Association between circ_0004365 and cisplatin resistance in esophageal squamous cell carcinoma.

Cisplatin is one of the most predominant drugs for the chemotherapy of esophageal squamous cell carcinoma (ESCC); however, the underlying resistance mechanisms are still almost unknown. The present study performed RNA sequencing of human circular RNA (circRNA) in TE11 cells and cisplatin-resistant TE11 cells (TE11R). The expression profiles determined using CIRCexplorer2 revealed that the expression of circ_0004365, mapped on the Semaphorin 3C gene, was significantly greater in TE11R compared with in TE11. In reverse transcription-quantitative PCR, circ_0004365 expression was observed in human ESCC and non-tumor tissues and was significantly upregulated in ESCC tumor tissues after chemotherapy. Circ_0004365 expression was significantly upregulated in patients with poor pathological response (P=0.02). Furthermore, patients with advanced pT stage showed an upregulation in circ_0004365 expression after chemotherapy (P=0.02). The MTT assay revealed that knockdown of circ_0003465 in TE11 significantly decreased resistance to cisplatin. In conclusion, the present study suggested that circ_0004365 was associated with cisplatin resistance in ESCC and can be used as both a novel biomarker and a therapeutic target.

Neutrophil-to-lymphocyte ratio after neoadjuvant chemotherapy as an independent prognostic factor in patients with esophageal squamous cell carcinoma.

Studies have shown that neoadjuvant chemotherapy (NAC) followed by surgical resection improves the survival of patients with esophageal squamous cell carcinoma (ESCC), and that the neutrophil-to-lymphocyte ratio (NLR) nay be a prognostic biomarker in various types of cancer. Despite the noTable changes in the tumor and its microenvironment during NAC, it remains unclear how the NLR changes and which values (before or after NAC) best predict prognosis. The present study aimed to analyze changes in the NLR before and after NAC, and to determine which was a better prognostic factor. This study retrospectively analyzed 338 consecutive patients with ESCC who received NAC followed by curative resection. NLRs before (pre-NLR) and after (post-NLR) NAC were calculated, after which the impact of NAC on NLR, overall survival (OS) and recurrence-free survival (RFS), as well as the relationship between hematological toxicities and NLR, was evaluated. Cutoff values for pre- and post-NLR were 3.7 and 2.5, respectively. Patients with high post-NLR had a worse OS (P=0.0001) and 3-year RFS (P=0.03) than those with low post-NLR. Multivariate analysis identified high post-NLR, pN1 and clinical response as independent prognostic factors. In conclusion, post-NLR was revealed as a better prognostic factor than pre-NLR for patients receiving NAC followed by surgical resection.

Bromodomain protein BRDT directs ΔNp63 function and super-enhancer activity in a subset of esophageal squamous cell carcinomas.

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer with a particularly high prevalence in certain geographical regions and a poor prognosis with a 5-year survival rate of 15-25%. Despite numerous studies characterizing the genetic and transcriptomic landscape of ESCC, there are currently no effective targeted therapies. In this study, we used an unbiased screening approach to uncover novel molecular precision oncology targets for ESCC and identified the bromodomain and extraterminal (BET) family member bromodomain testis-specific protein (BRDT) to be uniquely expressed in a subgroup of ESCC. Experimental studies revealed that BRDT expression promotes migration but is dispensable for cell proliferation. Further mechanistic insight was gained through transcriptome analyses, which revealed that BRDT controls the expression of a subset of ΔNp63 target genes. Epigenome and genome-wide occupancy studies, combined with genome-wide chromatin interaction studies, revealed that BRDT colocalizes and interacts with ΔNp63 to drive a unique transcriptional program and modulate cell phenotype. Our data demonstrate that these genomic regions are enriched for super-enhancers that loop to critical ΔNp63 target genes related to the squamous phenotype such as KRT14, FAT2, and PTHLH. Interestingly, BET proteolysis-targeting chimera, MZ1, reversed the activation of these genes. Importantly, we observed a preferential degradation of BRDT by MZ1 compared with BRD2, BRD3, and BRD4. Taken together, these findings reveal a previously unknown function of BRDT in ESCC and provide a proof-of-concept that BRDT may represent a novel therapeutic target in cancer.

A case of mixed adenoneuroendocrine carcinoma of the pancreas: Immunohistochemical analysis for histogenesis.

