Primary duodenal carcinoma suspected to arise from ectopic gastric mucosa: a case report.

BACKGROUND: Ectopic gastric mucosa mainly occurs in the duodenal bulb, and its etiology is thought to be congenital straying of gastric tissues. Primary duodenal carcinoma is a rare disease; however, reports of carcinoma arising from ectopic gastric mucosa are extremely rare. We report a case of primary duodenal carcinoma suspected to arise from ectopic gastric mucosa, which discovered as a result of duodenal stenosis. CASE PRESENTATION: The patient was a 71-year-old man with persistent weight loss and white stools. Enhanced computed tomography showed stenosis of the third portion of the duodenum and main pancreatic duct dilatation. Upper gastrointestinal endoscopy revealed irregularity of the duodenal mucosa from the anorectal side of the papilla of Vater to the stenosis of the third portion. No malignant cells were found by biopsies from the duodenal mucosa. Endoscopic ultrasonography did not detect the tumor in the pancreatic head. The possibility of a pancreatic tumor could not be ruled out based on findings of main pancreatic duct dilatation in the pancreatic head, and the patient had long-term poor oral intake because of duodenal stenosis; thus, surgical treatment was planned. Intraoperative findings showed palpable induration of the third portion of the duodenum and white nodules on the serosal surface. This was diagnosed as primary duodenal carcinoma, and pylorus-preserving pancreatoduodenectomy was performed. Histopathological diagnosis revealed ectopic gastric mucosa in the papilla of Vater and well-differentiated tubular adenocarcinoma invaded the normal duodenal submucosa and extended to the duodenal serosa. No mass lesion was detected in the pancreas, and an intraductal papillary mucinous neoplasm was observed in the branch pancreatic duct. The main pancreatic duct stricture was caused by the duodenal carcinoma invasion. CONCLUSIONS: This case of primary duodenal carcinoma was suspected to arise from ectopic gastric mucosa and review the relevant literature.

RAB11A Expression Is Associated With Cancer Aggressiveness Through Regulation of FGFR-Signaling in Lung Squamous Cell Carcinoma.

BACKGROUND: Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling. METHODS: Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo. RESULTS: The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells. CONCLUSION: As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors.

Successful Treatment of Pancreatic Fistula Following Surgery for Congenital Biliary Dilatation with Endoscopic Ultrasound-Guided Transduodenal Drainage.

Despite improvements in surgical techniques and perioperative management, postoperative pancreatic fistula (PF) is often difficult to treat and can be fatal due to various complications without effective drainage. Here, we report a case of PF following surgery for congenital biliary dilatation (CBD) successfully managed by endoscopic ultrasound (EUS)-guided transduodenal drainage. A 55-year-old woman underwent extrahepatic bile duct resection, including the gallbladder, and biliary tract reconstruction for CBD. On the 10th postoperative day (POD), computed tomography (CT) showed fluid retention observed from the upper edge of the pancreatic head to the surface of the right lobe of the liver. First, percutaneous fine-needle aspiration was performed on the fluid retention in the lateral part of the liver on the 11th POD. The amylase level in the drainage was high (30,156 U/L), and we diagnosed it as PF. Percutaneous drainage was difficult for fluid retention on the cut surface of the pancreas; thus, drainage under EUS guidance was decided. On the 13th POD, EUS was performed, a scan of the duodenal bulb revealed fluid retention with debris inside, and approximately 20-mL fluid was aspirated (amylase: 139,200 U/L). Although the inflammatory response temporarily improved, it recurred, so we decided to perform continuous drainage. On the 21st POD, EUS was performed again; a 19-G needle was used; a 0.025-in angle-type Jagwire was advanced into the fluid retention and expanded using a 7-Fr dilator; and then, a 6-Fr endoscopic nasoabscess drain (ENAD) tube was placed. On the 29th POD, CT showed that the fluid retention on the upper edge of the head of the pancreas had shrunk to a thickness of approximately 20 mm. On the 30th POD, the patient started eating. The ENAD tube was removed on the 38th POD. The patient was discharged from the hospital on the 45th POD without any symptoms. EUS-guided transduodenal drainage is an effective treatment option for postoperative PF following surgery for CBD.

