A Pilot Study Analyzing the Clinical Utility of Comprehensive Genomic Profiling Using Plasma Cell-Free DNA for Solid Tumor Patients in Japan (PROFILE Study).

BACKGROUND: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population. METHODS: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360. RESULTS: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010). CONCLUSIONS: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.

[A Case of Advanced Gastric Cancer with Multiple Bone Metastases, Virchow Lymph Node and Para-Aortic Lymph Node Metastases That Responded to Combined Modality Therapy and Underwent Conversion Surgery].

A 41-year-old woman with type 3 advanced gastric cancer and Virchow lymph node, para-aortic lymph node, and multiple bone metastases was diagnosed with U-less cType 3 cT4aN3M1, cStage IV. We administered docetaxel, cisplatin, and S-1 (DCS)therapy for unresectable gastric cancer. After 11 courses of DCS, we confirmed that the distant lymph node metasta- ses were significantly reduced. We performed radiotherapy(30 Gy/10 Fr)on the thoracic lumber vertebrae. Because the patient was successfully downstaged, we performed total gastrectomy with Roux-en-Y reconstruction. The histopathological diagnosis was ypT3N2M0, ypStage III A. In this case, DCS therapy successfully treated gastric cancer with distant metastases, including multiple bone metastases.

Stool color card screening for early detection of biliary atresia and long-term native liver survival: a 19-year cohort study in Japan.

OBJECTIVE: To evaluate the sensitivity and specificity of a stool color card used for a mass screening of biliary atresia conducted over 19 years. In addition, the age at Kasai procedure and the long-term probabilities of native liver survival were investigated. STUDY DESIGN: From 1994 to 2011, the stool color card was distributed to all pregnant women in Tochigi Prefecture, Japan. Before or during the postnatal 1-month health checkup, the mothers returned the completed stool color card to the attending pediatrician or obstetrician. All suspected cases of biliary atresia were referred for further examination. Diagnosis was confirmed by laparotomy or operative cholangiography for high-risk cases before the Kasai procedure. Patients with biliary atresia were followed from the date of their Kasai procedure until liver transplantation, death, or October 31, 2013, whichever comes sooner. RESULTS: A total of 313,230 live born infants were screened; 34 patients with biliary atresia were diagnosed. The sensitivity and specificity of stool color card screening at the 1-month check-up was 76.5% (95% CI 62.2-90.7) and 99.9% (95% CI 99.9-100.0), respectively. Mean age at the time of Kasai procedure was 59.7 days. According to Kaplan-Meier analysis, the native liver survival probability at 5, 10, and 15 years was 87.6%, 76.9%, and 48.5%, respectively. CONCLUSIONS: The sensitivity and specificity of the stool color card have been demonstrated by our 19-year cohort study. We found that the timing of Kasai procedure and long-term native liver survival probabilities were improved, suggesting the beneficial effect of stool color card screening.

The Prognostic Significance of Plakophilin-1 Expression in Esophageal Cancer.

BACKGROUND/AIM: Plakophilin 1 (PKP1) expression is inversely related to cancer grade. This study aimed to evaluate whether PKP1 is a prognostic marker for esophageal cancer (EC). MATERIALS AND METHODS: We tested immunohistochemically for PKP1 in squamous cell carcinoma EC specimens from 99 patients, including cytoplasmic (C), membrane (M), and nuclear (N) cellular areas, and analyzed their relationships with clinicopathological factors. RESULTS: PKP1stains were stratified into strong and weak for all three cellular areas. Staining was inversely related to tumor depth (C: p=0.002, M: p=0.00007, N: p=0.02), lymph node metastasis (C: p=0.003, M: p=0.001, N: p=0.004) and pathological stage (C: p=0.0004, M: p=0.0001, N: p=0.006). Cytoplasmic and membrane staining were inversely related to vessel invasion. Patients with strong C stain had a better overall survival than those with weak C stains (p=0.01). Disease-free survival of patients with strong M stains was better than that of those with weak staining (p=0.01). CONCLUSION: Cytoplasmic and membrane PKP1 expression is a possible prognostic marker for EC.

Histopathological evaluation of the effectiveness of oral Eppikajutsuto treatment for lymphatic malformation.

