The Geriatric Nutritional Risk Index and Prognostic Nutritional Index Predict the Overall Survival of Advanced Non-Small Cell Lung Cancer Patients.

We aimed to assess the prognostic and predictive significance of pretreatment Geriatric Nutritional Risk Index (GNRI) and Prognostic Nutritional Index (PNI) measurements on advanced non-small cell lung cancer (NSCLC) patients treated with first-line therapy. Patients with advanced NSCLC treated between February 2014 and August 2020 were retrospectively analyzed. The optimal cutoff points for GNRI and PNI were measured with receiver operating characteristic (ROC) curve analysis according to overall survival (OS). The predictive factors for progression-free survival (PFS) and OS were evaluated with univariate and multivariate analyses via the Cox hazards regression. A total of 160 patients were included in the study. Significant differences between the low and high-GNRI or PNI groups were found regarding ECOG-PS. The low-GNRI and low-PNI groups had significantly shorter PFS and OS than the high-GNRI and high-PNI groups. A multivariate analysis using a Cox regression model revealed that the high-GNRI group was an independent prognostic factor of OS and PFS, and the PNI group was an independent prognostic factor of OS. Pretreatment GNRI and PNI may therefore be a potential effective predictor of the survival of advanced NSCLC patients undergoing first-line treatment.

Programmed cell death-1 blockade in kidney carcinoma may induce eosinophilic granulomatosis with polyangiitis: a case report.

BACKGROUND: Immune checkpoint inhibitors have potential applications in treating various cancers but are associated with immune-related adverse events, such as inflammation, in a wide range of organs; however, allergic inflammation caused by these agents has not been extensively studied. CASE PRESENTATION: A 65-year-old man was diagnosed with a kidney neuroendocrine carcinoma. Three months after kidney resection surgery, the tumor cells had metastasized to his liver and lymph nodes. Subsequently, the patient started chemotherapy; however, regardless of treatment, the tumor grew, and the patient experienced a series of adverse effects, such as taste disorder, anorexia, and general fatigue. Finally, he was administered a programmed cell death (PD)-1 inhibitor, nivolumab (biweekly, toal 200 mg/body), which was effective against kidney carcinoma. However, the patient had a bronchial asthma attack at 22 cycles of nivolumab treatment and chest computed tomography (CT) revealed an abnormal bilateral shadow after 37 cycles of nivolumab treatment. Bronchoscopy findings revealed eosinophil infiltration in the lungs along with severe alveolar hemorrhage. Paranasal sinus CT scanning indicated sinusitis and nerve conduction analysis indicated a decrease in his right ulnar nerve conduction velocity. Based on these findings, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis; he was treated with prednisolone, which alleviated his bronchial asthma. To restart nivolumab treatment, the dose of prednisolone was gradually tapered, and the patient was administered a monthly dose of mepolizumab and biweekly dose of nivolumab. To date, there have been no bronchial attacks or CT scan abnormalities upon follow up. CONCLUSIONS: We present a rare case in which a patient with cancer was diagnosed with eosinophilic granulomatosis with polyangiitis following treatment with a PD-1 inhibitor. Blockade of PD-1 and the programmed cell death ligand (PD-L) 1/PD-1 and PD-L2/PD-1 signaling cascade may cause allergic inflammation. Further studies are needed to identify the specific mechanisms underlying allergic inflammation after PD-1 blockade.

Intratubular epithelial-mesenchymal transition and tubular atrophy after kidney injury in mice.

