe degeneration and adhesion in the peritoneal cavity were observed in the untreated rats than in the rats treated with adipose-derived stem cell sheets. The levels of ascitic amylase in the untreated, adipose-derived stem cell-sheet-treated, and adipose-derived stem cell-sheet-with-mannose-treated rats were 10.7 ± 2.9 × 104 U/L, 2.6 ± 0.9 × 104 U/L, and 1.5 ± 0.3 × 104 U/L, respectively. The levels of ascitic lipase in the untreated, adipose-derived stem cell-sheet-treated and adipose-derived stem cell-sheet-with-mannose-treated rats were 9.5 ± 2.9 × 103 U/L, 4.0 ± 3.3 × 103 U/L, and 0.4 ± 0.2 × 103 U/L, respectively. Significant differences were found in both the ascitic and serum levels of amylase and lipase between the untreated rats and the rats treated with adipose-derived stem cell sheets with mannose (P < .05). Fibroblast growth factor 2 gene expression levels were greater in human adipose-derived stem cells treated with mannose than in human adipose-derived stem cells treated without mannose. CONCLUSION: Adipose-derived stem cell sheets treated with mannose are effective for preventing pancreatic fistulas and have promising potential for clinical applications. The enhancing effect of mannose on the function of adipose-derived stem cells may be partially explained by induction of fibroblast growth factor 2.