Small renal cell carcinoma accompanied by extensive inferior vena cava tumor thrombus diagnosed by percutaneous transvenous biopsy.

Introduction: Up to 10% of patients with renal cell carcinoma present with tumor thrombus in the inferior vena cava. We report that a case of small renal cell carcinoma with tumor thrombus extending above the diaphragm for which transvenous biopsy was performed for diagnosis. Case presentation: A 79-year-old man performed computed tomography to evaluate hepatic dysfunction, which revealed intravenous tumor extending above the diaphragm and a 15-mm-sized exophytic tumor in right kidney. Imaging suggested that the renal tumor was renal cell carcinoma. As this tumor was small and exophytic, confirmation of the intravenous tumor being tumor thrombus associated with renal cell carcinoma was difficult. We simultaneously performed transvenous biopsy on the intravenous tumor and percutaneous biopsy on the renal tumor for obtaining histologic diagnoses. The final diagnosis was small renal cell carcinoma accompanied by tumor thrombus above the diaphragm. Conclusion: Transvenous biopsy may be useful for the definitive diagnosis of inferior vena cava-tumor thrombus in cases of small renal cell carcinoma.

An approach for improvement of the accuracy of cancer gene panel testing.

BACKGROUND: Tissue-based comprehensive genomic profiling (CGP) is increasingly being employed for genotype-directed therapies in patients with advanced cancer. However, tissue availability may limit their potential applications. In Japan, the cost of cancer gene panel tests is covered by public insurance for patients diagnosed with advanced solid tumors once in their lifetime. Therefore, it is essential to improve the success rate (reportability) and accuracy of CGP tests. The purpose of this study was to identify the factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data. METHODS: This study included 159 samples analyzed using tumor-only panel FoundationOne® CDx cancer genome profiling (F1CDx) and 85 samples analyzed using matched-pair panel OncoGuide™ NCC Oncopanel system (NCCOP) at St. Marianna University Hospital. Sample characteristics (fixation conditions, storage period, histology, tumor cell ratio, and genomic tumor cell content), CGP performance, and quality control status were evaluated across all 244 tested samples. RESULTS: In 237/244 samples (97.1%), CGP testing results were successfully obtained [F1CDx, 99.4% (158/159) and NCCOP, 92.9% (79/85)]. An increased number of fibroblasts, inflammatory cells, and necrotic tumor cells, long-term storage, and/or prolonged fixation of tissue sections were involved in the unreported results and/or qualified CGP results. In addition, a negative correlation between median insert size values and ΔΔCq was observed in the NCCOP system. CONCLUSION: We identified various factors associated with efficient and accurate CGP testing using relevant information obtained from real-world data, suggesting that thorough selection and preparation of tissue sections could optimize CGP and maximize useful information.

Clinicopathological differences in focal segmental glomerulosclerosis depending on the accompanying pathophysiological conditions in renal allografts.

Primary focal segmental glomerulosclerosis (FSGS) is thought to be caused by circulating factors leading to podocytopathy, whereas segmental sclerotic lesions (FSGS lesions) have several causes. We studied the clinicopathological differences of FSGS-lesions in 258 cases of FSGS in renal allografts, depending on the following accompanying pathophysiology: recurrence of primary FSGS, calcineurin inhibitor (CNI)-induced arteriolopathy, antibody-mediated rejection (ABMR), and other conditions. All cases were categorized with the Columbia classification. Recurrent FSGS developed the earliest after transplantation and showed the highest percentage of the collapsing (COL) variant in which collapse of the glomerular capillaries with epithelial hypertrophy was apparent. FSGS accompanying CNI-induced arteriolopathy predominantly developed the not otherwise specified (NOS) variant, showing severe ultrastructural endothelial injury. On the contrary, approximately 7% of the cases showed the COL variant, presenting glomerular endothelial damage such as double contours of glomerular basement membrane and endothelial cell swelling as well as epithelial cell proliferation. FSGS with ABMR had the highest creatinine levels and cellular variant percentage, with marked inflammation and ultrastructural endothelial injury. Approximately two-thirds of the cases without ABMR, CNI-induced arteriopathy, or recurrent FSGS had other coexisting conditions such as glomerulonephritis, T cell-mediated rejection, and reflux nephropathy with progressive tubulointerstitial fibrosis. Most of these cases were of the NOS variant. The clinicopathologic features of post-transplant FSGS differed depending on the associated conditions, and endothelial injury was apparent especially in cases of CNI-induced arteriolopathy and ABMR. Precise observation of FSGS lesions may facilitate the diagnosis and clinical management of FSGS during renal transplantation.