Tubular atrophy is a common pathological feature of kidney fibrosis. Although fibroblasts play a predominant role in tissue fibrosis, the role of repairing tubular epithelia in tubular atrophy is unclear. We demonstrated the essential role of focal adhesion kinase (FAK)-mediated intratubular epithelial-mesenchymal transition (EMT) in the pathogenesis of tubular atrophy after severe ischemia-reperfusion injury (IRI). Actively proliferating tubular epithelia undergoing intratubular EMT were noted in the acute phase of severe IRI, resulting in tubular atrophy in the chronic phase, reflecting failed tubular repair. Furthermore, FAK was phosphorylated in the tubular epithelia in the acute phase of severe IRI, and its inhibition ameliorated both tubular atrophy and interstitial fibrosis in the chronic phase after injury. In vivo clonal analysis of single-labeled proximal tubular epithelial cells after IRI using proximal tubule reporter mice revealed substantial clonal expansion after IRI, reflecting active epithelial proliferation during repair. The majority of these proliferating epithelia were located in atrophic and nonfunctional tubules, and FAK inhibition was sufficient to prevent tubular atrophy. In vitro, transforming growth factor-ß induced FAK phosphorylation and an EMT phenotype, which was also prevented by FAK inhibition. In an in vitro tubular epithelia gel contraction assay, transforming growth factor-ß treatment accelerated gel contraction, which was suppressed by FAK inhibition. In conclusion, injury-induced intratubular EMT is closely related to tubular atrophy in a FAK-dependent manner.

Glycogen synthase kinase-3ß participates in acquired resistance to gemcitabine in pancreatic cancer.

Acquisition of resistance to gemcitabine is a challenging clinical and biological hallmark property of refractory pancreatic cancer. Here, we investigated whether glycogen synthase kinase (GSK)-3ß, an emerging therapeutic target in various cancer types, is mechanistically involved in acquired resistance to gemcitabine in human pancreatic cancer. This study included 3 gemcitabine-sensitive BxPC-3 cell-derived clones (BxG30, BxG140, BxG400) that acquired stepwise resistance to gemcitabine and overexpressed ribonucleotide reductase (RR)M1. Treatment with GSK3ß-specific inhibitor alone attenuated the viability and proliferation of the gemcitabine-resistant clones, while synergistically enhancing the efficacy of gemcitabine against these clones and their xenograft tumors in rodents. The gemcitabine-resensitizing effect of GSK3ß inhibition was associated with decreased expression of RRM1, reduced phosphorylation of Rb protein, and restored binding of Rb to the E2 transcription factor (E2F)1. This was followed by decreased E2F1 transcriptional activity, which ultimately suppressed the expression of E2F1 transcriptional targets including RRM1, CCND1 encoding cyclin D1, thymidylate synthase, and thymidine kinase 1. These results suggested that GSK3ß participates in the acquisition of gemcitabine resistance by pancreatic cancer cells via impairment of the functional interaction between Rb tumor suppressor protein and E2F1 pro-oncogenic transcription factor, thereby highlighting GSK3ß as a promising target in refractory pancreatic cancer. By providing insight into the molecular mechanism of gemcitabine resistance, this study identified a potentially novel strategy for pancreatic cancer chemotherapy.

Development of a novel T cell-oriented vaccine using CTL/Th-hybrid epitope long peptide and biodegradable microparticles, against an intracellular bacterium.

Antigen-specific CD8+ T-lymphocytes (cytotoxic T-lymphocytes: CTL), as well as CD4+ T-lymphocytes (helper T-lymphocytes: Th), simultaneously play an important role in the elimination of intracellular bacteria such as Mycobacterium tuberculosis and Listeria monocytogenes. Administration of T-cell epitope short peptide needs large numbers of peptides for effective vaccination due to its easily degradable nature in vivo. In this respect, biocompatible and biodegradable microparticles combined with CTL/Th-hybrid epitope long peptide (long peptide) have been used to diminish the degradation of loaded peptide. The aim of this study is to develop a novel T cell-oriented vaccine against intracellular bacteria that is composed of long peptide and poly (lactic-co-glycolic acid) (PLGA) microparticles. Mouse bone marrow-derived dendritic cells (BMDCs) were loaded with L. monocytogenes listeriolysin O (LLO)-derived or ovalbumin (OVA)-derived long peptide/PLGA or other comparative antigens. The antigen-loaded BMDCs were injected subcutaneously into the flank of mice twice, and then, the spleens were collected and lymphocyte proliferation and interferon-γ production were evaluated. The median diameter of the PLGA spheres was 1.38 µm. Both LLO- and OVA-long peptide/PLGA showed significantly more robust CTL and Th proliferations with higher interferon-γ production than the long peptide alone or CTL and Th short peptides/PLGA vaccination. Furthermore, the LLO-long peptide/PLGA vaccination showed a significantly lower bacterial burden in spleens compared with the long peptide alone or the CTL and Th short peptides/PLGA vaccination after the challenge of lethal amounts of L. monocytogenes. These results suggest that the novel vaccine taking advantages of CTL/Th-hybrid epitope long peptide and PLGA microparticle is effective for protection against intracellular bacteria.

Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia.

BACKGROUND AND OBJECTIVE: Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). METHODS: Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. RESULTS: Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took ≥1085 mg/m2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). CONCLUSION: BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP.

Renal artery stenosis following nilotinib administration in a patient with chronic myelogenous leukemia.

A 63-year-old male was diagnosed as having chronic phase CML in 2001. He obtained a major molecular response with imatinib (IM). In 2012, amulodipin was started for hypertension. In January 2013, IM was switched to nilotinib (NIL) in a clinical trial, and in February 2015, NIL was discontinued because MR4.5 had been maintained for two years. One month later, he was admitted to our hospital because of headache and high blood pressure (194/108 mmHg). His urine test showed protein 3+ and occult blood 2+. His eGFR rapidly deteriorated from 45.6 to 28.5 after admission. MR angiography showed left renal artery stenosis. He thus underwent angioplasty of the left renal artery with a stent implantation. His renal function subsequently improved. Cardiovascular events such as PAOD (peripheral artery occlusive disease) during NIL treatment were recently reported. However, to date, only four cases including our present patient with renal artery stenosis associated with NIL have been reported. These observations suggest assessment of risk factors for cardiovascular events at the start of NIL and careful monitoring to be important during tyrosine kinase inhibitor treatment of CML patients.

Glycogen synthase kinase-3ß is a pivotal mediator of cancer invasion and resistance to therapy.

Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3ß is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3ß sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3ß. This review focuses on the role of GSK3ß as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3ß in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes.

Estimation of Skin Blood Flow Artefacts in NIRS Signals During a Verbal Fluency Task.

The aim of this study was to clarify effects of skin (scalp) blood flow on functional near infrared spectroscopy (fNIRS) during a verbal fluency task. In the present study, to estimate the influence of skin blood flow on fNIRS signals, we conducted examinations on 19 healthy volunteers (39.9±13.1 years, 11 male and 8 female subjects). We simultaneously measured the fNIRS signals, skin blood flow (i.e., flow, velocity, and number of red blood cells [RBC]), and pulse wave rates using a multimodal fNIRS system. We found that the effects of skin blood flow, measured by the degree of interference of the flow, velocity, and number of RBCs, and pulse wave rates, on NIRS signals varied considerably across subjects. Further, by using the above physiological parameters, we evaluated application of the independent component analysis algorithm proposed by Molgedey and Schuster (MS-ICA) to remove skin blood flow artefacts from fNIRS signals.

Relationship Between Peritoneal Transport Characteristics and Natriuretic Peptides in Peritoneal Dialysis Patients.

Few studies have attempted to evaluate the relationship between peritoneal permeability and fluid status in peritoneal dialysis (PD). The aim of the present study was to clarify the relationship between change in the dialysate-to-plasma ratio of creatinine (D/P Cr) and change in fluid status as evaluated by natriuretic peptides. We studied 49 PD patients (29 men, 62 ± 11 years, 36.7% with diabetes) who underwent a peritoneal equilibration test at least twice after PD initiation. We evaluated correlations between the rate of change in the D/P Cr (R C-D/P Cr), the rate of change in a human atrial natriuretic polypeptide (RC-αhANP), and the rate of change in brain natriuretic peptide (RC-BNP). The RC-αhANP was strongly correlated with RC-BNP (r = 0.637, p < 0.001). In contrast, the RC-D/P Cr was not correlated with RC-αhANP (r = 0.041, p = 0.781) or with RC-BNP (r = 0.114, p = 0.435). However, positive correlations between RC-D/P Cr and RC-αhANP (r = 0.530, p = 0.006) and between RC-D/P Cr and RC-BNP (r = 0.625, p = 0.001) were observed in patients with increased D/P Cr The present study showed a positive correlation between change in peritoneal transport characteristics and change influid status in patients whose D/P Cr increased.

