The pathology according to p53 pathway.

Background Observations play a pivotal role in the progress of science, including in pathology. The cause of a disease such as cancer is analyzed by breaking it down into smaller organs, tissues, cells, and molecules. The current standard cancer diagnostic procedure, microscopic observation, relies on preserved morphological characteristics. In contrast, molecular analyses explore oncogenic pathway activation that leads to genetic mutations and aberrant protein expression. Such molecular analyses could potentially identify therapeutic targets and has gained considerable attention in clinical oncology. Summary This review summarizes the cardinal biomarkers of the p53 pathway, p53, p16, and mouse double minute 2 (MDM2), in the context of traditional surgical pathology and emerging genomic oncology. The p53 pathway, which is dysregulated in more than a half of all cancers, can be applied in several diagnostic settings. A four-classification model of immunophenotype for p53 pathway gene status, tumor types with a high frequency of abnormalities for each p53 pathway gene, and a minimal p53 pathway immunohistochemical panel is also described. Key messages Immunohistochemistry of oncogenic signals should be interpreted according to molecular findings based on genomic oncology, in addition to the microscopic findings of diagnostic pathology.

Combination of naproxen and a chemically-stable eicosapentaenoic acid analog provide additive tumor protection in Pirc rats.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Patients with the genetic disorder Familial Adenomatous Polyposis (FAP) develop hundreds to thousands of polyps that unless removed by prophylactic colectomy will progress to CRC at an early age. Nonsteroidal anti-inflammatory drugs (NSAIDs) and the ω-3 polyunsaturated fatty acid (PUFA) eicosapentaenoic acid (EPA), have been evaluated for their chemopreventive potential in delaying CRC onset in high-risk patients. In our study, we determined whether the NSAID, naproxen, alone or in combination with a chemically-stable EPA analog (TP-252), affects tumor formation in the ApcPirc rat model. When compared to control diet, animals fed naproxen or HD TP-252 had 66% and 82% fewer tumors, respectively. However, animals fed a combination of naproxen and HD TP-252, exhibited a 95% reduction in tumor formation and a 98% reduction in tumor volume, respectively. To elucidate potential mechanisms of tumor protection, a comprehensive, targeted lipidomic analysis was performed on colonic mucosa to determine changes in eicosanoid metabolism. Animals receiving TP-252 alone or in combination with naproxen had significantly reduced mucosal levels of proinflammatory ω-6 eicosanoids (PGE2 , 5-HETE and 14,15-DiHETrE), along with a simultaneous increase in anti-inflammatory EPA-derived ω-3 eicosanoids. A comprehensive lipidomic analysis also uncovered several potential pharmacodynamic (PD) lipid biomarkers, including resolvin E2, 9-HEPE, 12-HEPE and 18-HEPE, that were significantly correlated with tumor protection. Further studies with this drug combination should be focused on dose optimization and the role of EPA-derived lipid mediators in CRC initiation and progression.

A comparative analysis of MRI findings in endometrial cancer: differentiation between endometrioid adenocarcinoma, serous carcinoma, and clear cell carcinoma.

OBJECTIVE: To assess the magnetic resonance imaging (MRI) findings of endometrial cancers and to reveal the differences between endometrioid carcinoma (EC), serous carcinoma (SC), and clear cell carcinoma (CCC). METHODS: In this study, 274 consecutive patients with histopathologically confirmed endometrial cancer (231 ECs, 25 SCs, and 18 CCCs) who underwent MRI before hysterectomy were enrolled. MRI images were retrospectively reviewed and compared between the three pathologies. RESULTS: The maximum diameters (55.6 ± 34.7 vs. 39.3 ± 21.6 vs. 39.4 ± 26.8 mm) (p < 0.05) and apparent diffusion coefficient (ADC) values (1.11 ± 0.21 vs. 0.84 ± 0.17 vs. 0.86 ± 0.16 × 10-3 mm2/s) (p < 0.01) were significantly greater in CCCs than in ECs and SCs, respectively. Infiltrative growth pattern (33% vs. 6%) (p < 0.01) was more frequent in CCCs than in ECs. Peritoneal dissemination (16% vs. 0%) (p < 0.01) and heterogeneous signal on diffusion-weighted (61% vs. 32%) (p < 0.05) images were more frequent in SCs than in ECs, respectively. Abnormal ascites (12% vs. 11% vs. 0%) and heterogeneous signal on T1-weighted (28% vs. 50% vs. 9%), T2-weighted (64% vs. 72% vs. 36%), and fat-suppressed gadolinium-enhanced T1-weighted (80% vs. 90% vs. 46%) images were more frequent in SCs and CCCs than in ECs, respectively (p < 0.05). CONCLUSIONS: SCs frequently exhibited a heterogeneous signal with peritoneal dissemination and abnormal ascites. Alternatively, CCCs tended to have a larger tumor size and higher ADC values with an infiltrative growth pattern, heterogeneous signal, and abnormal ascites. KEY POINTS: • SCs tend to have a heterogeneous signal intensity with peritoneal dissemination and abnormal ascites compared to ECs. • CCCs tend to have a heterogeneous signal intensity with an infiltrative growth pattern and abnormal ascites compared to ECs. • CCCs have a larger tumor size and higher ADC values compared to ECs and SCs.

