The relationship between observation interval and prognosis in pancreatic cancer concomitant with intraductal papillary mucinous neoplasia.

BACKGROUND: Intraductal papillary mucinous neoplasia (IPMN) is a risk factor for pancreatic cancer (PC). PC concomitant with IPMN shows rapid progression similar to de novo PC, therefore, the appropriate observation interval (OI) is not yet clear. PATIENTS AND METHOD: This was a multicenter retrospective observational study, and patients with PC concomitant with IPMN were analyzed. OI was defined as the interval between the date of imaging at PC diagnosis and just before the diagnosis. Clinical factors of PC and prognosis were assessed according to OI. RESULTS: From January 2010 to December 2018, 73 patients from 11 institutions were enrolled. The images performed just before PC diagnosis were contrast-enhanced CT/magnetic resonance imaging/endoscopic ultrasonography in 44/27/2 patients, respectively. The median cyst size was 14.0 mm, and the median main pancreatic duct diameter was 3.0 mm. The median OI was 6.8 months. In OI 6 months or less (OI ≤ 6 M)/OI more than 6 months (OI > 6 M), the mean tumor size, the frequencies of metastatic PC, resectable PC and early-stage PC were 20.1/21.5 mm (P = 0.91), 12.1 %/32.5 % (P = 0.05), 72.7 %/52.5 % (P = 0.09) and 27.3 %/25.0 % (P = 1.00), respectively. The median overall survival was 35.5 months in OI ≤ 6 M and 16.2 months in OI > 6 M (P = 0.05). CONCLUSION: In OI 6 months or less, the rate of resectable PC was high, however, the rate of early PC was almost the same as that of OI more than 6 months. Approximately 10 % of cases found in the advanced stage with metastasis even if OI 6 months or less.

[A case of severe colitis induced by the administration of pembrolizumab for pulmonary adenocarcinoma in a patient with ulcerative colitis].

Pembrolizumab is an immunoglobulin G4 isotype antibody that targets the programmed cell death protein 1 (PD-1) receptor of lymphocytes. It is used in the treatment of advanced non-small cell lung cancer (NSCLC). The safety and efficacy of immunotherapy for autoimmune disease are currently unknown;immune-related adverse events induced by immune checkpoint inhibitors (ICIs) have been reported. We report a case of severe colitis induced by the administration of pembrolizumab for pulmonary adenocarcinoma in a patient with ulcerative colitis. A 72-year-old man with a 3-year history of ulcerative colitis maintained clinical remission with mesalazine. The recurrence of lung adenocarcinoma was diagnosed and treated with pembrolizumab as second-line treatment. Diarrhea and bloody stool recurred 5 months after the first administration of pembrolizumab. The colitis did not respond to corticosteroids and infliximab. Because of the recurrence of ulcerative colitis, treatment of the lung adenocarcinoma was discontinued, and the patient died 1 year after the first administration of pembrolizumab. Few cases of severe colitis induced by the administration of pembrolizumab in patients with ulcerative colitis have been reported. This case suggests that the clinical stratification of autoimmune disease and typical standards of effectiveness of treatment are needed for patients with autoimmune disease who are treated with ICIs.

[A case of idiopathic thrombocytopenic purpura development after total colectomy for ulcerative colitis].

Ulcerative colitis (UC) is known to be associated with extraintestinal manifestations. However, idiopathic thrombocytopenic purpura (ITP) has rarely been reported as one of the extraintestinal manifestations in UC. In most cases, ITP develops as an extraintestinal manifestation during the treatment for UC. After treatment with medications or colectomy, there is often a remission of UC and ITP. However, we experienced a case of ITP development after total colectomy for UC. An 83-year-old man was diagnosed as having UC and started treatment with medications. After 3 years, total colectomy and ileostomy were performed to prevent UC remission. Subsequently, no further treatment was provided. Two years later, he presented to the hematology department in our hospital with the chief complaint of thrombocytopenia and was diagnosed as having ITP. ITP was treated with steroids, and his platelet count increased to within the normal range. Immunological abnormalities may be involved in the development of extraintestinal manifestation, including UC-associated ITP. In previous reports, ITP was cured by colectomy for UC. In contrast, peripheral arthritis is a common extraintestinal manifestation of UC, and it is known that 75% of these patients develop or continue to experience such symptoms after colectomy. Some extraintestinal manifestations may equally persist after colectomy. However, the underlying mechanisms are poorly understood. Ileitis and small intestinal and duodenal inflammation are all known bowel complications associated with colectomy, and some immunological mechanisms have been suggested to be involved. Therefore, careful monitoring in these patients is necessary to detect any possibility of developing extraintestinal manifestations after colectomy. Further studies to examine the mechanisms underlying the immunological abnormality between UC and extraintestinal manifestations such as ITP are needed.

