Integrated policy of medical expense subsidies and clinical registry for patients with liver cancer and decompensated cirrhosis in Japan.

Chronic hepatitis B and C are among the most significant infectious diseases worldwide, and are major risk factors for liver cirrhosis and liver cancer. In Japan, comprehensive hepatitis measures are implemented for the testing and treatment of viral hepatitis, thus enabling the early diagnosis of liver cancer. Nevertheless, patients with decompensated cirrhosis and liver cancer often have unfavorable prognoses and require repetitive long-term treatment. In fiscal year 2018, an integrated policy of medical expense subsidies and research was established in Japan that aimed to alleviate patients' financial burden and launch the clinical registry of advanced liver disease. Over time, updates to the eligibility for the subsidy increased access to patients and has led to an increased number of beneficiaries. Additionally, the accumulation of clinical data in the registry has revealed the treatment choices for these diseases. However, the disparities in efforts across prefectures have also become evident. Raising public awareness of the policy and tightening the multisector healthcare network are keys to success in supporting qualifying patients with advanced liver disease.

[Examination of Factors Related to Walking Ability in Patients with Abdominal Cancer].

It has been reported that preoperative rehabilitation reduces the risk of postoperative complications. We examined the factors impacting the efficacy of preoperative rehabilitation. Forty-three cancer patients who underwent abdominal surgery after preoperative rehabilitation at our hospital were assessed". Walkable"was defined as having the ability to walk to the toilet(distance>30 meters)without requiring support. Following the clinical path, if patients became"walkable"by the second day after surgery, they belonged to the smooth group, while the remaining patients belonged to the delayed group. We examined the factors influencing walking ability. The smooth group consisted of 34 patients(79%), and the delayed group consisted of 9 patients(21%). The significant factors related to delays in acquiring walking ability were old age and weakened lower limb function. Improving lower limb function through preoperative rehabilitation may lead to patients acquiring walking ability earlier after surgery, especially in older patients.

[Thyroid Metastasis of Rectal Cancer].

A 65-year-old woman underwent laparoscopic low anterior resection for rectal cancer with distant metastasis to the right lobe of her liver and mediastinal and right subclavian lymph nodes. Since the postoperative chemotherapy resulted in the disappearance of the lymph node metastasis and diminished hepatic metastasis lesion, the enlarged anterior segment of the liver was performed. She was administered chemotherapy for 1 year after the second surgery. Thoracoabdominal computed tomography performed 18 months after the end of the treatment revealed swelling of the left lobe of the thyroid. Ultrasonography showed a 23mm lobulated hypoechoic tumor in the left lobe of the thyroid gland. We suspected thyroid metastasis by aspiration biopsy cytology. Left thyroid lobectomy was performed for definitive diagnosis and local control. Histological examination revealed thyroid metastasis of the rectal cancer. We experienced a rare case of thyroid metastasis from rectal cancer.

Comparison of vascularity observed using contrast-enhanced 3D ultrasonography and pathological changes in patients with hepatocellular carcinoma after sorafenib treatment.

Aim: The aim of this study was to compare vascularity observed using contrast-enhanced 3D ultrasonography and pathological changes in human hepatocellular carcinoma (HCC) and surrounding non-tumorous areas after sorafenib treatment. Materials and methods: Twelve patients with HCC were enrolled in this clinical study. The maximum tumor diameter as measured using sonography ranged from 15 to 33 mm (mean, 24.0 mm; SD, 5.7 mm). Assessments using contrast-enhanced (0.2 mL of Sonazoid suspension; Daiichi Sankyo, Tokyo, Japan) 3D ultrasonography (LOGIQ 7; GE Healthcare, Milwaukee) were performed in all the patients before and 1 week after sorafenib treatment. The microvessel density (MVD) of the HCC and surrounding non-tumorous area was evaluated based on the immunohistochemical staining of microvessels using an antigen for CD34. Results: Blood flow in the tumor was decreased in all 12 cases after sorafenib treatment. The MVD of the tumorous area at 1 week after sorafenib administration (38.8 ± 5.2) was significantly lower than that observed before sorafenib administration (72.4 ± 13.0) (P < 0.01). Blood flow in the non-tumorous area had decreased in 6 cases at 1 week after sorafenib treatment and had not changed in the 6 other cases. In the reduced blood flow group, the MVD of the non-tumorous area at 1 week after sorafenib administration had decreased significantly, compared with the MVD of the non-tumorous area before sorafenib administration. However, in the group with no change in blood flow, the MVD of the non-tumorous area at 1 week after sorafenib treatment had not changed, compared with the MVD of the non-tumorous area before sorafenib treatment. Conclusion: Contrast-enhanced 3D ultrasonography studies showed a correlation between vascularity and pathological changes in human HCC and the surrounding non-tumorous area after sorafenib treatment.

