[A case of unresectable gastric cancer treated with triplet combination chemotherapy with itraconazole and conversion surgery].

A 73-year-old woman visited our hospital due to carcinoembryonic antigen (CEA) level elevation (110ng/ml). She underwent an upper gastrointestinal endoscopy (EGD), enhanced computed tomography (CT), and positron emission tomography (PET) -CT. She was diagnosed with type 3 esophagogastric junction cancer with paraaortic lymph node (LN) metastases at stage IVA (cT3N4M0). She underwent triplet combination chemotherapy with itraconazole (ITCZ):nab-paclitaxel, oxaliplatin, and S-1 with ITCZ. After six cycles of this regimen, the CEA level was within normal range, and EGD and PET-CT showed no evidence of malignancy. She underwent laparoscopic proximal gastrectomy and lower esophagectomy. The surgical specimen revealed no residual tumor (pathological complete response). Three months later, her CEA level increased to 60.5ng/ml, and she had longitudinal LN recurrence. However, she took S-1 orally for 11 cycles, and the recurrent metastatic LNs improved. She received chemotherapy, including nivolumab followed by ramucirumab and nab-paclitaxel with ITCZ. The CEA level returned to the normal range, and PET-CT showed no evidence of malignancy. Her progression has been stable for 45 months after diagnosis. In summary, we encountered a case of unresectable gastric cancer with conversion surgery after triplet combination chemotherapy with ITCZ.

[A Case of Long-Term Survival with S-1/Cisplatin for Liver Hilum Lymph Node Metastasis of Anal Canal Squamous Cell Carcinoma after Chemoradiotherapy].

A 70-year-old woman was admitted to a local hospital because of anal pain during defecation. Anoscopy revealed an anal mass lesion, and the patient was referred to our hospital. Colonoscopy revealed an anal canal tumor with ulceration, and biopsy showed squamous cell carcinoma. The patient was treated with chemoradiotherapy(chemotherapy with capecitabine plus mitomycin C and 54 Gy radiation in the anal region)and achieved complete response. However, metastatic recurrence was detected in a lymph node in the hepatic hilar region. We administered an S-1/CDDP combination chemotherapy (5 courses). For 3 years and 5 months since the initial treatment, the patient survived with no signs of recurrence. We report a rare case of long-term survival with S-1/CDDP for distant metastasis of anal canal squamous cell carcinoma after chemoradiotherapy.

[A Rapid Clinical Course of Pulmonary Embolism Associated with Gallbladder Mucinous Carcinoma].

A 51-year-old woman with edema of the lower extremities and exertional dyspnea was admitted to our hospital. Enhanced CT revealed thrombi of the pulmonary artery and a gallbladder tumor. After anticoagulation therapy was started on her, anemia and jaundice progressed; thus, endoscopic retrograde cholangiopancreatography(ERCP)was performed on suspicion of bleeding from a gallbladder tumor. We performed cholecystectomy in emergency to control the anemia due to hemorrhage. Oxygenation suddenly worsened intraoperatively, maintaining her blood pressure became difficult, and the patient decompensated. The histopathological diagnosis was gallbladder mucinous carcinoma with severe lymphatic invasion. Although an autopsy was not performed, pulmonary artery embolism derived from a tumor embolus was the suspected cause of the sudden change of the clinical course.

Neoadjuvant Modified Short-Course Radiotherapy Followed by Delayed Surgery for Locally Advanced Rectal Cancer.