Macroscopic visible core length can predict the histological sample quantity in endoscopic ultrasound-guided tissue acquisition: Multicenter prospective study.

OBJECTIVES: Measurement of the macroscopic visible core (MVC) length during macroscopic on-site quality evaluation (MOSE) may allow estimation of sample adequacy for next-generation sequencing (NGS), and prediction of correct diagnosis in endoscopic ultrasound-guided tissue acquisition (EUS-TA) of pancreatic masses. METHODS: This multicenter prospective study included consecutive patients who underwent EUS-TA for pancreatic masses using a 22-G Franseen needle. MVC length and pathological samples obtained from two needle passes were analyzed on a per-pass basis. Outcome measures included respective correlations of MVC length with histological sample quantity and diagnostic yields. RESULTS: The analysis included 204 passes from 102 EUS-TAs. MVC length correlated positively with histological sample quantity (P < 0.01). On the receiver operating characteristic curve for MVC length, the cut-off value and area under the curve for obtaining a candidate sample for NGS were 30 mm and 0.74 (95% confidence interval [CI] 0.65-0.83), respectively. On multivariate analysis, MVC length ≥30 mm was a significant factor affecting suitability for NGS (odds ratio 6.19; 95% CI 2.72-14.10). Histologic diagnostic yield correlated positively with MVC length (P = 0.01); however, there was no positive correlation between MVC length and overall (histology plus cytology) diagnostic yield. CONCLUSIONS: Measuring MVC length to predict histological sample quantity on MOSE may be of clinical significance during EUS-TA using a 22-G Franseen needle. It may be an effective method, particularly while submitting samples for NGS. REGISTRATION: University Hospital Medical Information Network Trials Registry (UMIN000036528).

Endothelial cell-specific reduction of heparan sulfate suppresses glioma growth in mice.

PURPOSE: Heparan sulfate (HS) is one of the factors that has been suggested to be associated with angiogenesis and invasion of glioblastoma (GBM), an aggressive and fast-growing brain tumor. However, it remains unclear how HS of endothelial cells is involved in angiogenesis in glioblastoma and its prognosis. Thus, we investigated the effect of endothelial cell HS on GBM development. METHODS: We generated endothelial cell-specific knockout of Ext1, a gene encoding a glycosyltransferase and essential for HS synthesis, and murine GL261 glioblastoma cells were orthotopically transplanted. Two weeks after transplantation, we examined the tumor progression and underlying mechanisms. RESULTS: The endothelial cell-specific Ext1 knockout (Ext1 CKO ) mice exhibited reduced HS expression specifically in the vascular endothelium of the brain capillaries compared with the control wild-type (WT) mice. GBM growth was significantly suppressed in Ext1 CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1 CKO mice than in WT mice. We investigated how the effect of fibroblast growth factor 2 (FGF2), which is known as an angiogenesis-promoting factor, differs between Ext1 CKO and WT mice by using an in vivo Matrigel assay and demonstrated that endothelial cell-specific HS reduction attenuated the effect of FGF2 on angiogenesis. CONCLUSIONS: HS reduction in the vascular endothelium of the brain suppressed GBM growth and neovascularization in mice. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12672-021-00444-3.

[Paraurethral Leiomyoma in a Female Patient who Had Clinical Symptoms with Increase of Tumor Volume: A Case Report].