Primary hepatic choriocarcinoma in an 83-year-old woman.

We present a case of primary hepatic choriocarcinoma in an 83-year-old Japanese woman with gastric wall and lymph node metastases and a splenic vein tumor thrombus. Multiple irregular hepatic tumors with massive necrosis and hemorrhage were observed during autopsy. Syncytiotrophoblast-like and mononucleated cytotrophoblast-like cell morphology with focal hepatocellular carcinoma (HCC)-like trabecular structures was observed. In immunohistochemical analyses, the tumor cells expressed human chorionic gonadotropin (hCG) and cytokeratins (AE1/AE3, CK7, CK19) but were negative for alpha-fetoprotein (AFP), glypican-3, and vimentin. Immunohistochemical findings did not reveal evidence of HCC or angiosarcoma. We concluded the liver tumor was primary hepatic choriocarcinoma.

[A Case of Liver Metastasis from Esophageal Cancer Successfully Treated by Surgical Resection after Chemotherapy with Weekly-Paclitaxel].

A 58-year-old man complaining of dysphagia was admitted to our hospital and diagnosed with esophageal cancer.He underwent thoracoscopic subtotal esophagectomy with 3-field lymph node dissection and reconstruction with a gastric tube created by hand-assisted laparoscopy.The pathological diagnosis was classified as AeLtG, pT3N2M0, pStage III .He was subsequently treated with systemic chemotherapy with 5-fluorouracil and cisplatin.After 2 courses, a single liver metastatic tumor appeared at segment 5.As chemotherapy against the recurrence, weekly-paclitaxel was administered.After 2 courses, the metastatic liver tumor reduced in size.Subsequently, laparoscopic partial liver resection was performed 11 months after first surgery.The pathological finding was negative for malignancy(pathological complete response).

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma.

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.

Interleukin 10 Level in the Cerebrospinal Fluid as a Possible Biomarker for Lymphomatosis Cerebri.

A 71-year-old immunocompetent man developed cognitive decline and gait disturbance. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without a mass lesion. An analysis of the cerebrospinal fluid (CSF) showed elevated levels of interleukin (IL)-10. The condition of the patient progressively deteriorated, and intravenous high-dose steroids proved ineffective. Detection of non-destructive, diffusely infiltrating, large B-cell lymphoma in biopsy and autopsy specimens led to a diagnosis of lymphomatosis cerebri (LC). On serial MRI, the basal ganglia and white matter lesions increased in parallel with the levels of IL-10. These findings suggest that the IL-10 level in the CSF may represent a potentially useful biomarker for the early diagnosis and monitoring of the disease progression in LC.

Adjuvant S-1 chemotherapy after surgical resection for pancreatic adenocarcinoma.

BACKGROUND/AIMS: The aim of this study was determine the effectiveness of adjuvant S-1 chemotherapy for patients with resected pancreatic cancer. METHODOLOGY: Patients with pancreatic carcinoma who underwent pancreatic resection without adjuvant S-1 chemotherapy (n = 11) or with adjuvant S-1 chemotherapy (n = 10) were included. S-1 was administered orally at a dose of 40 mg/m2 twice daily for 28 consecutive days followed by a 14-day pause. The cycle was repeated 4 times. Overall and disease-free survival curves were generated using the Kaplan-Meier method, and statistical differences between groups were analyzed using the log-rank test. RESULTS: The disease-free survival and overall survival were longer among recipients of adjuvant S-1 chemotherapy than among those who received surgery alone (P < 0.05; 5-year disease-free survival rate, 30% versus 0%; 5-year overall survival rate, 65% vs 0%). Although dose reduction was needed in 2 patients because of grade 2 anorexia, only 1 patient with grade 2 hypoalbuminemia discontinued adjuvant chemotherapy because of long-term hospitalization. CONCLUSIONS: S-1 administered as a single agent showed promise as an adjuvant chemotherapy for resected pancreatic cancer.

Late-onset bile leakage after hepatic resection.