Favorable outcome with direct-acting antiviral treatment in hepatitis C patients coinfected with HIV.

AIM: To investigate the efficacy and safety of all-oral direct-acting antiviral treatments in patients coinfected with hepatitis C virus (HCV) and HIV. METHODS: In all, 35 patients with HCV/HIV coinfection (22 patients with HCV genotype 1 infection, 6 with genotype 2, and 7 with genotype 3) were treated with sofosbuvir and ledipasvir (for genotype 1 patients) or sofosbuvir and ribavirin (for genotypes 2 and 3). Sustained virological response (SVR) at 24 weeks after end of treatment and adverse events were assessed. RESULTS: The overall SVR rate was 91.4% (32/35). One patient with genotype 1 infection discontinued treatment on day 2 due to severe headache, which subsided after the cessation of medication; all other patients completed their treatment without severe adverse events. Two patients who had a relapse of HCV were infected with a genotype 3 strain. We observed hyperbilirubinemia in a patient with genotype 3, who was under antiretroviral therapy including atazanavir. He completed the treatment and achieved SVR. CONCLUSION: Direct-acting antiviral treatment for patients coinfected with HCV/HIV is as effective as in patients infected only with HCV. It was generally well tolerated, except in one patient who discontinued the treatment due to severe headache.

[A case of refractory pouchitis following surgery for ulcerative colitis successfully treated with adalimumab].

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is widely accepted as the operation of choice for refractory ulcerative colitis (UC), UC with dysplasia or cancer, or familial adenomatous polyposis. Pouchitis is the most frequent complication after IPAA for UC. Although the pathogenesis of pouchitis remains unclear, current evidence suggests that dysbiosis and mucosal immune response are important mechanisms. Antibiotics are the first-line treatment for the condition, but some patients develop chronic refractory pouchitis. Such cases can be treated with regimens such as longer courses of antibiotic combinations, mesalazine, corticosteroids, probiotics, or biologics. But if pouch inflammation is not ameliorated, a permanent ileostomy may be required. A 40-year-old man had undergone IPAA for UC and was diagnosed with pouchitis according to the Pouchitis Disease Activity Index. Antibiotics, mesalazine, and corticosteroids were given, but the inflammation was difficult to control. He developed chronic refractory pouchitis associated with perianal abscesses and anal fistulae. Following a seton procedure for fistulae, adalimumab (ADA) was administered. After 42 weeks, the ulcers in the pouch became scarred, and the anal fistulae were closed endoscopically. After remission was induced, it has been maintained. ADA is a fully human anti-tumor necrosis factor-α (TNF-α) monoclonal antibody that has been successfully used to treat refractory Crohn disease of the ileoanal pouch. Although some studies report that infliximab, a chimeric anti-TNF-α monoclonal antibody, is efficacious in patients with refractory pouchitis, clinical evidence for the use of ADA is limited. This case illustrates achievement of induction and maintenance of remission of refractory pouchitis with ADA. It is possible that patients with this condition can avoid a permanent ileostomy with anti-TNF-α therapy. In the near future, further study of long-term clinical outcomes of anti-TNF-α therapy is expected.

[Squamous cell carcinoma of the anal canal treated with chemoradiotherapy in a patient with HIV].