Glomerular lipidosis as a feature of renal-limited macrophage activation syndrome in a transplanted kidney: a case report.

BACKGROUND: Glomerular lipidosis is a rare histological feature presenting the extensive glomerular accumulation of lipids with or without histiocytic infiltration, which develops under various conditions. Among its various etiologies, macrophage activation syndrome (MAS) is a condition reported to be associated with histiocytic glomerular lipidosis. Here we describe the first case of glomerular lipidosis observed in a renal allograft that histologically mimicked histiocytic glomerulopathy owing to MAS. CASE PRESENTATION: A 42-year-old man underwent successful living-donor kidney transplantation. However, middle-grade proteinuria and increased serum triglyceride levels indicative of type V hyperlipidemia developed rapidly thereafter. An allograft biopsy performed 6 months after the transplantation showed extensive glomerular infiltration of CD68+ foam cells (histiocytes) intermingled with many CD3+ T-cells (predominantly CD8+ cells). Furthermore, frequent contact between glomerular T-cells and histiocytes, and the existence of activated CD8+ cells (CD8+, HLA-DR+ cells) were observed by double immunostaining. There was no clinicopathological data suggesting lipoprotein glomerulopathy or lecithin cholesterol acyltransferase deficiency, both of which are well-known causes of glomerular lipidosis. The histological findings were relatively similar to those of histiocytic glomerulopathy caused by MAS. As systemic manifestations of MAS, such as fever, pancytopenia, coagulation abnormalities, hyperferritinemia, increased liver enzyme levels, hepatosplenomegaly, and lymphadenopathy were minimal, this patient was clinicopathologically diagnosed as having renal-limited MAS. Although optimal treatment strategies for MAS in kidney transplant patients remains unclear, we strengthened lipid-lowering therapy using pemafibrate, without modifying the amount of immunosuppressants. Serum triglyceride levels were normalized with this treatment; however, the patient's extensive proteinuria and renal dysfunction did not improve. Biopsy analysis at 1 year after the transplantation demonstrated the disappearance of glomerular foamy changes, but the number of glomerular infiltrating cells remained similar. CONCLUSION: To our knowledge, this is the first reported case of glomerular lipidosis in a transplanted kidney. Increased interaction-activation of histiocytes (macrophages) and CD8+ T-cells, the key pathogenic feature of MAS, was observed in the glomeruli of this patient, who did not demonstrate overt systemic manifestations, suggesting a pathological condition of renal-limited MAS. The clinical effects of triglyceride-lowering therapy were limited, suggesting that hypertriglyceridemia was not the cause of but rather may be a consequence of renal-limited MAS.

Ultrasound Doppler Findings in Fetal Vascular Malperfusion Due to Umbilical Cord Abnormalities: A Pilot Case Predictive for Cerebral Palsy.