BACKGROUND: Postoperative bile leakage can be a serious complication after hepatic resection. Few studies have analyzed patients according to the time of onset of bile leakage. We analyzed differences between patients with early- and late-onset bile leakage after hepatic resection and assessed clinical characteristics and outcomes in patients with late-onset leakage. METHODS: Between 2008 and 2010, 1,009 patients underwent hepatic resection at 4 participating university hospitals and 2 community hospitals. Fifty-two patients (5.1%) with postoperative bile leakage were divided into an early-onset group (<2 weeks after surgery, n = 34) and a late-onset group (≥2 weeks after surgery, n = 18). Patient characteristics and outcomes were collected prospectively and analyzed retrospectively. RESULTS: The proportion of patients who underwent intra-abdominal placement of a drainage catheter was significantly less in the late-onset group than the early-onset group. All 18 patients in the late-onset group developed intra-abdominal infection, and 2 died of sepsis. The proportion of patients who underwent invasive treatment (abdominal paracentesis, endoscopic biliary drainage, or second hepatic resection) was significantly greater in the late-onset group than in the early-onset group. The time to resolution of bile leakage was significantly greater in the late-onset group than the early-onset group. CONCLUSION: Patients should be monitored carefully for bile leakage for several weeks after hepatic resection, because late-onset bile leakage can cause serious complications. Intra-abdominal infection should also be treated as soon as possible, because it may induce refractory bile leakage with serious complications.

Hepatic resection for hepatocellular carcinoma in super-elderly patients aged 80 years and older in the first decade of the 21st century.

PURPOSE: We evaluated the preoperative and postoperative characteristics and prognosis of super-elderly patients with hepatocellular carcinoma (HCC). METHODS: Four hundred and thirty-one patients who underwent hepatic resection for HCC were classified into three groups according to their age at the time of surgery: super-elderly (≥80 years; n = 20), elderly (70-80 years; n = 172) and younger (<70 years; n = 239). We compared the clinical characteristics, preoperative and postoperative factors and prognosis among the groups to evaluate whether liver resection is appropriate for super-elderly patients. RESULTS: The liver function was not significantly different among the groups. The proportion of patients with preoperative cardiovascular and respiratory disease and hypertension was higher in the super-elderly group compared to the other groups. The super-elderly group had shorter operations and reduced hemorrhage rates compared to the other groups. Postoperative cardiovascular complications and delirium were more frequently observed in the super-elderly group. The overall and tumor-free survival rates were not significantly different among the groups. Super-elderly patients had a lower rate of liver or HCC-related death and a higher rate of death due to other causes than the other groups. CONCLUSIONS: Super-elderly HCC patients who are appropriately evaluated and selected might have a favorable prognosis after undergoing hepatic resection.

Changes in laboratory test results and diagnostic imaging presentation before the detection of occupational cholangiocarcinoma.

OBJECTIVES: A cholangiocarcinoma outbreak among workers of an offset color proof-printing department in a printing company was recently reported. It is important to understand the clinical course leading to occupational cholangiocarcinoma development for investigation of the carcinogenesis process and for surveillance and early detection. We evaluated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma. METHODS: We investigated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma in 2 patients because the data were available. Results The clinical courses observed in the 2 participating patients showed persistent elevation of serum γ-glutamyl transpeptidase levels with or without elevated serum levels of alanine aminotransferase and/or aspartate aminotransferase before cholangiocarcinoma detection. Dilatation of the bile ducts without tumor-induced stenosis was observed several years before cholangiocarcinoma detection and progressed gradually in both patients. The serum concentration of carbohydrate 19-9 also increased prior to cholangiocarcinoma detection in both patients. Eventually, observation of stenosis of the bile duct and a space-occupying lesion strongly suggested cholangiocarcinoma. Pathological examination of the resected specimens showed chronic bile duct injury and neoplastic lesions, such as "biliary intraepithelial neoplasia" and "intraductal papillary neoplasm of the bile duct" in various sites of the bile ducts, particularly in the dilated bile ducts. CONCLUSIONS: The changes in laboratory test results and diagnostic imaging might be related to the development of cholangiocarcinoma. It is important to monitor diagnostic imaging presentation and laboratory test results in workers with extended exposure to organic solvents.

Doppler ultrasound findings correlate with tissue vascularity and inflammation in surgical pathology specimens from patients with small intestinal Crohn's disease.