Advantages of additional PET vs. MRI in the clinical diagnosis of anterior mediastinal tumors.

The present study retrospectively examined the diagnostic utility of adding positron emission tomography (PET) or magnetic resonance imaging (MRI) to computed tomography (CT) alone for preoperative diagnosis of anterior mediastinal tumors. A total of 104 consecutive patients who had undergone surgical resection of anterior mediastinal tumors were divided into two groups: Additional PET to another modality and no additional PET to another modality, and further subdivided into three groups: CT alone, additional MRI to CT and additional PET to CT. The sensitivity, specificity, and accuracy for diagnosing malignant tumors in each subgroup was calculated. Comparing the two groups, the diagnostic sensitivity was similar for additional PET (98.0%) and no additional PET (95.2%) groups; however, the specificity and accuracy for additional PET (75.0 and 92.2%, respectively) were significantly improved compared with no additional PET (31.6 and 65.0%, respectively). In the subgroup analysis, adding PET to CT showed an improvement in specificity and positive predictive value for detecting malignant tumors, compared with either additional MRI to CT or CT alone. Additional PET, but not MRI, has advantages over CT alone in clinically distinguishing benign from malignant tumors of the mediastinum.

Successful treatment of enterocutaneous fistula after esophagectomy with scopolamine ointment and negative pressure wound therapy: a case report.

BACKGROUND: Despite improved surgical techniques and perioperative management, anastomotic leakage (AL) after esophageal cancer surgery remains a potential complication. In most cases, spontaneous healing upon proper drainage is observed, but sometimes, AL results in intractable enterocutaneous fistulas. We here report a case of intractable enterocutaneous fistula caused by post-esophagectomy AL and successfully treated by scopolamine ointment and negative pressure wound therapy (NPWT). CASE PRESENTATION: A 77-year-old man underwent thoracoscopic subtotal esophagectomy with 3-field lymph node dissection, followed by gastric tube reconstruction through the posterior mediastinal route. On the 6th postoperative day, AL was identified, forming an enterocutaneous fistula. Initially, conservative treatment was performed, but the fistula failed to close. We hypothesized that the substantial amount of exudate might be hampering fistula closure. Scopolamine ointment was used to reduce the amount of fluid. NPWT was also initiated to promote wound healing. Approximately 3 weeks after the beginning of the treatment, the fistula closed; oral intake became possible, and the patient was discharged from the hospital without any symptoms. CONCLUSIONS: The combination of scopolamine ointment and NPWT may be regarded as one effective treatment option for intractable enterocutaneous fistula due to AL after esophagectomy.

Quantitative analysis of metabolic parameters at 18F-fluorodeoxyglucose positron emission tomography in predicting malignant potential of anterior mediastinal tumors.

To evaluate the utility of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for predicting the malignancy of anterior mediastinal tumors, the present study retrospectively examined a total of 105 consecutive patients who underwent surgical resection of anterior mediastinal tumors at Gunma University Hospital after undergoing a preoperative FDG-PET scan. Patients were divided into benign and malignant groups in accordance with the following three classification systems: i) Clinical classification, benign or malignant (thymoma and carcinoma); ii) recurrence-based classification, low-risk recurrence (benign and low-risk thymoma) or high-risk recurrence (high-risk thymoma and carcinoma); and iii) pathological classification, benign (benign and thymoma) or malignant (carcinoma). The present study analyzed the differences between the benign and malignant groups in terms of FDG-PET parameters, including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). The malignant group exhibited a significantly greater SUVmax than the benign group according to all classification systems. By contrast, there was only a slight difference between groups in volume-based metabolic parameters (MTV and TLG) using the clinical classification, and no intergroup differences using the recurrence-based and pathological classifications. The area under the curve in receiver-operating characteristic curve analysis for predicting malignancy was significantly greater for SUVmax than for volume-based metabolic parameters using all classification methods. The respective optimal cut-off value, sensitivity and specificity of SUVmax to predict malignancy were 1.77, 92.0 and 87.0% for the clinical classification, 2.54, 93.6 and 60.3% for the recurrence-based classification, and 5.15, 78.9 and 90.7% for the pathological classification. SUVmax was the most useful parameter for predicting the malignancy of anterior mediastinal tumors.