BACKGROUND: Lymphatic malformation (LM) is a congenital disease caused by lymphatic vessel malformation. Although standard therapies for LMs are sclerotherapy and/or surgical excision, a new therapy using Japanese herbal medicine Eppikajutsuto (TJ-28) has been recently reported as clinically effective. We aimed to experimentally confirm the therapeutic effectiveness of TJ-28 for LMs. METHODS: LM lesions were generated in the mesentery and peritoneum of mice by intraperitoneal injection of Freund's incomplete adjuvant. Mice with LMs were treated by gavage or dietary administration of TJ-28 for 2 months. Formalin-fixed paraffin-embedded tissue sections of mesentery and peritoneum tissues were histologically and immunohistochemically examined by focusing on lymph nodes and perinodal lymph vessels. RESULTS: Multiple Freund's incomplete adjuvant-associated foreign-body granulomas were formed in the mesentery and peritoneum, resulting in congestion of lymph fluid and dilatation of lymph vessels. The numbers and sizes of lymph nodes were not significantly different between TJ-28-treated and control groups. However, the luminal areas of lymphatic vessels were reduced significantly in the TJ-28 treatment group by both gavage and dietary administrations. CONCLUSION: TJ-28 conspicuously reduced congestion of lymph fluid. This is the first histopathological evaluation of LM model mice to study the effectiveness of oral TJ-28 treatment.

Treatment strategy for brain metastases from esophageal cancer.

BACKGROUND: This study aimed to examine the treatment outcomes of patients with brain metastases from esophageal cancer. Brain metastases from esophageal cancer are rare and have a poorer prognosis than brain metastases from lung and breast cancer. METHODS: This study included patients who were diagnosed with and treated for esophageal cancer in our department and subsequently developed brain metastases between April 2010 and December 2014. We examined the differences in survival in patients based on receiving chemotherapy. RESULTS: In total, 8 patients (7 men and 1 woman) with a mean age of 65 years (range 51-73) were included. Seven presented with neurologic symptoms. Two were diagnosed via computed tomography (CT), 5 via magnetic resonance imaging, and 1 via positron emission tomography/CT. They were treated using whole-brain irradiation or with a gamma knife. In 5 patients, chemotherapy was administered after treatment of the brain metastases. The mean survival from the start of treatment was 358 days (range 31-1196). CONCLUSION: The relatively successful local control of brain metastases in these patients indicates that long-term survival may be attainable via concomitant chemotherapy.

Nutritional status predicts adjuvant chemotherapy outcomes for stage III colorectal cancer.

OBJECTIVES: Previously, adjuvant chemotherapy using oxaliplatin was a standard treatment for patients with node-positive colorectal cancer (CRC) who underwent curative surgery. The factor predicting adverse events and therapeutic effect have not yet been established. METHODS: A retrospective cohort of 42 patients diagnosed with stage III CRC between April 2009 and March 2013 in our institution were included in this study. The indicators of host nutritional status were body weight (BW), body mass index (BMI), serum albumin, Onodera's prognostic nutritional index (OPNI), and Glasgow Prognostic Score (GPS). The indicators of host immunocompetence was total lymphocyte counts, total neutrophil counts, granulocytes/lymphocytes ratio (G/L ratio). RESULTS: The overall recurrence rate was 26.1%. Patients who had a recurrence were more likely to be older. The recurrence was not associated with type of regimen or adverse events. The cases with a few cumulative doses and relative dose intensity of oxaliplatin experienced significantly more recurrence. Nutritional status indicators, such as the serum albumin level, OPNI, and the modified Glasgow prognostic score (mGPS) were associated with the adjuvant chemotherapy outcome. Our study results indicated worse nutritional status induced worse disease-free survival (DFS) and more recurrence. CONCLUSION: The host's nutritional status associated with outcomes in stage III CRC patients.

MERS associated with bacterial translocation in a pediatric patient with congenital portal vein hypoplasia: A case report.

A case of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in a female child who developed bacterial translocation from a congenital portal vein hypoplasia is reported. The patient was diagnosed as having portal hypertension after examinations and laboratory results showing splenomegaly and thrombocytopenia at the age of 1 year. The patient required three endoscopic variceal ligation (EVL) surgeries before the age of 9 due to development of multiple esophageal varices. After the second and third EVL procedures, she developed septicemia, possibly due to bacterial translocation associated with the administration of general anesthesia. The day after the third EVL, the patient presented with high fever and neurological disturbances (altered consciousness). Magnetic resonance imaging detected abnormal intensities in the corpus callosum ampulla and cerebral white matter, which suggested a diagnosis of MERS type 2. Considering this clinical course, the possible association between bacterial translocation and MERS in a patient with congenital portal vein hypoplasia and portal hypertension is discussed.