BACKGROUND: Crohn's disease (CD) is routinely evaluated using clinical symptoms, laboratory variables, and the CD activity index (CDAI). However, clinical parameters are often nonspecific and do not precisely reflect the actual activity of CD small-intestinal lesions. The purposes of this prospective study were to compare color Doppler ultrasound (US) findings with histological findings from surgically resected specimens and confirm the hypothesis that color Doppler US can distinguish tissue inflammation and fibrosis. METHODS: Among 1764 consecutive patients who underwent color Doppler US examinations, 10 patients with CD (12 small-intestinal CD lesions) who underwent US examinations before elective small-intestine resection were evaluated in the present study. Areas of thickened intestinal walls were evaluated in terms of blood flow using color Doppler US imaging. The blood flow was semiquantitatively classified as "hyper-flow" and "hypo-flow" according to the Limberg score. Resected lesions were macroscopically and histopathologically processed. Inflammatory cell infiltration, fibrosis and vascularity were evaluated by myeloperoxidase (granulocytes), CD163 (macrophages), CD79a (B cells), CD3 (T cells), Masson's trichrome (fibrosis), and factor VIII staining (vascular walls). All histopathological images were entered into virtual slide equipment and quantified using a quantitative microscopy integrated system (TissueMorph™). RESULTS: There were no significant differences in disease features or laboratory findings between "hypo-flow" lesions (n = 4) and "hyper-flow" lesions (n = 8). Histopathologically, "hyper-flow" lesions showed significantly greater bowel wall vascularity (factor VIII) (p = 0.047) and inflammatory cell infiltration, including CD163 macrophages (p = 0.008), CD3 T cells, and CD79a B cells (p = 0.043), than did "hypo-flow" lesions. There was no apparent association between the blood flow and CDAI. CONCLUSIONS: In this study, active CD lesions were macroscopically visible in surgical specimens of patients with increased blood flow on preoperative color Doppler US imaging. Additionally, these CD lesions exhibited significantly greater vascularity and numbers of inflammatory leukocytes microscopically. Color Doppler US may predict tissue inflammation and fibrosis in small-intenstinal CD lesions.

Case series of 17 patients with cholangiocarcinoma among young adult workers of a printing company in Japan.

BACKGROUND: An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma. METHODS: This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young. RESULTS: The cholangiocarcinoma was diagnosed at 25-45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available. CONCLUSIONS: The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents.

Perivascular epithelioid cell tumor of the rectum: report of a case and review of the literature.

We report a case of perivascular epithelioid cell tumor arising in the rectum of a 55-year-old woman. The tumor was treated by transanal endoscopic microsurgery. After 1 year follow-up, the patient is alive with no radiologic or endoscopic evidence of recurrence. Perivascular epithelioid cell tumor is a rare mesenchymal tumor characterized by co-expression of melanocytic and smooth muscle markers. This rare tumor can arise in various organs, including the falciform ligament, uterus, uterine cervix, liver, kidney, lung, breast, cardiac septum, pancreas, prostate, thigh, and gastrointestinal tract. Perivascular epithelioid cell tumor of the gastrointestinal tract is very rare, with only 23 previously reported cases. We review the literature on perivascular epithelioid cell tumors arising in the gastrointestinal tract.

The Pathological Response to Anthracycline is Associated with Topoisomerase IIα Gene Amplification in the HER2 Breast Cancer Subset.

BACKGROUND: HER2-positive breast cancer sensitivity to anthracyclines is enhanced when topoisomerase IIα (TOP2A) is co-amplified under both adjuvant and metastatic settings. However, the relationship between anthracycline sensitivity and TOP2A amplification in HER2-positive breast cancers in neoadjuvant settings is not known. METHODS: The TOP2A gene status was examined by FISH in biopsies from 18 patients who received anthracycline and cyclophosphamide before surgery. RESULTS: The TOP2A gene was amplified in 6/17 patients and was significantly associated with pathological response to the chemotherapy regimen. CONCLUSIONS: TOP2A amplification could predict anthracycline-sensitivity. Thus, the HER2/TOP2A co-amplified subtype may be effectively treated by anthracycline-containing regimens alone.

Morbihan disease and extrafacial lupus miliaris disseminatus faceie: a case report.