A 34-year-old woman underwent total hysterectomy for management of uterine leiomyoma. At the same time, a paraurethral tumor (2 cm in size) was diagnosed based on magnetic resonance imaging (MRI). However, the patient was not treated for the tumor considering its small size. Eight years later, the patient was referred to our institution with a chief complaint of urethral bleeding. Computed tomography revealed a paraurethral mass at the same location, which was 13 cm in size. A percutaneous needle biopsy was performed and the tumor was diagnosed as leiomyoma. Tumor extirpation was performed and immunohistochemical analysis of the specimen demonstrated positive estrogen and progesterone receptors. Recurrence was not observed on MRI taken 6 months after the surgery. Paraurethral leiomyoma is rare, but relatively common in young women.

ALDH1 and SALL4 Expression in Cell Block Samples from Patients with Lung Adenocarcinoma and Malignant Pleural Effusion.

Malignant pleural effusion (MPE) can accompany advanced lung adenocarcinoma. Recent studies suggest that MPE could contain a heterogeneous subpopulation of cells with stem-like properties, such as tumorigenicity and self-renewal, indicating that they could be the source of metastasis. Although previous studies analyzed the correlation between cancer stem cell (CSC) marker expression and clinical outcomes using lung cancer tissues, investigations regarding the association of MPE with CSC marker expression are limited. We performed immunohistochemistry to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and Sal-like 4 (SALL4) in 46 cell block samples of MPE from patients with lung adenocarcinoma. ALDH1-positive and SALL4-positive cancer cells in MPE were detected in 30 (65.2%) and 21 samples (45.7%), respectively. Cluster formation was detected in 26 samples (56.5%). The number of clusters was significantly higher in ALDH1-positive/SALL4-negative samples. SALL4 expression was inversely correlated with the cluster ratio (r = -0.356) and positively associated with the Ki-67 index (r = 0.326), suggesting that MPE cells with high SALL4 expression comprised the proliferative subpopulation. In conclusion, we demonstrated that MPE contains an ALDH1-positive/SALL4-negative subpopulation exhibiting cluster formation and a SALL4-positive proliferative subpopulation.

Virus-Driven Carcinogenesis.

Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era of precision oncology, carcinogens contributing to neoplastic process are still an important focus of research. Comprehensive genomic analyses have revealed various combinations of base substitutions, referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein-Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex network of data for virus-associated carcinogenesis.

[Renal Cell Carcinoma in the Left Pelvic Kidney : A Case Report].

We report the case of a 61-year-old man who was incidentally diagnosed with a left pelvic ectopic kidney with renal tumor. Computed tomography showed a hypervascular tumor at the posterior surface of the ectopic kidney with five arterial and two venous supply vessels. On preoperative examination, this patient had respiratory dysfunction. For these reasons, an open radical nephrectomy was performed. Histological examination revealed a clear cell renal cell carcinoma, pT1aN0M0, G1, and a Fuhrman nuclear grading system grade of G2. No evidence of disease was observed 15 months after surgery.

Clinically relevant umbilical cord inflammation identified based on CD15-associated vasculitis patterning.

INTRODUCTION: Acute funisitis, a granulocyte-related inflammation of the umbilical cord, is associated with chorioamnionitis and perinatal adverse events. However, there is no efficient procedure for detecting clinically relevant umbilical cord inflammation. The objective of this study was to identify such inflammation, based on immunohistochemical assessment of umbilical cord vasculitis patterns. METHODS: Accordingly, 261 cases were retrieved from a single medical institute. Using the well-established granulocyte marker CD15, we developed a five-tier umbilical cord inflammation-scoring system. Additionally, previous morphological assessments from pathological reports were compared to the immunohistochemical findings. RESULTS: Analysis of results based on our new scoring system revealed that severe umbilical phlebitis (score 3) was significantly associated with maternal inflammatory response and that severe umbilical arteriophlebitis (score 4) was correlated with low umbilical arterial blood pH, a feature linked to fetal mortality and morbidity. These results corresponded with and were validated by the morphology-based assessments. Additionally, immunohistochemical analysis revealed the clinical and pathological relevance of vitelline vasculitis, a recently proposed condition. We found that analyzing three umbilical cord sections enabled superior detection of severe umbilical vasculitis than analyzing two sections. However, whether these sections were sampled from multiple distant sites or a single localized site did not significantly affect the detection of clinically relevant inflammation. DISCUSSION: CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation. CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation.

Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas.

Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.