Salvage esophagectomy combined with partial aortic wall resection following thoracic endovascular aortic repair.

OBJECTIVE: Definitive chemoradiotherapy is useful for locally advanced esophageal cancer. However, salvage esophagectomy is required when residual or recurrent tumor is evident after chemoradiotherapy. We performed salvage esophagectomy combined with partial aortic wall resection after thoracic endovascular aortic repair for aortic invasion, and we evaluated the results. METHODS: Four patients underwent esophagectomy combined with aortic wall resection after thoracic endovascular aortic repair because the lesion was diagnosed as stage T4b. We evaluated short-term outcomes, including duration of thoracic surgery, blood loss, duration of intubation, intensive care unit stay, and postoperative morbidity, as well as survival after salvage surgery. RESULTS: Lesions were resected with no intraoperative procedural adverse events. Mean thoracic operation time was 444 min, and mean thoracic blood loss was 506 g. In all patients, complete resection of the lesion was possible with no intraoperative adverse events. All patients were extubated on postoperative day 0, and all were discharged from the intensive care unit on postoperative day 1. One patient experienced grade II wound pain (bilateral chest pain), and another patient experienced difficult sputum expectoration (grade IIIA). The mean follow-up time was 19.8 months, and two patients were alive with no disease recurrence at the time of this report. However, the remaining two patients had died secondary to lymph node metastasis. CONCLUSIONS: Salvage esophagectomy combined with partial aortic wall resection after thoracic endovascular aortic repair provides acceptable short-term outcomes. Future studies are needed to evaluate long-term survival and patient selection criteria.

Efficacy and safety of cardioversion with continuous landiolol infusion for atrial tachyarrhythmia in an inflammatory state caused by volvulus in a child with TARP syndrome and postoperative tetralogy of Fallot.

A 2-year-old boy was diagnosed with TARP syndrome and underwent surgery for tetralogy of Fallot. He developed fever and had an acute abdomen. After 12 hours, atrial tachyarrhythmia (300 beats/min [bpm]) occurred. After nine administration of adenosine and two cardioversions, it relapsed promptly. Landiolol (10 µg/kg/min) was administered until the heart rate decreased to 270 bpm, and cardioversion was performed until sinus rhythm was normal. Exploratory laparotomy revealed small bowel volvulus. Systemic inflammation causing an acute abdomen may be associated with atrial tachyarrhythmia in postoperative tetralogy of Fallot. We speculated that landiolol lowered the defibrillation threshold of the atrium.

Waardenburg syndrome with isolated deficiency of myenteric ganglion cells at the sigmoid colon and rectum.

Waardenburg syndrome (WS) has the characteristic clinical features caused by the embryologic abnormality of neural crest cells. WS patients sometimes suffer from functional intestinal obstruction. When it is Hirschsprung disease (HD), the WS is diagnosed as type 4 WS. We report a case of WS which did not have myenteric ganglion cells in the sigmoid colon and rectum. Whether to diagnosis this case as type 1 or 4 WS is controversial. Moreover, this is the third report which has peristalsis failure caused by abnormal myenteric plexus. In all three cases, the eosinophils had aggregated in the myenteric layer of the transition zone. During embryonic life, enteric ganglion cells migrate to the myenteric layer from the proximal to the distal side sequentially and, subsequently, to the submucosal layer through the circular muscle. Therefore, we hypothesize that myenteric ganglion cells that had already migrated were eliminated by an eosinophil-mediated mechanism in these three cases. We believe this report may be helpful to elucidate the pathogenesis of some types of HD.

Laparoscopic surgery for a Bochdalek hernia triggered by pregnancy in an adult woman: A case report.

INTRODUCTION: A Bochdalek hernia (BH) is a type of congenital diaphragmatic hernia. We herein describe an adult woman with a BH triggered by pregnancy and treated by laparoscopic surgery. PRESENTATION OF CASE: A 26-year-old woman was referred to our hospital because of abdominal pain and dyspnea resulting from a left diaphragmatic hernia. She was diagnosed with a BH and underwent laparoscopic surgery. Her postoperative progress was satisfactory, and no recurrence was found at follow-up approximately 1 year later. DISCUSSION: A recently published study reviewing detailed cases of laparoscopic and/or thoracoscopic repair of adult BH from 1999 to 2016 identified 30 cases. A laparoscopic approach for treatment of BH has recently attracted increasing interest. CONCLUSION: Laparoscopic surgery can be safely performed on adults with BH without complications.