This study aimed to assess the clinical outcomes and predictive factors of neoadjuvant modified short-course radiotherapy (mSC-RT) for locally advanced rectal cancer (LARC). Data from 97 patients undergoing mSC-RT followed by radical surgery for LARC were retrospectively analyzed. A 2.5 Gy dose twice daily up to a total dose of 25 Gy in 10 fractions was administered through mSC-RT, and this was delivered with oral chemotherapy in 95 (97.9%) patients. Radical surgery was performed 6 (range, 3-13) weeks after mSC-RT. The median follow-up among surviving patients was 43 (8-86) months. All patients completed neoadjuvant radiotherapy with no acute toxicity grade ≥ 3. Three- and five-year local control rates were 96.3% and 96.3%, respectively. Three- and five-year overall survival (OS) rates were 92.7% and 79.8%, respectively. Univariate analyses revealed that poor OS was associated with no concurrent administration of capecitabine, C-reactive-protein-to-albumin ratio ≥ 0.053, carcinoembryonic antigen ≥ 3.4 ng/mL, and neutrophil-to-lymphocyte ratio (NLR) ≥ 1.83 (P = 0.045, 0.001, 0.041, and 0.001, respectively). Multivariate analyses indicated that NLR ≥ 1.83 was independently associated with poor OS (p = 0.018). mSC-RT followed by delayed surgery for LARC was deemed feasible and resulted in good clinical outcomes, whereas poor OS was associated with high NLR.

S-1, Oxaliplatin, Nab-paclitaxel and Itraconazole for Conversion Surgery for Advanced or Recurrent Gastric Cancer.

AIM: To evaluate the efficacy of chemotherapy with itraconazole for advanced or recurrent gastric cancer. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2 (HER2) negative unresectable gastric cancer referred to our hospital were included. The regimen comprised 160 mg/m2 nab-paclitaxel i.v. and 100 mg/m2 oxaliplatin i.v. on day 1, 60 mg/m2 S-1 orally on days 1-3, and 400 mg itraconazole orally on days -2 to 2, repeated every 2 weeks for 6-8 cycles. RESULTS: Twenty-three patients aged 40-80 years (median age=68 years) were enrolled, of whom 21 had stomach cancer and two gastroesophageal junction cancer. Regarding stage, two, one, and 20 patients had stage IIIA, IIIB, and IV, respectively. Among patients with liver metastases, 2/10 had simultaneous lung metastases. Nine patients had peritoneal dissemination, and five patients with stage IV disease developed recurrence after primary surgery followed by adjuvant S-1. The other 18 patients had no history of surgery or chemotherapy. The response rate was 70% (complete response in two; partial response in 14). Among 12 patients (67%) who underwent conversion surgery, R0 resection was conducted in eight, and no residual tumour was observed in two. For the population overall, the median overall survival was 24 months (95% confidence intervaI=21 months-not reached) and the 1-year overall survival rate was 95% (95% confidence intervaI=67-98%). Grade 3/4 neutropenia and grade 2 peripheral sensory neuropathy occurred in five (22%) and six (26%) patients, respectively, while no patient developed grade 3/4 thrombocytopenia. CONCLUSION: Chemotherapy with itraconazole is promising for patients with unresectable gastric cancer.

[Hepatectomy for Intrahepatic Combined Hepatocellular Carcinoma Recurrence in a Hemophilia a Patient with Human Immunodeficiency Virus and Hepatitis C Virus-A Case Report].

A 40's Japanese man had a history of blood transfusion and administration of treatment coagulation factors for hemophilia A since he was 6 years old. He has been on IFN treatment for hepatitis C since he was 14 years old. Lastly, he has been undergoing HAART therapy for human immunodeficiency virus infection since he was 18 years old. Three years ago, he underwent partial hepatectomy for a tumor located in segment 8 of his liver and was diagnosed with combined hepatocellular carcinoma(CHC). Two years and 7 months after the operation, 2 intrahepatic recurrences were detected in the left lobe. He was referred to our hospital to undergo curative resection, and we performed a left lobectomy of the liver for the CHC recurrences. Perioperatively, supplemental factor Ⅷ was administered via APTT. Its activity was used as an index. Postoperatively, the patient was well, was discharged 13 days after surgery, and remained recurrence-free for 4 months.

[A Resected Case of Metachronous Solitary Metastasis of Jejunum after Surgery of Triple Colon Cancers].