Cancer exosomal microRNAs from gefitinib-resistant lung cancer cells cause therapeutic resistance in gefitinib-sensitive cells.

PURPOSE: Exosomes and their cargo microRNAs play a significant role in various biological processes in cancer. We hypothesized that microRNAs in exosomes secreted by gefitinib-resistant lung cancer cells might induce resistant phenotypes in otherwise gefitinib-sensitive lung cancer cells. METHODS: We isolated exosomes generated by the gefitinib-resistant human lung adenocarcinoma cell line PS-9/ZD. PC-9, which is a gefitinib-sensitive cell line, was treated with the PC-9/ZD exosomes, and these PC-9 cells were analyzed for cell proliferation after treatment with gefitinib. miRNA arrays were analyzed in PC-9 and PC-9/ZD cells, and we isolated microRNAs that were expressed at elevated levels in PC-9/ZD cells. Furthermore, we transfected these microRNAs into PC-9 cells and analyzed the effects on the cells' sensitivity to gefitinib. RESULTS: Exosomes isolated from PC-9/ZD cells significantly increased the proliferation of PC-9 cells during gefitinib treatment. A microRNA array analysis showed that miR-564, miR-658, miR-3652, miR-3126-5p, miR-3682-3p and miR-6810-5p were significantly upregulated in PC-9/ZD cells. PC-9 cells transfected with miR-564 or miR-658 showed chemo-resistant phenotypes. CONCLUSION: Exosomal miR-564 and miR-658 derived from gefitinib-resistant lung cancer cells induce drug resistance in sensitive cells. Cell-to-cell interaction via exosomal microRNAs may be a novel mechanism and therapeutic target of resistance against gefitinib.

Skeletal muscle mass predicts the outcome of nivolumab treatment for non-small cell lung cancer.

Nivolumab, a monoclonal antibody targeting programmed cell death-1, significantly prolongs survival for patients with advanced non-small-cell lung cancer (NSCLC). However, little is known about the value of predictive biomarkers. Hence, we investigated the impact of skeletal muscle (SM) mass loss on clinical outcomes in NSCLC patients undergoing nivolumab treatment. Thirty patients with histologically confirmed NSCLC treated with nivolumab were included in this study. Computed tomography was used to determine SM loss based on the SM index (SMI). The SMI is the cross-sectional area of the bilateral psoas muscles at the third lumbar vertebra, divided by height squared. The cut-off values were defined as 6.36 cm/m for men and 3.92 cm/m for women. Among the 30 patients, 13 (43%) had SM loss. There was no significant association between SM loss and immune-related adverse events. The SM loss group had undergone significantly more prior chemotherapy cycles (P = .04). SM loss was significantly associated with fewer nivolumab cycles (P = .01). No patients in the SM loss group achieved a partial response. Patients with SM loss had a significantly shorter progression-free survival period (P = .008) and median overall survival than those with normal SM mass (10 vs 25 months, respectively, P = .03). SM loss was an independent prognostic factor of poor survival. In conclusion, SM loss may be a predictive factor of poor outcomes in NSCLS patients undergoing nivolumab therapy.

Medial-basal segment (S7)-sparing right basal segmentectomy.

The technique of medial-basal segment (S7)-sparing basal segmentectomy has not previously been reported. Herein we report the technical details of thoracoscopic anatomical basal segmentectomy preserving S7 in patients with B7ab branching pattern.