Fetal Vascular Malperfusion (FVM), a pathologic condition in the feto-placental circulation, is a chronic vaso-occlusive disorder in the umbilical venous blood flow. Microthrombi are caused by the umbilical cord's blood flow deficiency in a congested umbilical vein, which also causes microvascular damage to fetal organs, especially the brain, resulting in cerebral palsy. Thrombo-occlusive events also adversely affect the upstream chorionic or stem vessels in the placenta, resulting in fetal growth restriction and fetal hypoxia. An umbilical cord structural anomaly or multiple entanglements may involve FVM. In the present report, we demonstrate a case of FVM caused by multiple umbilical cord abnormalities obtained from antenatal ultrasound Doppler findings, and we also discuss FVM, which is chronically associated with CP, comparing the ultrasonographic findings to the pathologic findings.

Immunoglobulin G deposition on proximal tubules and the tubular basement membrane in acute tubular injury complicated with focal segmental glomerulosclerosis (FSGS): A possible prediction tool for subclinical FSGS.

Immunofluorescent deposition of immunoglobulin G (IgG) in the tubular basement membrane (TBM) has been evaluated in the diagnosis of various diseases; however, few studies have investigated the immunofluorescence of acute tubular injury (ATI). Herein, we attempted to clarify IgG expression in the proximal tubular epithelium and TBM in ATI due to various causes. Patients with ATI with nephrotic-range proteinuria, including focal segmental glomerulosclerosis (FSGS, n = 18) and minimal change nephrotic syndrome (MCNS, n = 8), ATI with ischemia (n = 6), and drug-induced ATI (n = 7), were enrolled. ATI was evaluated by light microscopy. CD15 and IgG double staining and IgG subclass staining were performed to evaluate immunoglobulin deposition in the proximal tubular epithelium and TBM. IgG deposition was identified in the proximal tubules only in the FSGS group. Furthermore, IgG deposition in the TBM was observed in the FSGS group showing severe ATI. IgG3 was predominantly deposited by the IgG subclass study. Our results indicate that IgG deposition in the proximal tubular epithelium and TBM suggests the leaking of IgG from the glomerular filtration barrier and its reabsorption by proximal tubules, which may predict disruption of the glomerular size barrier, including subclinical FSGS. FSGS with ATI should be included as a differential diagnosis when IgG deposition in TBM is observed.

Overexpression of Plasmalemmal Vesicle-Associated Protein-1 Reflects Glomerular Endothelial Injury in Cases of Proliferative Glomerulonephritis with Monoclonal IgG Deposits.

Introduction: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) occasionally presents refractory nephrotic syndrome resulting in poor renal prognosis, but its etiology is not fully elucidated. Given that glomerular endothelial cell (GEC) stress or damage may lead to podocytopathy and subsequent proteinuria, as in thrombotic microangiopathy (TMA), diabetic kidney disease, and focal segmental glomerulosclerosis, we investigated the evidence of glomerular endothelial injury by evaluating the expression of plasmalemmal vesicle-associated protein-1 (PV-1), a component of caveolae in the cases of PGNMID. Methods: We measured the immunofluorescent PV-1 intensities of 23 PGNMID cases and compared with those of primary membranoproliferative glomerulonephritis (MPGN) (n = 5) and IgA nephropathy (IgAN) (n = 54) cases. PV-1 localization was evaluated with Caveolin-1, and CD31 staining, and the ultrastructural analysis was performed using a low-vacuum scanning electron microscope (LVSEM). To check the association of podocyte injury, we also conducted 8-oxoguanine and Wilms tumor 1 (WT1) double stain. We then evaluated PV-1 expression in other glomerulitis and glomerulopathy such as lupus nephritis and minimal change disease. Results: The intensity of glomerular PV-1 expression in PGNMID is significantly higher than that in the other glomerular diseases, although the intensity is not associated with clinical outcomes such as urinary protein levels or renal prognosis. Immunostaining and LVSEM analysis revealed that glomerular PV-1 expression is localized in GECs in PGNMID. 8-oxoguanine accumulation was detected in WT1-positive podocytes but not in PV-1-expressing GECs, suggesting GEC-derived podocyte injury in PGNMID. Conclusion: PV-1 overexpression reflects glomerular endothelial injury, which could be associated with podocyte oxidative stress in PGNMID cases.