A 68-year-old man underwent partial colectomy and double-barrel colostomy for an obstructive colon cancer of the splenic flexure at another hospital 10 years before. He was referred to us with an examination of anemia pointed out in human dock. Lower gastrointestinal endoscopy revealed the tumor occupied the remnant descending colon. We performed remnant left hemicolectomy and diagnosed as triple colon cancers. Six months after the initial operation, he was admitted to us with the chief complaints of abdominal fulness and vomit. Abdominal CT and radiologic enteroclysis after decompression used the ileus tube revealed complete stenosis at the small intestine. We performed surgery with a suspicion of obstruction of the small intestine. The tumor, 5 cm in diameter, occupied the jejunum was detected, and partial resection of the jejunum was performed. Histologically, the tumor was diagnosed as solitary metastasis of jejunum.

[A Resected Case of Hilar Cholangiocarcinoma Confirmed as Pathological Complete Response Following Neoadjuvant S-1 Monotherapy].

A 74-year-old man was admitted to a local hospital with liver dysfunction. Imaging modalities revealed bile duct stenosis at the bifurcation of the anterior and posterior trunk. Exfoliative cytology of the bile and brushing cytology of the bile duct both revealed Class Ⅴ, and biopsy from the stenotic bile duct showed well differentiated adenocarcinoma. We diagnosed the patient with hilar cholangiocarcinoma and performed extended right bisectionectomy and biliary reconstruction after percuta- neous transhepatic right portal vein embolization(PTPE). Preoperatively, he was administered S-1(80mg/body weight/day) orally for 19 days. Histopathological assessment of the resected specimen revealed hemosiderin-laden macrophages without viable cancer cells, confirmingpatholog ical complete response(pCR).

The impact of the radiation-induced regression of positive nodes on survival in patients with rectal cancer treated with chemoradiotherapy.

BACKGROUND: Although preoperative chemoradiotherapy exerts a destructive effect on positive lymph nodes, microscopic examination reveals different degrees of tumor regression. The aim of the present study is to investigate the impact of the radiation-induced regression of positive nodes on survival in patients with rectal cancer treated with preoperative chemoradiotherapy. METHODS: From 2001 to 2015, 229 patients with T3 rectal cancer underwent total mesorectal excision after preoperative chemoradiotherapy. The patients were classified into 3 groups according to their lymph node status: residual cancer cells in positive nodes (Group A), total regression of positive nodes after preoperative chemoradiotherapy with complete fibrosis (Group B), and the entire lymph node filled with lymph nodules and the absence of fibrosis (Group C). The survival of the 3 groups was compared, and a Cox model was used to evaluate the prognostic value of the regression of the positive nodes by preoperative chemoradiotherapy. RESULTS: Groups A, B, and C included 57, 18, and 154 patients, respectively. Group B showed significantly better overall survival than Group A (P = .041) and similar outcomes to Group C (P = .383). Among the patients with positive lymph nodes prior to treatment (Groups A and B), the total regression of the positive nodes after preoperative chemoradiotherapy was the only independent factor to be associated with good overall survival (hazard ratio; 6.26, 95% confidence interval; 1.28-113.0, P = .020). CONCLUSION: Total regression of positive nodes by preoperative chemoradiotherapy improves the prognosis of patients with rectal cancer with positive lymph nodes prior to treatment.

Keratin 19-positive cutaneous squamous cell carcinoma with elevated serum cytokeratin 19 fragment 21-1 level: A case report.

cytokeratin 19 fragment 21-1 (CYFRA21-1) is a marker of lung cancer useful for evaluating clinical diagnosis and prognosis. To the best of our knowledge, there have been no reports of cutaneous squamous cell carcinoma (SCC) with high levels of CYFRA21-1 to date. We herein report a case of a 79-year-old man with a large subcutaneous tumor of the left shoulder, which was diagnosed as primary cutaneous poorly differentiated SCC. The tumor nests were composed of poorly differentiated atypical squamous cells exhibiting high-grade malignancy and mitotic figures; multinuclear cells were also identified inside lymph vessels. Keratin 19 (K19) was intensely expressed in tumor cells. A significantly elevated level of CYFRA21-1 (33 ng/ml) was observed preoperatively. After surgery, the level of CYFRA21-1 was significantly decreased (from 33 to 5.0 ng/ml). Our case demonstrated that K19-positive primary cutaneous undifferentiated SCC induced high levels of CYFRA21-1 in the serum. Thus, CYFRA 21-1 may be a marker indicative of poorly differentiated cutaneous SCC exhibiting K19 expression.