Lupus miliaris disseminatus faciei (LMDF) is characterized by discrete dome-shaped papules on the bilateral face and neck. We report the first case of LMDF with a widespread distribution of extrafacial papules and concomitant bilateral eyelid edema. A unique case of a 30-year-old man presented with nonpruritic, painless, papular eruptions (3-5 mm in diameter) involving the bilateral trunk and upper extremities, along with bilateral eyelid edema. There was no facial eruption involved. The outbreak initially involved the back, and gradually spread to the chest and wrists. The histologic examination of the eyelids revealed histiocytic epitheloid cells, dermal intercellular edema, and an expanded vascular space, which led to the diagnosis of Morbihan disease. The immunohistochemical staining of the truncal eruption revealed nodular inflammatory changes involving the middle to lower dermis around the follicles, containing histiocytes, multinucleated giant cells, and small lymphocytes. This led to the diagnosis of LMDF. The truncal papular eruption ultimately improved with roxithromycin treatment, but the eyelid edema required surgical treatment.

Contrast-enhanced ultrasonography findings using a perflubutane-based contrast agent in patients with early hepatocellular carcinoma.

OBJECTIVE: We evaluated the contrast-enhanced ultrasonography (US) imaging features of early hepatocellular carcinomas (HCCs) and compared these findings with those obtained using contrast-enhanced computed tomography (CT). SUBJECTS AND METHODS: Forty-three patients with 52 early HCCs with a mean maximal diameter of 15.6mm were enrolled in this retrospective study. After confirming the location of the target lesion using fusion imaging combining conventional US and hepatobiliary phase of contrast-enhanced magnetic resonance (MR) imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid, we evaluated findings of contrast-enhanced US using a perflubutane-based contrast agent. The contrast-enhanced US detection rates for hyper-vascularity in early HCCs were compared with those obtained for contrast-enhanced CT. RESULTS: Transient hypo-vascularity subsequent to iso-vascularity during arterial phase and iso-vascularity during portal and post-vascular phases were the predominant contrast-enhanced US findings seen for 25 (48.1%) of the 52 early HCCs. Nine (17.3%) showed iso-vascularity during all three phases, while 1 (1.9%) showed hypo-vascularity during all three phases. The remaining 17 (32.7%) showed partial or whole hyper-vascularity during arterial phase, iso-vascularity during portal phase, and iso- or hypo-vascularity during post-vascular phase. The detection rate for the hyper-vascularity of early HCCs using contrast-enhanced US (32.7%, 17/52) was significantly higher than that obtained using contrast-enhanced CT (21.2%, 11/52) (P<0.05 by McNemar test). CONCLUSION: Hypo-vascularity, iso-vascularity, and hyper-vascularity were observed during the arterial phase of contrast-enhanced US in 50.0%, 17.3%, and 32.7% of the early HCCs, respectively. Contrast-enhanced US was more sensitive than contrast-enhanced CT for the detection of hyper-vascularity in early HCCs. Of note, early HCCs might not exhibit the early arterial enhancement that is generally considered to be a typical finding for HCCs.

Tumor-suppressive function of protein-tyrosine phosphatase non-receptor type 23 in testicular germ cell tumors is lost upon overexpression of miR142-3p microRNA.

Protein-tyrosine phosphatase non-receptor type 23 (PTPN23) is a candidate tumor suppressor involved in the tumorigenesis of various organs. However, its physiological role(s) and detailed expression profile(s) have not yet been elucidated. We investigated the function and regulation of PTPN23 in the formation of testicular germ cell tumors (TGCTs). Expression of PTPN23 in human TGCT cell lines was significantly lower than that in spermatogonial stem cells in mice. Overexpression of PTPN23 in NEC8, a human TGCT cell line, suppressed soft agar colony formation in vitro and tumor formation in nude mice in vivo. These data indicate that PTPN23 functions as a tumor suppressor in TGCTs. Multiple computational algorithms predicted that the 3' UTR of human PTPN23 is a target for miR-142-3p. A luciferase reporter assay confirmed that miR-142-3p bound directly to the 3' UTR of PTPN23. Introduction of pre-miR-142 in the PTPN23 transfectant of NEC8 led to suppressed expression of PTPN23 and increased soft agar colony formation. Quantitative RT-PCR data revealed a significantly higher expression of miR-142-3p in human seminomas compared with normal testes. No difference in mRNA expression between seminoma and non-seminoma samples was detected by in situ hybridization. Both quantitative RT-PCR and immunohistochemical analyses revealed that PTPN23 expression was significantly lower in TGCTs than in normal testicular tissues. Finally, a lack of PTPN23 protein expression in human TGCTs correlated with a relatively higher miR-142-3p expression. These data suggest that PTPN23 is a tumor suppressor and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of TGCTs.