Since the introduction of combination antiretroviral therapy (ART), the life expectancy has increased for patients infected with human immunodeficiency virus (HIV). This has been associated with reductions in the incidences of some AIDS-defining malignancies, such as Kaposi sarcoma and non-Hodgkin lymphoma, but has coincided with an increased incidence of non-AIDS-defining malignancies, such as anal cancer. However, anal cancers are rare in patients with HIV in Japan. We report the case of an HIV-infected patient with anal cancer treated with chemoradiotherapy. A 37-year-old man receiving ART for HIV infection presented with a 1-month history of left inguinal lymphadenopathy and anal pain. Magnetic resonance imaging and computed tomography revealed a 56-mm mass, left inguinal lymphadenopathy, and left external iliac lymphadenopathy. The mass had infiltrated from the anal canal to the right levator ani and corpus spongiosum. Colonoscopy revealed a tumor with an ulcer in the anal canal. Histological examination of the tumor biopsy specimens confirmed the diagnosis of squamous cell carcinoma. The patient was diagnosed with anal cancer (T4N2M1 stage IV), and he received 5-fluorouracil (1000mg/m(2) on days 1-4 and 29-32) plus mitomycin C (10mg/m(2) on days 1 and 29) and concurrent radiotherapy (total dose, 59.4Gy in 33 fractions) along with ART. The treatment-related adverse events were grade 4 leukopenia and neutropenia, grade 3 thrombocytopenia, and grade 2 radiation dermatitis. Moreover, CD4 suppression was observed:the CD4 count decreased from 190 cells/µl before chemoradiotherapy to 138 cells/µl after 3 months, but increased to 210 cells/µl after 1 year. Because of the grade 4 leukopenia and neutropenia, the dose of 5-fluorouracil was reduced to 800mg/m(2) on days 29-32. A complete response was confirmed on magnetic resonance imaging, and colonoscopy confirmed the disappearance of the anal cancer. The patient is living with no signs of recurrence at 2 years after chemoradiotherapy. When treating HIV-infected patients with anal cancer by chemoradiotherapy and ART, clinicians should be aware of the possibility of CD4 suppression.

A case report of a duodenal adenocarcinoma: a complication with Crohn's disease.

The prevalence of Crohn's disease (CD) in Japan is increasing, and so is the incidence of colorectal and small bowel cancers associated with CD. However, few reports have described the malignant transformation of duodenal lesions; moreover, such a diagnosis is rarely possible preoperatively. We present a case of malignant degeneration in the duodenal mucosa associated with CD. A 54-year-old man had been receiving treatment for CD for more than 20 years. Seven years ago, he was diagnosed with duodenal stenosis related to CD. He was asymptomatic, and biopsy results from the proximal stricture showed inflammatory changes without malignant transformation. The lesion was then monitored during follow-up. In 2013, he underwent an endoscopy, which revealed an ulcerated, nodular mucosa, immediately proximal to a high-grade obstruction of the descending duodenum. A biopsy of the ulcer lesion confirmed a diagnosis of adenocarcinoma. The patient then underwent duodenopancreatectomy. Histopathological results from the resected duodenum confirmed a poorly differentiated adenocarcinoma that had invaded the subserosa. The patient recovered, and no recurrence has been observed. Although the duodenum can be accessed without difficulty during endoscopy, it is challenging to preoperatively diagnose malignant transformation. There are only four reported cases of duodenal cancer stemming from CD-associated stricture, and only one of them received a preoperative diagnosis of malignancy based on endoscopic biopsy results. Progressive duodenal narrowing and ulceration in patients with CD should indicate a need for careful endoscopic evaluation and biopsy in order to exclude malignant degeneration of Crohn's duodenitis. Early diagnosis of cases of CD-associated cancers is necessary. We report the features of a rare and illustrative case of duodenal adenocarcinoma in a patient with CD.

Administration of low-dose epoetin-alpha facilitates adherence to ribavirin in triple therapy with pegylated interferon-alpha-2b and telaprevir.

AIM: Anemia frequently develops in patients given pegylated interferon, ribavirin (RBV), telaprevir (TVR) triple therapy and restricts treatment by forcing reduction or discontinuation of RBV administration. We investigated whether erythropoietin (EPO) could alleviate RBV-induced anemia to help maintain the RBV dose during the first 12 weeks, the triple therapy phase. METHODS: Twenty-two patients with hepatitis C virus (HCV) genotype 1 were enrolled. Hemoglobin (Hb) concentration was measured every week. If Hb reduction from the baseline was 2 g/dL or more, 12 000 IU of epoetin-α was administrated. When further reduction (≥3 g/dL) was observed, 24 000 IU of epoetin-α was used. Inosine triphosphatase (ITPA) single nucleotide polymorphism (rs1127354) was genotyped for all patients. RESULTS: Among the 22 patients enrolled in this study, three required RBV dose reduction due to anemia, two had to discontinue or reduce TVR and RBV due to creatinine elevation. The remaining 17 patients completed the treatment during the triple therapy phase without reduction of the RBV dose or adverse events attributable to EPO. Regardless of ITPA genotype, Hb decline was well controlled by EPO administration, whereas the total EPO dose tended to be higher in the CC genotype group. The average adherence to RBV during the triple therapy phase was 97.5%. SVR was achieved in 17 patients; two patients had viral breakthrough and three patients had relapse of HCV RNA. CONCLUSION: EPO can be a favorable alternative to reduction of RBV to facilitate the adherence of patients on TVR-based triple therapy.