¹8F-Fluorodeoxyglucose Positron Emission Tomography for Evaluating the Response to Neoadjuvant Chemotherapy in Advanced Esophageal Cancer.

BACKGROUND/AIM: The purpose of the present study was to improve the diagnostic precision of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) after neoadjuvant chemotherapy (NAC) in patients with advanced esophageal cancer. PATIENTS AND METHODS: Thirty patients underwent FDG-PET/CT before and after NAC. The maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) were measured. Patients were divided into two pathological response groups: "responders" (grades 1b-3) or "non-responders" (grades 0-1a). RESULTS: Overall, 11 patients were responders. Significant differences were present for the post-NAC SUVmax (p=0.070), %decrease in SUVmax (p=0.017), post-NAC MTV (p=0.014), and %decrease in MTV (p=0.003). CONCLUSION: Receiver operating characteristic curve analysis showed that the %decrease in MTV of the primary tumor was the best indicator of response to NAC. We are currently striving to improve the accuracy of this assessment method.

Expression of DNA double-strand break repair proteins predicts the response and prognosis of colorectal cancer patients undergoing oxaliplatin-based chemotherapy.

DNA intrastrand cross-linking agents such as oxaliplatin induce DNA double-strand breaks (DSBs) during DNA repair and replication. In the present study, we hypothesized that DNA intrastrand cross-linking agents may significantly benefit colorectal cancer patients with deficiencies in DSB repair. Seventy-eight patients with metastatic or recurrent colorectal cancer who had measurable target lesions and who underwent resection for primary colorectal cancer in our institution between April 2007 and March 2013 were included in the present study. The median age was 64.5 years, and the cohort consisted of 49 males and 29 females. The median progression-free survival (PFS) was 10.9 months. The expression of DSB repair proteins such as RAD51 and MRE11 was investigated by immunohistochemistry, and associations between RAD51 and MRE11 expression and clinicopathological factors or chemotherapeutic effect were assessed. MRE11-negative cases and RAD51-negative cases achieved significantly better tumor reduction compared with cases with positive expression. Cases with negative expression of both proteins or negative expression of either protein had significantly longer PFS than cases with positive expression for both proteins. In conclusion, DSB repair protein expression-negative colorectal cancer cases may be more highly sensitive to chemotherapy, and thus DSB repair protein expression may be a useful prognostic indicator for colorectal cancer patients.

Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography for Follow-Up of 13-cis-Retinoic Acid Treatment for Residual Neuroblastoma After Myeloablative Chemotherapy.

13-cis-retinoic acid (13-cis-RA) treatment is used as a second-line treatment for residual or recurrent neuroblastoma. However, determining the duration of 13-cis-RA treatment for residual and recurrent neuroblastoma can be a problem because it is difficult to evaluate the effectiveness of the treatment.We performed 13-cis-RA treatment to remove residual active neuroblastoma cells in an 8-year-old boy with stage 4 neuroblastoma that developed from a left sympathetic ganglion and had been treated with chemotherapy, surgery, autologous peripheral blood stem-cell transplantation, and radiotherapy. F-fluorodeoxyglucose positron emission tomography (F-FDG-PET) and iodine-123 metaiodobenzylguanidine (I-MIBG) scintigraphy obtained immediately before 13-cis-RA treatment both showed positive findings in the area of the primary lesion. At 18 months after 13-cis-RA treatment, there was accumulation on I-MIBG scintigraphy but no uptake on F-FDG-PET, and 13-cis-RA treatment was suspended. The patient has been in complete remission for 3 years. In comparing the effectiveness of the 2 imaging modalities for monitoring the response to 13-cis-RA treatment, we considered that F-FDG-PET was superior to I-MIBG scintigraphy because F-FDG-PET images were not affected by the cell differentiation induced by 13-cis-RA treatment in our case. Thus, F-FDG-PET was useful for determining the treatment response and outcomes.We have reported a case of residual neuroblastoma treated with differentiation-inducing 13-cis-RA therapy. Different results were produced with F-FDG-PET and I-MIBG scintigraphy. The cessation of 13-cis-RA treatment was based on F-FDG-PET findings and there has been no relapse for 3 years.