Glucose transporter Glut1 controls diffuse invasion phenotype with perineuronal satellitosis in diffuse glioma microenvironment.

BACKGROUND: Gliomas typically escape surgical resection and recur due to their "diffuse invasion" phenotype, enabling them to infiltrate diffusely into the normal brain parenchyma. Over the past 80 years, studies have revealed 2 key features of the "diffuse invasion" phenotype, designated the Scherer's secondary structure, and include perineuronal satellitosis (PS) and perivascular satellitosis (PVS). However, the mechanisms are still unknown. METHODS: We established a mouse glioma cell line (IG27) by manipulating the histone H3K27M mutation, frequently harboring in diffuse intrinsic pontine gliomas, that reproduced the diffuse invasion phenotype, PS and PVS, following intracranial transplantation in the mouse brain. Further, to broadly apply the results in this mouse model to human gliomas, we analyzed data from 66 glioma patients. RESULTS: Increased H3K27 acetylation in IG27 cells activated glucose transporter 1 (Glut1) expression and induced aerobic glycolysis and TCA cycle activation, leading to lactate, acetyl-CoA, and oncometabolite production irrespective of oxygen and glucose levels. Gain- and loss-of-function in vivo experiments demonstrated that Glut1 controls the PS of glioma cells, that is, attachment to and contact with neurons. GLUT1 is also associated with early progression in glioma patients. CONCLUSIONS: Targeting the transporter Glut1 suppresses the unique phenotype, "diffuse invasion" in the diffuse glioma mouse model. This work leads to promising therapeutic and potential useful imaging targets for anti-invasion in human gliomas widely.

Magnetic resonance imaging findings of extrauterine high-grade serous carcinoma based on new pathologic criteria for primary site assignment.

BACKGROUND: There has been no study that has reported magnetic resonance imaging (MRI) findings of extrauterine high-grade serous carcinomas (HGSCs) that have been histologically determined by the new criteria. PURPOSE: To assess MRI findings of extrauterine HGSCs based on new pathologic criteria. MATERIAL AND METHODS: Fifty patients with histopathologically proven extrauterine HGSCs, who underwent pretreatment gadolinium-enhanced MRI, were included in this study. After surgery, the primary sites were histopathologically determined based on new criteria for primary site assignment in extrauterine HGSCs as follows: fallopian tube (n = 34); ovary (n = 9); primary peritoneal HGSC (n = 1); and tubo-ovarian (n = 6). We retrospectively reviewed MR images and compared the MR findings between tubal and ovarian primaries. RESULTS: MRI patterns with tubal primaries were classified as ovarian cancer (62%), peritoneal cancer (35%), and fallopian tube cancer (3%). MRI patterns with ovarian primaries were classified as ovarian cancer (78%) and peritoneal cancer (22%). The frequency of the involvement of the fallopian tube, ovary, peritoneum, uterus, and lymph node was not significantly different between the two pathologies. There was no significant difference in the abnormal amount of ascites, hemorrhagic ascites, or characteristics of the ovarian lesions between the two pathologies. CONCLUSION: On MR images, tubal primaries almost always exhibited ovarian or peritoneal cancer pattern, but rarely exhibited fallopian tube cancer pattern. MR findings could not accurately differentiate between tubal and ovarian primaries; therefore, histopathologic investigation is essential for determination of the primary site of extrauterine HGSCs.

Emphysematous cholecystitis during the treatment of heat stroke.

BACKGROUND: During a heat stroke, microvascular injury may occur as a result of thermal damage and systemic hypoperfusion. We present a case of an older woman who experienced emphysematous cholecystitis during a treatment of heat stroke. CASE PRESENTATION: A 91-year-old woman presented unconscious with a blood pressure, pulse, and core temperature of 73/48 mmHg, 135 bpm, and 39.8°C, respectively. The patient was diagnosed with heat stroke. Twenty-two hours after arrival, the patient fell into septic shock. We diagnosed emphysematous cholecystitis and performed an emergency cholecystectomy. As the bile culture was positive for Clostridium perfringens, meropenem was administered. The patient was transferred for rehabilitation 32 days after admission. CONCLUSIONS: Emphysematous cholecystitis can present during a treatment of heat stroke. An abdominal X-ray examination should be performed during treatment of heat stroke in the acute phase regardless of the physical assessment.

Can MRI features differentiate ovarian mucinous carcinoma from mucinous borderline tumor?