RATIONALE: Tumors with multiple histological features, such as adenocarcinomas and neuroendocrine carcinomas, were included as a new category of neuroendocrine carcinomas in the 2010 World Health Organization classification. We recently experienced a rare case of a pancreatic carcinoma with both adenocarcinoma and neuroendocrine carcinoma components, a so-called mixed adenoneuroendocrine carcinoma. PATIENT CONCERNS AND DIAGNOSIS: A 66-year-old man was referred to our hospital with obstructive jaundice. Contrast-enhanced computed tomography images indicated a tumor located at the pancreatic head measuring 3.0 × 2.5 cm in diameter and invading the common bile duct. Cytological examination of the bile juice obtained by endoscopic retrograde cholangiopancreatography revealed adenocarcinoma cells. Pancreaticoduodenectomy was performed safely as radical resection. INTERVENTIONS: Microscopically, the resected tumor consisted of tightly intermingled adenocarcinoma and neuroendocrine carcinoma components. On the immunohistochemical examination, p53 was ubiquitously positive in both components, whereas chromogranin A, synaptophysin and neuron-specific enolase, neuroendocrine markers, were limited to the neuroendocrine carcinoma component. OUTCOMES: Thus, such features of both adenocarcinoma and neuroendocrine carcinoma observed microscopically and immunohistochemically seemed to indicate a composite tumor. LESSONS: The findings of this case suggest that adenocarcinoma and neuroendocrine carcinoma may be derived from a single cancer stem cell.

[A Case of Metachronous Liver Metastases of Gall Bladder Cancer Successfully Treated by Liver Resection].

A 73-year-old woman was diagnosed with gall bladder cancer by contrast enhanced CT images.The tumor was detected at the fundus of the gall bladder and enhanced heterogeneously.She underwent radical cholecystectomy including Japanese D2 lymph node dissection for gall bladder cancer.After 4 courses of oral S-1(80mg/m2 administered for 4 weeks and then stopped for 2 weeks)as adjuvant chemotherapy, a liver metastasis at segment 5 appeared 11 months postoperatively.It showed a ring enhanced tumor on contrast enhanced CT images.FDG accumulated in a similar lesion on PET-CT images.The patient successfully underwent partial hepatectomy of segment 5 of the liver.However, another liver metastasis at segment 7 appeared 5 months after the second operation, but it was resected successfully.The primary lesion and both liver metastases showed similar microscopic appearances.Seven courses of gemcitabine therapy(gemcitabine 1,000mg/m2 once every week for 3 weeks and then stopped for 1 week)were administered as adjuvant chemotherapy.She is now doing well without any sign of recurrence 2 years after the initial operation and 14 months after the secondary liver resection.

[A Case of Gastric Cancer with Multiple Liver Metastases Treated with XP Chemotherapy and RFA Resulting in a Complete Response for a Long Time].

A 60-year-old man underwent total gastrectomy with Japanese D2 lymph node dissection for advanced gastric cancer. The resected specimen was diagnosed as well-differentiated tubular carcinoma, pT3, pN1, cM0, and the final stage was considered as ⅡB. During adjuvant chemotherapy with S-1 (120 mg/day, administered for 4 weeks and then stopped for 2 weeks), multiple liver metastases were detected by contrast-enhanced CT images 6 months after the operation. Eight courses of XP therapy (capecitabine 1,600 mg/m2/day: day 1-14, cisplatin 70 mg/m2/day: day 1, then stopped until days 15-21) were administered in consideration of the recurrence during adjuvant chemotherapy with S-1, resulting in a partial response. Adverse events such as grade 1-2 abdominal pain, general fatigue, and the resultant deterioration of ADL led to discontinuation of chemotherapy. The residual liver metastasis was treated with RFA therapy, causing it to disappear completely. Serum CEA level was 5.5 ng/mL postoperatively, elevated to 13.9 ng/mL at the time of recurrence and 2.4 ng/mL after XP and RFA therapy. He is doing well without any recurrence 2 years and 6 months later.

[A Case of Pancreatic Cancer with Multiple Liver Metastases That Developed Postoperatively and Showed a Complete Response with S-1 Monotherapy].

We encountered a case of pancreatic cancer with multiple liver metastases that developed postoperatively and showed a complete response with S-1 monotherapy for a long time. A pancreaticoduodenectomy was successfully performed on an 80- year-old man. Multiple liver metastases developed 6 months postoperatively. Microscopically, the primary lesion was diagnosed as adenosquamous carcinoma with anaplastic carcinoma component, and the final diagnosis was considered to be Stage Ⅲ disease. S-1monotherapy (80 mg/day, administered for 4 weeks and then stopped for 2-weeks) was effective. A partial response was noted after 3 months, and 9 months after the initial administration of S-1, a complete response was achieved, which persisted for more than 12 months, according to contrast-enhanced CT evaluations.Serum CEA and CA19-9 levels, which became slightly elevated at the time of liver metastasis development, normalized promptly and remained within normal limits. Adverse effects of chemotherapy of more than grade 2 severity were not apparent, and the patient tolerated the 11th course of S-1 administration, consistently. A standard therapeutic strategy and its outcomes in cases of pancreatic cancer recurrence are not clearly outlined in the Japanese Guideline for the Treatment of Pancreatic Cancer. A case of pancreatic cancer with multiple liver metastases that developed postoperatively and showed a complete response with S-1 monotherapy is reported in this paper.

[A Case of Unresectable Rectal Cancer Associated with Hemorrhage of the Primary Tumor after Chemotherapy].