Optimal indications for second-line chemotherapy in advanced gastric cancer.

As it remains uncertain whether patients with advanced gastric cancer who progress after first-line chemotherapy should receive second-line chemotherapy, we attempted to identify the optimal indications for second-line chemotherapy. In this retrospective study, 101 patients were included in univariate and multivariate analyses to identify clinicopathological variables independently associated with longer survival postprogression (SPP), defined as the time from recognition of disease progression on first-line chemotherapy to death from any cause or last follow-up. The median SPP was 340 days. On multivariate analysis, performance status 2 [hazard ratio (HR), 14.234; 95% confidence interval (CI), 2.766-73.258], serum albumin level less than 3.5 g/dl (HR, 2.088; 95% CI, 1.047-4.060) at initiation of second-line chemotherapy, and time to progression less than 170 days on first-line chemotherapy (HR, 2.497; 95% CI, 1.227-5.083) were identified as independent prognostic factors associated with shorter SPP. The median SPP was 496, 375, and 232 days in patients with 0, 1, and 2 of these 3 negative prognostic factors, respectively (P=0.0002). The present study suggests that second-line chemotherapy would not be beneficial in patients with two or more of the following three negative prognostic factors: performance status 2, serum albumin less than 3.5 g/dl at initiation of second-line chemotherapy and time to progression less than 170 days on first-line chemotherapy.

[Efficacy of combined chemotherapy with nedaplatin, adriamycin, and 5-FU (NAF), and clinical factors affecting its effect in patients with advanced esophageal cancer].

We retrospectively evaluated the efficacy of combined chemotherapy with nedaplatin, adriamycin, and 5-FU (NAF), as well as clinical factors affecting its effect in patients with advanced esophageal cancer. A total of 104 patients with advanced esophageal cancer received 2 courses of NAF-chemotherapy between February 2003 and March 2010. The response rate according to the RECIST criteria was 38. 5%, and the response of the primary lesion was 51. 9%, according to the endoscopic evaluation of chemotherapy by the Japanese Esophageal Society. On multivariate analysis, factors such as nutritional status, CRP levels before treatment and adverse effects during chemotherapy did not significantly affect the efficacy of the NAF regimen. NAF-chemotherapy for advanced esophageal cancer was very effective even when patients had malnutrition or high CRP levels.

[Synchronous double cancer of the gallbladder and rectum successfully treated with S-1 as second-line chemotherapy- a case report].

A 66-year-old man was referred to our hospital with obstructive jaundice. Computed tomography(CT)scan showed thickening of the gallbladder wall, invasion into the liver bed, and thickening of the rectal wall. Colonoscopy revealed a type 2 rectal cancer, in which adenocarcinoma was identified by endoscopic biopsy. He was diagnosed with double-cancer of the gallbladder and rectum. Because his gallbladder cancer was more life threatening than his rectal cancer, gemcitabine was administered at 1, 000 mg/m2 on days 1, 8, and 15 of a 28-day course. After 3 courses of gemcitabine, the CT scan showed that the lymph nodes in the hepatoduodenal ligament had been enlarged, and duodenal stenosis had occurred as a result of gallbladder cancer invasion. S-1 was administered orally at doses of 120 mg/day twice daily on days 1-28 of a 42-day course. Partial response was confirmed by CT scan. After 8 courses of S-1, the gallbladder cancer had progressed and liver metastases had appeared. He subsequently died of disease progression. He survived for 17 months after the first course of chemotherapy, and the progression-free survival with S-1 was 10 months. Therefore, S-1 could be an effective agent for synchronous double cancer of the gallbladder and rectum.

Effect of S-1 adjuvant chemotherapy on survival following recurrence and efficacy of first-line treatment in recurrent gastric cancer.