Clear cell sarcoma of the kidney with calcification and a novel chromosomal abnormality: a case report.

A 9-year-old male presented with a renal tumor that showed a cystic structure with calcification on computed tomography. A pathological analysis of the resected tumor suggested clear cell sarcoma of the kidney (CCSK). Thus, this patient suffered atypical CCSK with significant calcification and gross necrosis. A novel chromosomal abnormality was also identified in the tumor.

Poor nutritional status before and during chemotherapy leads to worse prognosis in unresectable advanced or recurrent colorectal cancer.

OBJECTIVE: This study aimed to clarify the relationship between host nutritional status prior to first-line chemotherapy and therapeutic effect, and, whether these nourishment indexes could become factors that predict long-term convalescence in unresectable advanced or recurrent colorectal cancer or not. Summary of Background Date: It has previously been reported that postoperative complications and long-term prognosis of patients with gastrointestinal malignancies may be affected by their nutritional status. But, there is little information regarding the relationship between prognosis, nutritional status and immunocompetence in unresectable progressive or recurrent colorectal cancer. METHODS: Ninety patients who had measurable target lesions underwent resection for primary colorectal cancer in our institution, between April 2007 and March 2013. The indicators of host nutritional status was body weight (BW), body mass index (BMI), serum albumin, Onodera's prognostic nutritional index (OPNI) and Glasgow Prognostic Score (GPS). The indicators of host immunocompetence was total lymphocyte counts, total neutrophil counts, granulocytes/lymphocytes ratio (G/L ratio). RESULTS: The median overall survival (OS) was 32.5 months, and the median progression-free survival was 10.9 months. The relative change of target lesions were associated with BW, BMI and OPNI. Furthermore, there was strong correlation between the change ratio of the serum CEA level before and after chemotherapy administration and BMI. BW, BMI, serum albumin level, OPNI and GPS were significantly associated with overall survival (OS). CONCLUSION: Poor nutritional status and suppressive immunocompetence is associated with ineffective chemotherapy.

Asymptomatic Mesenchymal Hamartoma of the Chest Wall in Child With Fluorodeoxyglucose Uptake on PET/CT-Report of a Case.

We had experience with a case of mesenchymal hamartoma of the chest wall (MHCW) with fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography (PET/CT). We reported the first case of asymptomatic MHCW in a child with preoperative PET/CT. Mesenchymal hamartoma of the chest wall is a rare benign tumor that usually presents as a visible chest wall mass or respiratory problems secondary to compression of the lung in early infancy. It is often reported that malignant transformation is extraordinarily rare. Positron emission tomography/CT is useful for diagnosis of malignancy. There is no report of MHCW in a child with preoperative PET/CT before. We examined an asymptomatic 1-year-old girl with an incidental finding on a chest x-ray. Scans of CT and PET/CT were performed before surgical resection. After surgery, the resected tumor was examined histologically. Chest x-ray and CT scan of the chest confirmed a 25- × 20-mm round shaped intrapleural mass containing calcification and destructing the rib, arising from the third rib. Scan of PET/CT demonstrated the mass with light FDG accumulation. Histologically, the mass was homogenous, with thick funicular of hyaline cartilage interdigitating with scattered fiber. There were no malignant cells. No malignant MHCW was demonstrated in the mass, with light FDG accumulation by PET/CT. PET/CT might be a useful tool to distinguish malignant MHCW in children.

Utility of FDG-PET/CT in the evaluation of the response of locally advanced breast cancer to neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is effective in down-staging a primary tumor before surgery, and quick differentiation between responders to NAC and nonresponders is needed. We investigated the utility of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) in evaluating the therapeutic effectiveness of NAC. We investigated 25 patients who underwent NAC for stage II and III noninflammatory breast cancer. FDG-PET/CT was undertaken before and after NAC to determine the maximum standardized uptake value (SUVmax) reduction rate. Findings were compared with postoperative histopathologic evaluation of therapeutic response. It was not possible to accurately assess tumor response to NAC using CT. However, using the SUVmax reduction rate, we noted a significant difference (P=0.0420) between patients who were responsive and nonresponsive to NAC. The sensitivity and specificity were as high as 83.3% and 78.9%, respectively. This study demonstrated that FDG-PET/CT can differentiate responders from nonresponders. This improves patient management by avoiding unnecessary chemotherapy.