A 47-year-old man visited our hospital with complaints of abdominal pain and hematuria.He was diagnosed with unresectable rectal cancer invading the urinary bladder with multiple liver metastases. Systemic chemotherapy with mFOLFOX6 and panitumumab was started soon after sigmoid colostomy. Three months later, both the primary tumor and the liver metastases had partially responded. Another 2 months later, he complained of terrible abdominal pain. CT images revealed a huge primary tumor and hemorrhage in the sigmoid mesocolon occupying the pelvic cavity. A salvage operation was performed and the primary tumor was palliatively resected. Soon after the operation, a local recurrence appeared and grew rapidly. He died 8 months after diagnosis. Rapid growth of the primary tumor seemed a limiting factor for the prognosis.

[A Case of Recurrence of Rectal Cancer with Para-Aortic Lymph Node Metastases Successfully Resected Resulting in Long Term Survival].

Laparoscopy-assisted low anterior resection (Japanese D3 lymph node dissection) was performed to treat a 68-year-old man for rectal cancer. Microscopically, the resected specimen was diagnosed as a moderately differentiated adenocarcinoma and the final stage was considered as pT3, pN1, cM0, pStage Ⅲa. He was administered capecitabine for 6 months as adjuvant chemotherapy. Then, enlarged para-aortic lymph nodes, indicated by follow up CT at 1 year and 11 months postoperatively developed behind the left renal artery. FDG accumulated in it, consistent with the CT images. Para-aortic lymph node dissection was performed after the diagnosis of solitary lymph node metastases. Microscopically, the resected lymph nodes showed features similar to the primary lesion. He is doing well without recurrence for 4 year and 6 months, without any adjuvant chemotherapy. Para-aortic lymph node metastases are frequently associated with other distant metastases; if not, a complete cure may be possible by curative resection for solitary metastases.

[Concomitant use of romiplostim and chemotherapy for advanced rectal cancer associated with idiopathic thrombocytopenic purpura].

A woman in her 60s was referred to our department with advanced rectal cancer and multiple unresectable metastases of the liver and peritoneum. She had been diagnosed with idiopathic thrombocytopenic purpura (ITP) in her 20s, with a platelet count maintained at approximately 1.0×10(4)/µL by prednisolone; on admission, her platelet count was 0.9×10(4)/µL. Romiplostim, a thrombopoietin receptor agonist, was administered prior to chemotherapy. Her platelet count increased to approximately 10.0×10(4)/µL during chemotherapy with oxaliplatin plus capecitabine, and she developed deep venous thrombosis requiring inferior vena cava filter placement and anticoagulation. No other severe adverse events occurred. There is no standard regimen for the treatment of solid tumors in patients with ITP. This is the first reported case of the concomitant use of romiplostim and chemotherapy for advanced rectal cancer. We believe that romiplostim can effectively salvage the platelet count in emergency situations such as during chemotherapy.

[A case of locally advanced rectal carcinoma treated with preoperative chemoradiotherapy resulting in pathologically complete response].

An 84-year-old woman presented with the chief complaint of melena. Colonoscopy revealed a type 2 tumor that circumferentially occupied the lumen of the lower rectum about 6 cm from the anal verge. A biopsy specimen was obtained from the tumor and the patient was diagnosed with moderately differentiated adenocarcinoma. Computed tomography revealed that the rectal cancer had invaded the marginal fatty tissue, accompanied by several regional lymph node metastases with no distant metastasis. On the basis of this evidence, the tumor was staged as cT4a, cN2b, cM0 according to the TNM Classification of Malignant Tumors (7th Edition, UICC). Preoperative radiotherapy combined with an oral chemopreventive agent (RT 1.8 Gy × 25 frames; total 45 Gy, S-1 80 mg/day) was administered with trivial adverse effects. Laparoscopy-assisted low anterior resection with Japanese D3 dissection was performed successfully. The patient is doing well without recurrence after 14 months of surgery. Histological examination revealed that both the primary lesion and regional lymph nodes had no residual cancer; that is, the histological effect of the preoperative chemoradiotherapy was a pathologically complete response (pCR).

[A case of colon cancer with multiple liver metastases showing a long-term response following first-line therapy].

A 71-year-old man presented with sigmoid colon cancer and multiple unresectable liver metastases. As the sigmoid colon cancer caused anemia, we performed laparoscopic-assisted sigmoidectomy prior to the administration of systemic chemotherapy. Bevacizumab (Bv) plus modified Leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) was administered as first line therapy.At 3 months from the start of chemotherapy, computed tomography revealed that the size of the liver metastases reduced by 49.45%, as evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). The only adverse event observed was Grade 1 peripheral neuropathy after the eighth dose of oxaliplatin.As the progression of peripheral neuropathy was observed at the ninth dose of oxaliplatin, oxaliplatin was omitted from further therapy; the patient was converted to maintenance therapy with simplified biweekly Leucovorin and fluorouracil (sLV5FU2). Bv plus mFOLFOX6 followed by sLV5FU2 for first-line therapy was effective for disease management over 23 months, but a partial response (PR) was the best overall response achieved.