Immunosensitivity and specificity of insulinoma-associated protein 1 (INSM1) for neuroendocrine neoplasms of the uterine cervix.

OBJECTIVE: Previously, we reported that insulinoma-associated protein 1 (INSM1) immunohistochemistry (IHC) showed high sensitivity for neuroendocrine carcinoma of the uterine cervix and was an effective method for histopathological diagnosis, but that its specificity remained to be verified. Therefore, the aim was to verify the specificity of INSM1 IHC for a large number of non-neuroendocrine neoplasia (NEN) of the cervix. METHODS: RNA sequences were performed for cell lines of small cell carcinoma (TCYIK), squamous cell carcinoma (SiHa), and adenocarcinoma (HeLa). A total of 104 cases of formalin-fixed and paraffin-embedded specimens, 16 cases of cervical NEN and 88 cases of cervical non-NEN, were evaluated immunohistochemically for conventional neuroendocrine markers and INSM1. All processes without antigen retrieval were performed by an automated IHC system. RESULTS: The transcripts per million levels of INSM1 in RNA sequences were 1505 in TCYIK, 0 in SiHa, and HeLa. INSM1 immunoreactivity was shown only in the TCYIK. Immunohistochemical results showed that 15 cases of cervical NEN showed positive for INSM1; the positivity score of the tumor cell population and the stain strength for INSM1 were high. Two of the 88 cases of cervical non-NENs were positive for INSM1 in one case each of typical adenocarcinoma and squamous cell carcinoma. The sensitivity of INSM1 for cervical NEN was 94%; specificity, 98%; the positive predictive value, 88%; and the negative predictive value, 99%. CONCLUSION: INSM1 is an adjunctive diagnostic method with excellent specificity and sensitivity for diagnosing cervical NEN. Higher specificity can be obtained if morphological evaluation is also performed.

RET fusion mutation detected by re-biopsy 7 years after initial cytotoxic chemotherapy: A case report.

Personalized medicine using molecular-targeted drugs to achieve better therapeutic response and long-term prognosis is common practice for lung cancer treatment. However, in cases before gene batch tests were available, medical treatment continued without the detection of rare mutations. We report a sixty-seven-old year man diagnosed with adenocarcinoma T1cN3M1a, stage IVA. Initial screening performed 7 years earlier using EGFR mutation and ALK immunohistochemical tests were negative. Although first-line cytotoxic combination chemotherapy was remarkably effective, a gradual regression of the primary lesion was noted. After a recent bronchoscopic re-biopsy, RET fusion was detected by gene panel test. In addition, we were able to confirm RET from FFPE specimens obtained from 7-year-old pleural effusion cell blocks. Subsequent administration of the molecular-targeted drug selpercatinib, was highly effective for the primary lesion and all metastatic lesions including brain metastases. We describe a case of RET fusion-positive lung cancer where molecular targeted therapy and cytotoxic drug showed a drastic response and long-term therapy was well maintained. Next generation sequencing was able to correctly diagnose RET fusion mutation using re-biopsy specimen after going undiagnosed for 7 years.

Granulomatous interstitial nephritis with CTLA-4 haploinsufficiency: a case report.

BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential inhibitory regulator of immune activation. CTLA-4 haploinsufficiency is known to be associated with dysregulation of FOXP3+ regulatory T cells, hyperactivation of effector T cells, and lymphocytic infiltration of multiple organs. However, there have only been a few reports of renal involvement with CTLA-4. Herein, we present a case of acute granulomatous tubulointerstitial nephritis (TIN) in a patient with CTLA-4 haploinsufficiency. CASE PRESENTATION: A 44-year-old man presented with a 3-week history of fever and malaise, and subsequently developed acute kidney injury (AKI) a few days after treatment with levofloxacin (LVFX). A kidney biopsy and immunohistochemical staining revealed granulomatous TIN with dominantly infiltrating CD4+ T cells. General symptoms and renal impairment showed improvement after discontinuation of LVFX and initiation of oral steroids. However, they worsened following steroid tapering. Further, a colon biopsy analysis showed similar findings to the renal tissue analysis. We suspected that granulomatous TIN was possibly associated with CTLA-4 haploinsufficiency. Therefore, the patient was transferred to another hospital for further treatment of CTLA-4 haploinsufficiency using immunosuppressive agents. CONCLUSIONS: There have been few reports regarding renal involvement of CTLA-4 haploinsufficiency. In the present case, granulomatous TIN could have arisen due to instability of immune regulatory functions, such as CTLA-4 haploinsufficiency, and treatment with LVFX could have triggered immunologic activation and severe inflammation as well as renal dysfunction.

Lymph node recurrence and re-excision after primary tumor resection of a histiocytic sarcoma of duodenal origin: a case report.

BACKGROUND: Histiocytic sarcoma is a rare malignant tumor that is similar in characteristics to a mature histiocyte/macrophage and is a relatively new disease entity. In approximately one-third of cases, the site of origin is a lymph node; development from the gastrointestinal tract, spleen, soft tissue, and skin has further been reported. The tumor characteristics are not well-understood as reports on its clinical presentation and treatment are limited. We report a case of duodenal primary histiocytic sarcoma. CASE PRESENTATION: An elevated lesion in the second part of the duodenum was detected in a 70-year-old woman during routine examination using upper gastrointestinal tract endoscopy. Blood biochemistry findings were normal for tumor markers. No abnormal findings were observed in the blood count and biochemical examination. Upper gastrointestinal endoscopy revealed a 20-mm elevated lesion with a slight depression in the center, opposite to the papilla of the descending duodenum. The biopsy showed erosions of the mucosal epithelium and inflammatory cell infiltration, but no evidence of malignancy. Ultrasound-guided endoscopy revealed an ischemic tumor of submucosal origin, and bowel biopsy suggested a histiocytic sarcoma. Distant metastasis and lymph node enlargement were absent on abdominal sonography, computed tomography, and magnetic resonance imaging. Duodenal segmental resection was performed. Immunostaining of the excised lesion was positive for CD68, CD163, CD4, CD5, CD15, and CD45 and negative for CD1a, CD21, CD34, MPO, and S-100 protein. Ki-67 positivity was approximately 20%. Based on these findings, the diagnosis of histiocytic sarcoma was confirmed. Ten months after the surgery, a lymph node recurrence in the dorsum of the pancreatic uncus was observed. No evidence of recurrence was found in any other part; hence, we performed pancreaticoduodenectomy. Pathological findings of the excised lymph node confirmed the recurrence of histiocytic sarcoma in the lymph node. CONCLUSIONS: This is the first reported case of a duodenal primary histiocytic sarcoma with recurrence in the lymph node after the primary resection. The patient was treated for recurrence by lymph node excision and pancreaticoduodenectomy.

A Prospective Validation Study of Lung Cancer Gene Panel Testing Using Cytological Specimens.

Background: Genetic panel tests require sufficient tissue samples, and therefore, cannot always be performed. Although collecting cytological specimens is easier than tissue collection, there are no validation studies on the diagnostic accuracy of lung cancer gene panel tests using cytology samples. Methods: Using an amplicon-based high-sensitivity next-generation sequencing panel test capable of measuring eight druggable genes, we prospectively enrolled consecutive patients who underwent diagnostic procedures. We evaluated the analysis accuracy rate, nucleic acid yield, and the quality of cytological specimens under brushing, needle aspiration, and pleural effusion. We then compared these specimens with collected tissue samples. Results: In 163 prospectively enrolled cases, nucleic acid extraction and analysis accuracy was 100% in cases diagnosed with adenocarcinoma. Gene mutations were found in 68.7% of cases with 99.5% (95% CI: 98.2-99.9) concordance to companion diagnostics. The median DNA/RNA yield and DNA/RNA integrity number were 475/321 ng and 7.9/5.7, respectively. The correlation coefficient of the gene allele ratio in 64 cases compared with tissue samples was 0.711. Conclusion: The success of gene analysis using cytological specimens was high, and the yield and quality of the extracted nucleic acid were sufficient for panel analysis. Moreover, the allele frequency of gene mutations in cytological specimens showed high correlations with tissue specimens.