Milia may originate from the outermost layers of the hair bulge of the outer root sheath: A case report.

It has been hypothesized that milia originate from the hair bulge of the outer root sheath. To elucidate the histogenesis of milia, an immunohistochemical study was performed using anti-keratin and anti-filaggrin antibodies to determine the levels of keratin and filaggrin expression. Keratin expression was evaluated using anti-keratin antibodies against K1, K7, K8, K10, K14, K15, K16, K17, K18, K19 and K20. K1 and K10 expression were detected in the suprabasal layers of the more superficial section of the cyst walls, but not in the deeper section of the cyst walls. However, K14 and K17 were expressed in all layers of the cyst walls. Notably, K15 was expressed in the outermost layer of the deeper section of the cyst walls and hair germ structure, whereas filaggrin was expressed in the superficial layer of the more superficial section of the cyst walls. Therefore, the pattern of keratin and filaggrin expression indicates that milia may originate from the outermost cells of the hair bulge of the outer root sheath.

Comparison of the pathological response of the mesorectal positive nodes between short-course chemoradiotherapy with delayed surgery and long-course chemoradiotherapy in patients with rectal cancer.

BACKGROUND: The aim of this study was to compare the pathological response of mesorectal positive nodes between short-course chemoradiotherapy with delayed surgery (SCRT-delay) and long-course chemoradiotherapy (LC-CRT) in patients with rectal cancer. METHOD: The resected primary tumor specimens following the two different approaches were assessed utilizing the tumor regression grade (TRG 0-4), and each positive lymph node was assessed according to the lymph node regression grade (LRG 1-3), with TRG 4 and LRG 3 indicating total regression. The lymph node sizes were measured to elucidate any correlation with LRG scores. RESULTS: Seventy-four patients with ypN-positive rectal cancer had 220 positive lymph nodes following the SCRT-delay, and 48 patients had 141 positive lymph nodes following the LC-CRT. The distribution of LRG 1/2/3 in the two groups was 123/72/25 and 60/31/50 (p < 0.001), respectively, and the distribution of TRG 0/1/2/3/4 in the two groups was 36/19/19/0 and 12/15/20/1 (p = 0.005), respectively. The requirements of total regression of positive lymph nodes were a primary tumor degenerated to TRG 3 with a size less than 6 mm in SCRT-delay (sensitivity, 60.9 %) or a primary tumor degenerated to TRG 2-4 with a size less than 5 mm at TRG 2 (sensitivity, 57.6 %) or 6 mm at TRG 3 and 4 (sensitivity, 84.2 %) in LC-CRT as indicated by the receiver operating characteristic curve analysis. CONCLUSION: The tumor regression effect of LC-CRT on the primary tumor and positive nodes was more favorable than SCRT-delay, and LC-CRT is able to predict the LRG 3 response with a high sensitivity.

Short-course radiotherapy with delayed surgery versus conventional chemoradiotherapy: A comparison of the short- and long-term outcomes in patients with T3 rectal cancer.