Pulmonary cryptococcosis suspected due to inhalation of swallow excreta presenting with multiple infiltrative shadows.

A 70-year-old woman had been treated with methotrexate for rheumatoid arthritis by a rheumatologist who opened a clinic near our hospital. In January of a certain year, she had respiratory symptoms of cough, sputum, and fever. Laboratory test results showed a white blood cell count of 8600/µL (neutrophil count of 5330/µL, lymphocyte count of 2490 µ/L), C-reactive protein (CRP) of 3.30 mg/dL. Chest radiography showed multiple infiltrative shadows in the right middle and lower lobes. Bronchoalveolar lavage fluid (BAL) lymphocyte count was increased (65.1%), and histopathological findings were consistent with numerous bowl-shaped cryptococcus cells stained black by Grocott staining. Added measurement of serum cryptococcal antigen titers was 4096-fold. Treatment with fluconazole 400 mg/day was initiated, and her symptoms resolved; the shadows of the lung fields improved. When asked in detail, the cryptococcus infection route was suspected from swallow excreta. There have been no reported cases of pulmonary cryptococcosis suspected due to inhalation of swallow excreta presenting with multiple infiltrative shadows.

Glycogen synthase kinase 3ß: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer.

The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3ß in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3ß in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3ß as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3ß in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3ß has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.

Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

PURPOSE: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy. PATIENTS AND METHODS: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety. RESULTS: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity. CONCLUSION: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Eosinophilic pneumonia developed after dupilumab administration in a patient with atopic dermatitis.

A 63-year-old woman with refractory atopic dermatitis started treatment with dupilumab. She developed a cough 4 days later, sputum, and a slight fever 2 weeks later. Laboratory test results showed a blood eosinophil count of 7360/µL. Chest x-ray and computed tomography scan showed infiltrative shadows with surrounding consolidation of both upper lobes. Bronchoalveolar lavage fluid eosinophil count was increased (50.0%), and histopathological findings were consistent with numerous eosinophilic infiltrations. Treatment with prednisolone 30 mg/day (0.5 mg/kg/day) was initiated. Her symptom resolved, and the shadow of the lung fields improved. There have been no reported cases of eosinophilic pneumonia diagnosed 7 weeks after the administration of dupilumab for atopic dermatitis.

[Long-term progression-free survival after reduction surgery and postoperative low-dose imatinib administration for multiple liver metastases of duodenal gastrointestinal stromal tumor].

A fifty-six year-old woman visited our institute, suffering from lower abdominal pain. A tumor was palpable in the pelvic cavity, having the diameter of 9.7 cm, as measured by transvaginal ultrasonography (US). Computed tomography and magnetic resonance imaging (MRI) revealed a high contrast-enhancement and the central necrosis of the tumor. Surgical resection was performed, and the tumor was found to have originated in the duodenum. Immunohistochemistry confirmed positive KIT, and the mitotic index was 4 per 50 high power field, so that the final diagnosis was a gastrointestinal stromal tumor of intermediate risk. After two years of observation, multiple liver metastases were found. Hepatectomy was performed as a volume reduction surgery, leaving three small lesions in the remnant liver. Imatinib administration was initiated at 400 mg a day two weeks after the surgery, but was interrupted two weeks later because of severe anorexia and a body weight gain of 7 kg due to the increased ascites and edema. Imatinib was resumed at 200 mg/day after a one-month interval. She has been enjoying relapse-free survival for 8 years since the recurrence was diagnosed. Although neither reduction surgery nor dose reduction of imatinib below 300 mg/day is recommended, there may be a possibility that a smaller tumor might be controlled by a lower dose of imatinib.

[Recurrent liver sigmoid cancer responding remarkably to neoadjuvant chemotherapy using bevacizumab/XELOX: report of a case].