Factors influencing the development of Multicystic Dysplastic Kidney (MCDK) following urinary tract obstruction in the fetal lamb.

BACKGROUND: Creating obstructive uropathy (OU) during glomerulogenesis in the fetal lamb results in multicystic dysplastic kidney (MCDK) at term. We explored this using immunohistochemical techniques. METHOD: OU was created in fetal lambs at 60-day gestation, ligating the urethra and urachus. The kidneys of MCDK lambs, 60-day gestation fetal lambs, full-term lamb (145 days), term sham-operated lambs, and adult ewes were evaluated by HE staining, and immunohistochemistry with paired box genes 2 (PAX2) and CD10. RESULTS: Multiple cysts were found in the MCDK model. CD10 was expressed in proximal tubular epithelial cells, glomerular epithelial cells, and medullary stromal cells in the kidneys of 60-day gestation fetal lambs and full-term lambs and adult ewes. PAX2 expression was found in ureteric buds, C- and S-shaped bodies, epithelial cells of collecting ducts, and Bowman's capsule of fetal kidneys at 60-day gestation, but only in the collecting ducts of full-term fetal lambs and adult ewes. Both CD10 and PAX2 were expressed in the cystic epithelial cells of the MCDK model. DISCUSSION: PAX2 expression in cystic epithelial cells suggests that cyst formation is associated with disturbed down-regulation of PAX2 in the nephrogenic zone epithelial cells during the renal development in the OU model.

Histological Assessment of the Placenta Accreta Spectrum Diagnosed with a 33-MHz Linear Probe during Cesarean Section.

As placenta accreta spectrum (PAS) pathologies affect only the extremely thin tissues between the placenta and the uterine myometrium, superficial endometrial damage such as that caused by placenta creta and increta can be diagnosed only through histopathology. We performed direct uterine ultrasound of PAS using an ultrahigh frequency (33 MHz; i33LX9 Aplio i800) linear transducer. Here, we describe two cases with ultrasound images of placentas with PAS and a case without PAS to compare histological findings. In cases of PAS at the previous Cesarean scar, ultrasonography clearly revealed a thin uterine myometrium with some island-shaped sites where placental tissue was focally anchored to the uterine myometrium near the scar. Speckle blood flow pattern was absent at these sites during scanning with B-mode, but was detectable elsewhere. Histopathology samples from the same site revealed that villous tissue was directly attached to the uterine myometrium with a large area of infarction. In another case of diffuse PAS, speckle blood flow pattern was generally absent, and histopathology revealed deep fibrinoid deposits. We believe that histological evaluation following ultrasound use will improve the accuracy of ultrasound diagnosis and perinatal management of PAS in clinical practice.

Association between expanded criteria for living kidney donors and renal biopsy findings.

BACKGROUND: There are certain criteria for selecting living kidney donors. However, the association between clinical characteristics of these criteria and kidney biopsy findings in living kidney donors have not yet been elucidated. Thus, we investigated the association between kidney biopsy findings and clinical characteristics defined in the Japanese guidelines for living kidney donors. METHODS: A retrospective multicentre study was conducted on donors and their recipients who underwent kidney transplantation between July 2014 and June 2017. Multiple linear regression analysis and multiple logistic regression analysis were performed to investigate the association between biopsy findings and clinical characteristics. RESULTS: A total of 240 donors and 240 recipients were included. Age was significantly correlated with global glomerulosclerosis and intimal thickening in multiple linear regression analysis and multiple logistic regression analysis, whereas diabetes was correlated with tubular atrophy in multiple linear regression analysis after multiple imputation and multiple logistic regression analysis. CONCLUSIONS: Amongst the clinical factors investigated in our study, age was positively correlated and diabetes was possibly correlated with kidney tissue injury in living kidney donors. Age and diabetes may be more important for selecting suitable living kidney donors than other clinical factors.