INTRODUCTION: The aim of this study was to compare the short- and long-term outcomes between short-course radiotherapy with delayed surgery (SRT-delay) and a standard conventional chemoradiotherapy (CRT) regimen. METHODS: Two collaborating institutions adopted different regimens; the SRT-delay regimen was selected by Meiwa Hospital and the CRT regimen was selected by Hyogo College of Medicine. The inclusion criteria were T3 middle and low rectal cancer patients treated with radical surgery after preoperative therapy. The median follow-up period was 44 months (range, 12-85). RESULTS: From 2007 to 2013, 104 patients were treated using the SRT-delay regimen and 61 patients were treated using the CRT regimen. The pretreatment characteristics of the 2 groups were not significantly different. The sphincter-preserving rate (93.3%, 85.2%), T downstaging (37.5%, 37.7%), ypN(-) (74.0%, 67.2%), postoperative complications and the bowel, and urinary and sexual functioning of the SRT-delay regimen were noninferior to those of the CRT regimen. The 3-year local recurrence-free survival, recurrence-free survival, and overall survival in the SRT-delay and CRT groups were 90.6% and 90.6% (P = .764), 83.8% and 78.3% (P = .687) and 96.0% and 92.8% (P = .833), respectively. CONCLUSION: The SRT-delay regimen was noninferior in terms of the downstaging effect, and oncologic and functional outcomes compared with the CRT regimen for T3 middle and low rectal cancer.

Feasibility of modified short-course radiotherapy combined with a chemoradiosensitizer for T3 rectal cancer.

BACKGROUND: 5-Fluorouracil-based chemotherapy is considered to be a radiosensitizer; however, conventional short-course radiotherapy combined with chemotherapy is generally thought to not be feasible because of the prevalence of side effects. OBJECTIVE: The aim of this study was to evaluate the feasibility of modified short-course radiotherapy combined with a chemoradiosensitizer for T3 rectal cancer. DESIGN AND SETTINGS: This study was retrospective in nature and used a prospectively collected database. PATIENTS: Patients with T3 rectal cancer located below the peritoneum reflection were selected. INTERVENTIONS: A total dose of 25 Gy of radiotherapy was administered in 10 fractions of 2.5 Gy each for 5 days. Radiotherapy was performed with S-1 as a radiosensitizer from day 1 to day 10. Surgery was targeted to be performed 4 weeks after radiotherapy. MAIN OUTCOME MEASUREMENTS: The morbidity, sphincter-preserving rate, anal function, and long-term outcomes were assessed. RESULTS: All patients (n = 170) completed the radiotherapy regimen and 166 (97.6%) completed the combination regimen with chemotherapy. A total of 149 patients (87.6%) had sphincter-preserving surgery (double stapling technique (DST), 58 patients; intersphincteric resection (ISR), 91 patients), and postoperative complications were relatively mild (anastomotic leakage, 15.4%; intra-abdominal infection, 8.2%). Among those undergoing sphincter preserving surgery, the 5-year local relapse-free survival rate was 94.3% in the DST group, and 89.8% in the ISR group. With respect to the anal function, the Wexner score the first year after stoma closure for the double-stapling technique group was 6 and that for intersphincteric resection was 15; however, the score for the intersphincteric resection group was improved to 8 at 4 years after stoma closure. LIMITATIONS: This study had limitations because it was an uncontrolled, 1-arm, retrospective review with a small sample size. CONCLUSIONS: Modified short-course radiotherapy combined with chemoradiosensitizer is a feasible approach for treating T3 rectal cancer. With the use of the short-course approach, efforts to reduce the incidence of side effects by appropriately prolonging the waiting period enable the administration of combination treatment with short-course radiotherapy and chemotherapy.

Pathologic evaluation of the response of mesorectal positive nodes to preoperative chemoradiotherapy in patients with rectal cancer.