Significance of RAS mutations in pulmonary metastases of patients with colorectal cancer.

BACKGROUND: RAS/BRAF mutations of colorectal cancer (CRC) play a crucial role in carcinogenesis and cancer progression and need to be considered for the therapeutic strategy choice. We used next-generation-sequencing (NGS) technology to assess RAS/BRAF mutation differences between primary CRC and corresponding pulmonary metastases (PMs). METHODS: We examined the mutation statuses of the KRAS 12/13/61/146, NRAS 12/13/61/146, and BRAF 600 codons in genomic DNA from fresh-frozen or formalin-fixed paraffin-embedded tissues derived from 34 primary lesions and 52 corresponding PMs from 36 patients with CRC. RESULTS: We found RAS mutations in 76% (26/34) of primary CRC lesions and in 86% (31/36) of PMs. While 27% (7/26) of the primary CRC RAS mutations were heterogeneous, all the RAS mutations in PMs were homogeneous. Of the mutations in PMs, 71% (22/31) were KRAS G>A transitions, of which 82% (18/22) were KRAS G12D or G13D. The RAS mutation discordance between primary tumors and PMs was 12.1% (4/33). RAS mutations with the same genotyping were detected in all synchronous and metachronous PMs from 9 patients. We found no BRAF mutations in either primary or pulmonary tissues. CONCLUSION: Our NGS analysis suggests that RAS mutations of PM of patients with CRC are more common than initially thought. The presence of KRAS mutations in CRC specimens, especially G12D or G13D mutations, seems to promote PM formation.

High Stromal TGFBI in Lung Cancer and Intratumoral CD8-Positive T Cells were Associated with Poor Prognosis and Therapeutic Resistance to Immune Checkpoint Inhibitors.

BACKGROUND: We investigated whether the expression of transforming growth factor-beta-induced protein (TGFBI) and intratumoral immune cells including CD8- and Forkhead box protein P3 (Foxp3)-positive T cells in clinical lung cancer patients could predict the therapeutic response to nivolumab. METHODS: Thirty-three patients who were treated with nivolumab were enrolled in this study. Immunohistochemical analyses of TGFBI, PD-L1, CD8, Foxp3, and vimentin expression were conducted. Serum concentrations of TGFBI and transforming growth factor-beta1 (TGF-ß1) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Cancer TGFBI was not associated with prognosis and therapeutic response to nivolumab, but cancer stromal TGFBI and intratumoral CD8-positive T cells were associated with them. Therefore, we evaluated cancer stromal TGFBI and intratumoral CD8-positive T cells. The high-TGFBI-expression group had poorer clinical responses than did the low-TGFBI-expression group (p < 0.0001). The number of times nivolumab was administered in the high-CD8-expression group was significantly higher than that in the low-CD8-expression group (p = 0.0046). The high-CD8-expression group had better clinical responses than did the low-CD8-expression group (p = 0.0013). Interestingly, all patients in the high-TGFBI/low-CD8-expression group had progressive disease (PD). In contrast, all patients in the low-TGFBI/high-CD8-expression group had PR + SD (partial response + stable disease) by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CONCLUSIONS: The dual evaluation of stromal TGFBI and intratumoral CD8-positive T cells could be a useful predictive marker for nivolumab.

Clinicopathological features of small-sized peripheral squamous cell lung cancer.