BACKGROUND: As S-1 monotherapy has recently become the standard adjuvant regimen for stage II-III gastric cancer patients after curative gastrectomy in Japan, the question whether adjuvant S-1 affects the subsequent clinical course of relapsed patients has attracted great concern. PATIENTS AND METHODS: We retrospectively evaluated the effect of adjuvant S-1 on survival following recurrence and efficacy of first-line treatment in patients with recurrent gastric cancer after curative gastrectomy. A total of 89 patients were evaluated. Thirty patients received adjuvant S-1 (cohort A), 10 patients were given adjuvant chemotherapy with other oral 5-FU agents (cohort B) and 49 patients received no adjuvant chemotherapy (cohort C). RESULTS: Median survival time following recurrence was 287 days in cohort A, 451 days in B and 547 days in C, with a significant difference between A and C (p = 0.0034). Response rates of the first-line chemotherapy after recurrence were 6.7, 30.0 and 42.9% in cohorts A, B and C, respectively, with a significant difference between A and C (p = 0.0007). On multivariate analysis, S-1 adjuvant chemotherapy was independently associated with poor prognosis after recurrence (hazard ratio 2.64). CONCLUSION: S-1 adjuvant chemotherapy significantly reduced survival and response to first-line chemotherapy following recurrence in patients with recurrent gastric cancer.

[Case of primary hepatic neuroendocrine carcinoma diagnosed by needle biopsy].

The patient was a 55-year-old man with a large hepatic tumor measuring 12 × 12 cm in the left lobe. To obtain the histological diagnosis, the target liver biopsy was performed. Histologically, the tumor revealed as a neuroendocrine carcinoma. After the diagnosis, he received the chemotherapy (CTX) with etoposide and cisplatin. Serum levels of NSE and the tumor size were decreased after the first course of CTX. We here report a case of primary hepatic neuroendocrine carcinoma treated with CTX following the diagnosis by the needle biopsy.

Breast metastasis from rectal cancer with BRAF V600E mutation: a case report with a review of the literature.

Metastasis of rectal cancer to the breast is an extremely rare clinical event. We report the case of a 67-year-old woman with a metastatic breast tumor derived from a BRAF V600E mutant rectal carcinoma that was diagnosed and resected curatively 1 year previously. Computed tomography showed a left breast mass and multiple lung nodules suspected to be indicative of recurrent rectal cancer. The ultrasonography examination demonstrated a 10 × 10-mm hypoechoic solid lesion in the left breast with an elevation in the serum carcinoembryonic antigen level and serum carbohydrate antigen 19-9 level. Core needle biopsy was performed, and histopathologic examination showed Cytokeratin 20 and CDX-2 positivity, compatible with rectal cancer. To our knowledge, this is the first case of a metastatic breast tumor arising from rectal carcinoma with BRAF mutation. Although breast metastasis is very rare event, the possibility of breast metastasis from extra mammary sites should be considered when the breast tumor is found in cancer treatment.

[A case of liver metastasis of pancreatic duct carcinoma successfully treated with gemcitabine].

We report a patient in whom systemic chemotherapy using gemcitabine was effective against liver metastases of pancreatic cancer. A 72-year-old woman underwent pancreatoduodenectomy with lymphadenectomy and partial resection of the portal vein following a diagnosis of pancreatic cancer, and her postoperative course was uneventful. The diagnosis was stage III anaplastic ductal carcinoma (t2n1P0H0M0). One year and 3 months after the operation, however, her serum level of carbohydrate antigen 19-9 (CA19-9) was found to be elevated, and CT examination revealed a mass in the liver that was diagnosed as liver that was metastases. Systemic chemotherapy was performed with a regimen of gemcitabine 600 mg/m2/week for 3 weeks, followed by a week rest, for the first three courses. On and after fourth course, gemcitabine 1,000 mg/m2/week was administered. The serum CA19-9 level was down from 882 U/ml to normal after 5 courses of chemotherapy and CT examination revealed that liver metastases had completely vanished. Although no evidence of deterioration was observed, the patient died of infectious pneumonia 10 months after recurrence. The prognosis of liver metastases of pancreatic cancer is quite unfavorable. However, if remission is achieved with gemcitabine, the patient has the possibility to obtain a better outcome.