BACKGROUND: The response of positive mesorectal lymph nodes to chemoradiotherapy remains largely unstudied in patients with rectal cancer. The aim of this study was to investigate the requirements of the total regression of positive nodes treated with chemoradiotherapy. METHODS: The response of the primary tumor was evaluated according to the tumor regression grade (TRG 0-4) in resected specimens, and positive lymph nodes were assessed according to the lymph node regression grade (LRG 1-3), with TRG 4 and LRG 3 indicating total regression. We investigated the relationships among TRG, LRG, and the sizes of positive lymph nodes. RESULTS: Among 178 patients, 68 (38.2%) had 200 positive lymph nodes. We first investigated the relationship of positive nodes to TRG and LRG and found that the response of the primary tumor to chemoradiotherapy correlated with the response of positive nodes. Next, we investigated the correlation between LRG and the size of positive nodes. At TRG 1 and 2, LRG score was not correlated with the positive node size. In contrast, at TRG 3, LRG score was correlated with the size of positive nodes. Next, our assessment of the relationship between the sizes of positive nodes and complete degeneration to LRG 3 showed that the most accurate cut-off score on receiver-operator-characteristics curve analysis was 6 mm in maximum diameter for TRG 3. CONCLUSION: The requirements of the total regression of positive nodes are 1) degeneration of the primary tumor to TRG 3 and 2) a positive node diameter of <6 mm.

[A case of disease-free, long survival in a patient with mixed adenoneuroendocrine carcinoma of the gallbladder treated with induction CDDP/CPT-11 chemotherapy and resection].

A 57-year-old woman with a complaint of a right upper quadrant mass was referred to our hospital. Multimodal studies such as PET-CT revealed large hepatic tumors and swollen para-aortic lymph nodes, the origin of which was unclear. Pathological analysis of a biopsy specimen obtained from the liver tumor led to a diagnosis of neuroendocrine carcinoma. After 4 CDDP/CPT-11 chemotherapy treatment courses, remarkable shrinkage of liver tumors and disappearance of the swollen lymph nodes were achieved. Subsequently, liver tumor and extrahepatic bile duct resection and lymphatic dissection were performed. Pathological analysis of the resected specimens revealed that the liver tumors and metastatic lymph nodes originated from the gallbladder, leading to a diagnosis of mixed adenoneuroendocrine carcinoma. After 5 courses of adjuvant chemotherapy using the same regimen, the patient has remained disease free for 24 months since the initialdiagnosis.

Epithelial keratin and filaggrin expression in seborrheic keratosis: evaluation based on histopathological classification.

OBJECTIVES: Seborrheic keratosis (SK) is classified into six types: hyperkeratotic; acanthotic; irritated; clonal; reticulated; and adenoid. However, the origins of the respective types of SK remain unclear. METHODS: To clarify the histogenetic origins of SK, we performed immunohistochemical studies of keratin (K) and filaggrin expression, taking into account the histopathological classifications of SK. RESULTS: Hyperkeratotic SK mainly expressed K1, K10, and filaggrin. Acanthotic SK mainly expressed K14 with some K15. Irritated SK mainly expressed K14 and K17 in squamous eddies. Clonal SK, reticulated SK, and adenoid SK mainly expressed K14. The results show that hyperkeratotic SK differentiated towards squamoid terminal keratinization, whereas acanthotic, irritated, clonal, reticulated, and adenoid SK mainly differentiated towards basaloid undifferentiated cells. In addition, acanthotic SK differentiated towards the hair bulge, and irritated SK differentiated towards the follicular infrainfundibulum. CONCLUSIONS: Based on the patterns of keratin and filaggrin expression demonstrated by the histopathological types, SK demonstrated diverse differentiation towards epidermal keratinization, basaloid cells, the infrainfundibulum and hair follicle bulges, which suggests that SK is in an undifferentiated and hyperproliferative state with heterogeneous differentiation. The immunohistochemical method of investigating patterns of keratin expression is useful in the differential diagnosis of cutaneous epithelial tumors.

Keratin Expression in Mammary Paget's Disease in situ with Intraductal Invasion.

We performed immunohistochemical studies of epithelial keratins in intraductal carcinoma in situ (IDCIS) in mammary Paget's disease (MPD). K7, K8 and K18 were expressed in IDCIS in MPD. However, K19 was not expressed in IDCIS in MPD. Interestingly, K17 was expressed in some tumor cells in IDCIS. K17, a hyperproliferative keratin, may suggest ductal invasion and poor prognosis in MPD.