Recent advances in imaging technology have enhanced the detection rate of small-sized peripheral lung cancers. The present study aimed to identify the clinicopathological differences between patients with small-sized peripheral squamous cell carcinoma (SCC) and adenocarcinoma (ADC). Patients with lung cancer who underwent radical surgical resection at Gunma University Hospital between July 2007 and October 2012 were retrospectively analyzed. Patients who exhibited small-sized peripheral tumors (pathological size, ≤2 cm) located within the outer-third of the lung field on preoperative computed tomography were enrolled in the present study. A total of 26 patients were diagnosed with SCC and 214 with ADC. The results revealed that patients with SCC exhibited higher rates of pleural invasion, vascular invasion and lymphatic invasion compared with ADC patients. Additionally, the rate of postoperative recurrence was higher in patients with SCC compared with ADC patients. Patients with ADC were subsequently into two groups: Solid ADCs (sADC) and non-solid ADCs (nsADC), which included pure ground glass nodules and part-solid ADCs. The results revealed that the incidence of pleural invasion, vascular invasion and lymphatic invasion, and the rate of postoperative recurrence in patients with sADCs were similar to those with SCC, but were also significantly higher when compared with nsADC patients. The present study concluded that patients with SCC and sADC may not be suitable candidates for sublobar resection, despite exhibiting small tumors that are located in the peripheral lung.

Clinical Significance of Various Drug-Sensitivity Markers in Patients with Surgically Resected Pulmonary Pleomorphic Carcinoma.

Various drug-sensitivity markers are potentially responsible for tumor progression and chemotherapy resistance in cancer patients with both epithelial and sarcomatous components; however, the clinicopathological significance of drug-sensitivity markers in patients with pulmonary pleomorphic carcinoma (PPC) remains unknown. Here, we clarified the prognostic impact of these drug-sensitivity markers in PPC by performing immunohistochemical and clinicopathologic analyses of samples from 105 patients with surgically resected PPC in order to evaluate levels of vascular endothelial growth factor 2 (VEGFR2), stathmin 1 (STMN1), tubulin ß3 class III (TUBB3), thymidylate synthetase (TS), topoisomerase II (Topo-II), glucose-regulated protein, and 78 kDa (GRP78)/binding immunoglobulin protein (BiP). We observed the rates of high expression for VEGFR2, STMN1, TUBB3, TS, Topo-II, and GRP78/BiP were 33% (39/105), 35% (37/105), 61% (64/105), 51% (53/105), 31% (33/105), and 51% (53/105) of the samples, respectively. Moreover, multivariate analysis identified VEGFR2 and GRP78/BiP as significant independent markers for predicting worse prognosis. These findings suggested elevated VEGFR2 and decreased GRP78/BiP levels as independent factors for predicting poor outcomes following surgical resection in patients with PPC.

Fucosylated α1-acid glycoprotein as a biomarker to predict prognosis following tumor immunotherapy of patients with lung cancer.

Immunotherapy targeting immune checkpoint molecules has provided remarkable clinical benefits in cancer patients but no clinically relevant biomarker for predicting treatment outcomes exists. Recently, we demonstrated that glycan structures of serum α1-acid glycoprotein (AGP) changed dramatically in cancer patients and that α1,3fucosylated AGP (fAGP) levels increased along with disease progression and decreased responding to chemotherapy treatments. Here, the fAGP was analyzed in sera prospectively obtained from 39 patients with advanced lung cancer who underwent immunotherapy with anti-PD-1 antibody, nivolumab. Twenty-three patients had significantly high fAGP levels above the cut-off value (H-fAGP) at one month after starting the treatment and 20 patients in this group, whose tumor sizes did not decrease, maintained high fAGP levels continuously and subsequently died. However, the other 16 patients, whose fAGP levels decreased or maintained below the cut-off value (L-fAGP), survived during a 2-year observation even though 5 patients in this group had no tumor shrinkage. Accordingly, the overall survival rate was found to significantly correlate with the fAGP level. Multivariate analyses revealed that the H-fAGP was an independent risk factor for cancer progression. Therefore, the fAGP level appeared to be a reliable biomarker for predicting clinical efficacy of immunotherapy with nivolumab.

Long-term complete response in a patient with postoperative recurrent ALK-rearranged lung adenocarcinoma treated with crizotinib: A case report.