A 65-year-old male experiencing the recurrence of a solitary sigmoid cancer liver tumor was treated with bevacizumab (Bev)/XELOX chemotherapy, because he had refused surgical resection. After 5 courses, CT findings showed a partial response( 80% size-reduction)of the recurrent liver tumor. There was no recurrence in any other organ. He then requested hepatectomy, so we performed it, and there were no complications. The histological diagnosis was metastatic liver tumor, the estimation of the histological change by chemotherapy was Grade 2, and no abnormalities were found in the background of the liver. Bev/XELOX was relatively safe and successful for pre-operative patients with liver tumor recurrence.

[A case of pagetoid carcinoma of the breast in nearly complete response by primary systemic therapy].

A 62-year-old female presented with an erosion of the left nipple. At the preoperative examination, it was diagnosed as a Pagetoid carcinoma with an invasive carcinoma. After primary systemic therapy(weekly paclitaxel/trastuzumab), we performed an operation. The only remaining Paget cell was confirmed in the resected specimen, and no other malignant cells were confirmed. There is no report that the preoperative chemotherapy for the Pagetoid carcinoma with an invasive carcinoma. The patient has had no evidence of recurrence 1. 5 years after the operation.

Transcatheter aortic valve implantation in rheumatic aortic stenosis with a functioning mitral prosthesis.

Transcatheter aortic valve implantation (TAVI) for patients with rheumatic aortic stenosis (AS) is not well-known. We herein report a case of TAVI in rheumatic AS without significant calcification and prior mitral valve replacement. An 80-year-old woman underwent TAVI for severe AS. Preoperative computed tomography revealed tricuspid aortic valve leaflets with commissural fusion, minimal calcification, and a minimal distance between the aortic annulus and mechanical mitral valve. TAVI was performed through a transfemoral approach under general anesthesia. After predilatation of the aortic valve with a 20-mm balloon, a 23-mm SAPIEN 3 valve was successfully deployed via slow inflation. Valve embolization did not occur, and the valve did not interfere with the prosthetic mitral leaflets. This report shows that TAVI can be safe, feasible, and effective in patients with rheumatic AS without significant calcification and prior mitral valve replacement. .

Argon plasma coagulation with atezolizumab and chemoradiation in lung pleomorphic cancer showed a remarkable response: Case report.

RATIONALE: Lung pleomorphic carcinoma (LPC) is generally resistant to chemotherapy or radiotherapy. However, a combination of immune checkpoint inhibitors and radiotherapy has a remarkable efficacy against LPC. PATIENT CONCERNS AND DIAGNOSES: Here, we report the case of a 50-year old man diagnosed with progressive LPC. The tumor invaded the carina and predominantly obstructed the right main bronchus; therefore, a combination of palliative chemoradiotherapy and atezolizumab was initiated. However the trachea was gradually obstructed. INTERVENTION AND OUTCOME: Argon plasma coagulation (APC) was performed to prevent tumor invasion. After three APC sessions, the tumor showed a necrotic change and was easily excised using biopsy forceps. LESSONS: A combination of chemoradiotherapy, atezolizumab, and APC showed a good efficacy, and the patient had a good response to atezolizumab maintenance therapy. Multidisciplinary treatments, such as a combination of immune checkpoint inhibitors and APC, could have synergistic efficacy in lung cancer.

Familial clustering and genetic background of primary biliary cirrhosis in Japan.

BACKGROUND: Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease. AIMS: To elucidate the genetic background of PBC by investigating familial cases of PBC. METHODS: Familial cases were picked out from 171 PBC patients who enrolled in this study. We analyzed them and their family members, and compared them clinically and immunogenetically to non-familial cases. RESULTS: Out of 171 PBC patients, ten (5.8%) were identified as familial PBC in five families. The clinical features of familial PBC were almost comparable to those of non-familial PBC. The distribution of human leukocyte antigens (HLA)-A, -B and -DR in familial PBC showed no specificity. Two new PBC patients were identified in one family in addition to the two originally enrolled PBC patients, resulting in four patients with PBC within the same family. The two new PBC patients had an identical HLA haplotype. On the other hand, one HLA-identical sister of a PBC patient in another family did not develop PBC. CONCLUSIONS: Primary biliary cirrhosis can exhibit familial clustering without any HLA predisposition, however, a survey of families for PBC could be useful for identifying new patients with PBC in the asymptomatic stage for earlier diagnosis and treatment.