Novel ultrasound assessment of placental pathological function using superb microvascular imaging.

Ultrasound Doppler method of Superb Microvascular Imaging (SMI) can significantly visualize low-velocity blood flow using a unique algorithm. We scanned placenta antenatally using SMI and compared those findings with histological findings after delivery in cases with placental abnormalities. In normal, SMI expresses stem villous vessels connecting to the tertiary villous vessels which are sharply diminished, and expresses intervillous blood flow as "scatter." Placental infarction was expressed as an anechoic area in SMI. Avascular villi was expressed as absent villous blood trees in a background scatter flow in SMI. In this report, we demonstrated typical SMI findings of the pathologic placenta as a pilot study.

Accuracy of Prenatal Ultrasound in Evaluating Placental Pathology Using Superb Microvascular Imaging: A Prospective Observation Study.

Superb microvascular imaging (SMI) is a new Doppler method that enables the visualization of low-velocity blood flow. The aim of the study described here was to clarify whether SMI can detect prenatal pathological findings in pathologic placentas. In this prospective diagnostic observational study, pregnant women who were admitted to our center for perinatal management were enrolled. Ultrasound examinations to identify placental pathologies using SMI were performed before delivery. After delivery, the placental tissue was clipped for microscopic examination at locations determined under ultrasound guidance. The accuracy of prenatal ultrasound detection of placental pathologies was compared between women who were admitted because of fetal growth restriction (FGR), pre-eclampsia and other indications. The highest accuracy was observed with placental infarction in FGR (positive predictive value = 100%, sensitivity = 89%, area under the curve = 0.945). As a result, it became clear that SMI can accurately detect placental pathologic findings, such as placental infarction and avascular villi. This modality may improve perinatal management in cases of placental dysfunction.

Minichromosome maintenance 2 is an independent predictor of survival in patients with lung adenocarcinoma.

Minichromosome maintenance (MCM) protein deregulation is associated with tumor formation, progression and malignant transformation. MCM2 is frequently expressed during premalignant lung cell proliferation and is a sensitive marker for the early detection of pulmonary malignant lesions. The present study was undertaken to investigate whether MCM2 expression is of clinical and prognostic value in patients who have undergone lung adenocarcinoma resection. Between January 2009 and December 2010, 102 consecutive patients underwent complete pulmonary resection (involving lobectomy or more extensive resection) for lung adenocarcinoma at St. Marianna Medical University Hospital (Kanagawa, Japan). Among those, 73 patients, who had a final pathological diagnosis of lung adenocarcinoma measuring ≥10 mm, were enrolled in the present study. High MCM2 expression was found in 35 patients (48.0%). Univariate analysis of the overall survival (OS) revealed that pathological stage and MCM2 expression were significant prognostic factors in lung adenocarcinoma (P<0.001 and P<0.002, respectively). Univariate analysis of the recurrence-free survival (RFS), the significant prognostic factors included pathological stage, EGFR mutation status and MCM2 expression (P<0.001, P<0.034 and P<0.003, respectively). On multivariate survival analysis, high MCM2 expression and pathological stage II-III were identified as independent strong prognostic factors (OS: HR=5.084, 95% CI: 1.715-15.080, P=0.003; RFS: HR=2.761, 95% CI: 1.090-6.998, P=0.032). Therefore, the findings of the present study demonstrated that MCM2 may serve as a potential biomarker and therapeutic target for lung adenocarcinoma.