Anaplastic lymphoma kinase (ALK) gene rearrangements are identified in approximately 5% of patients with non-small cell lung cancer (NSCLC). Despite initial dramatic responses to ALK inhibitors, the majority of patients relapse within 1 year, owing to the development of resistance. Herein we present a case of variant type 2 ALK-rearranged lung adenocarcinoma recurrence with multiple lung metastasis that maintained complete response over 5 years with crizotinib, which is the first approved ALK inhibitor. The efficacy of crizotinib may vary among ALK fusion variants and thus, variant type may represent an important factor in guiding the treatment strategy for ALK-rearranged lung adenocarcinoma.

Pulmonary Artery Compression Facilitates Intersegmental Border Visualization.

Intravenous indocyanine green injection is useful for the identification of the intersegmental border by infrared thoracoscopy during anatomic segmentectomy. However, surgeons encounter cases in which visualization of the intersegmental border is difficult. In particular, intravenous indocyanine green fluorescence in the upper lobe is occasionally obscured by to the relatively lesser blood flow in the upper lobe pulmonary arteries. This report describes an interlobar pulmonary artery compression method that is a simple and effective technique for clearly visualizing the intersegmental border through infrared thoracoscopy with intravenous indocyanine green during upper lobe segmentectomy.

Post-treatment Glasgow Prognostic Score Predicts Efficacy in Advanced Non-small-cell Lung Cancer Treated With Anti-PD1.

BACKGROUND/AIM: No definitive biomarker exists for predicting treatment efficacy or response to therapy with antibody to programmed cell death-1 (PD1) for patients with advanced non-small cell lung cancer (NSCLC). Hence, we investigated whether the Glasgow prognostic score (GPS) predicted anti-PD1 treatment response for advanced NSCLC. PATIENTS AND METHODS: This study retrospectively identified 47 patients with NSCLC treated with anti-PD1 and assessed the prognostic value of the GPS. The GPS was calculated using C-reactive protein and albumin concentrations 1 month after starting anti-PD1 treatment. Kaplan-Meier method and Cox proportional hazard models were used to examine differences in progression-free (PFS) and overall (OS) survival, and clinical response. RESULTS: The post-treatment GPS independently predicted anti-PD1 treatment efficacy, as a good post-treatment GPS (GPS 0-1) was significantly associated with improved PFS. Intra-treatment GPS change was associated with clinical response. CONCLUSION: The post-treatment GPS independently predicted efficacy of anti-PD1 treatment for NSCLC.

Carbonic anhydrase 9 expression is associated with poor prognosis, tumor proliferation, and radiosensitivity of thymic carcinomas.

INTRODUCTION: Thymic epithelial tumors (TETs) comprise several histologies of thymoma and thymic carcinomas (TCs), and TC frequently metastasizes and causes death. We therefore aimed here to identify key molecules closely related to prognosis and their biological roles in high-risk TETs, particularly TCs. RESULTS: RNA sequence analysis demonstrated that hypoxia-related genes were highly expressed in TETs. The expression of the hypoxia-related gene CA9 was noteworthy, particularly in TCs. Immunohistochemical analysis revealed that CA9 was expressed in 81.0% of TCs and 20.7% of all TET samples. CA9 expression was significantly associated with Masaoka stage, WHO classification, and recurrence-free survival after tumor resection (P = 0.005). The down-regulation of CA9 transcription in TC cell lines by small interfering RNAs significantly inhibited CA9 expression, which inhibited proliferation and increased sensitivity to irradiation. CONCLUSIONS: CA9 expression may serve as a significant prognostic marker of TETs and therefore represents a potential target for the development of novel drugs and radiation-sensitizing therapy designed to improve the outcomes of patients with TCs. MATERIALS AND METHODS: We performed comprehensive transcriptome sequencing of 23 TETs and physiologic thymic specimens to identify genes highly and specifically expressed in high-risk TETs, particulary TCs. We performed immunohistochemical analysis of 179 consecutive surgically resected TETs to evaluate the significance of the association of protein expression with clinicopathological features and prognosis. The biological significance of the most promising prognostic marker was further studied using the TC cell lines, Ty-82 and MP57.