PURPOSE: Our purpose was to determine if MRI could be used to distinguish ovarian mucinous carcinoma (MC) from mucinous borderline tumor (MBT). MATERIALS AND METHODS: This study included 63 consecutive patients with histopathologically proven ovarian mucinous neoplasms (11 MCs and 52 MBTs) who underwent preoperative contrast-enhanced MRI. MRI images were retrospectively reviewed and compared between the 2 pathologies. RESULTS: The maximum tumor diameters (219.7 ±â€¯80.8 mm vs. 177.4 ±â€¯56.5 mm, p <  0.05) and maximum mural nodule (MN) diameters (41.7 ± 33.8 mm vs. 6.6 ± 8.9 mm, p <  0.01) were significantly larger in MCs than in MBTs. MNs larger than 5 mm (82 % vs. 29 %, p <  0.01) and abnormal ascites (45 % vs. 12 %, p <  0.05) were significantly more frequent in MCs than in MBTs. Apparent diffusion coefficient (ADC) values of MN were significantly lower in MCs than in MBTs (1.20 ± 0.25 × 10-3 mm2/s vs. 1.61 ±â€¯0.35 × 10-3 mm2/s, p <  0.05). No significant difference was found in number of loculi, honeycomb sign, stained glass appearance, fluid-fluid level, thickened septa larger than 5 mm, peritoneal dissemination, or T2 hypointense microcysts between MCs and MBTs. T2 hypointense microcysts were observed only in 7 MBTs (13%). CONCLUSION: MRI findings of these 2 pathologies overlapped considerably. Compared with MBTs, MCs exhibited larger tumor size, larger MN size, and lower ADC values of MN, and MCs more frequently had MNs larger than 5 mm and abnormal ascites. T2 hypointense microcysts might be a specific MRI finding in MBTs.

Metastatic colon cancer of the small intestine diagnosed using genetic analysis: a case report.

BACKGROUND: Intestinal-type adenocarcinoma is widely detected in the gastrointestinal tract, head and neck, lower respiratory and urinary systems. Determining the nature (monoclonal or multicentric) of the intestinal adenocarcinoma is sometimes a diagnostic challenge owing to its occurrence at various locations of the body, especially in the lower gastrointestinal tract. Herein, we successfully diagnosed metastatic colon cancer in the small intestine using tumor protein 53 gene (TP53) mutation analysis. CASE PRESENTATION: An 83-year-old woman presented with severe abdominal pain and nausea at the emergency department of the hospital. Her history included surgery and adjuvant chemotherapy for colon and breast cancers. Abdominal computed tomography revealed small intestinal dilation, which was associated with the mural nodule detected on fluorodeoxyglucose positron emission tomography. Laparoscopy-assisted small bowel resection was performed based on the diagnosis of small bowel obstruction, probably due to recurrence of the colon or breast cancer. Macroscopically, an ulcerated tumor was present in the resected small intestine. Histologically, the cancer cells showed infiltrative growth of colonic dysplastic glands, whose non-specific finding made it difficult to determine the relationship with past colon cancers. Retrospective pathological examination confirmed that the previous breast and colon carcinomas were primary cancers. Immunohistochemical analysis revealed that the small intestinal and colon cancer cells showed diffuse positive tumor protein 53 (p53) expression. However, the breast cancer cells showed only weakly positive p53 expression. In addition, TP53 mutational analysis detected an identical missense mutation (p.T211I) between the two intestinal cancers. Moreover, further molecular genetic work-up revealed that both small intestinal and colon adenocarcinomas harbored an identical missense mutation (p.G12D) of KRAS gene. In conclusion, the small intestinal cancer in this case was identified as a metastatic adenocarcinoma arising from a past colon cancer. CONCLUSIONS: Genetic analyses help in clarifying the identity of the cells in multiple cancer cases. In morphologically indeterminate cases, molecular analysis of common cancer-related genes can be useful for a precise and reproducible diagnosis.

Galectin-3: A Potential Prognostic and Diagnostic Marker for Heart Disease and Detection of Early Stage Pathology.

The use of molecular biomarkers for the early detection of heart disease, before their onset of symptoms, is an attractive novel approach. Ideal molecular biomarkers, those that are both sensitive and specific to heart disease, are likely to provide a much earlier diagnosis, thereby providing better treatment outcomes. Galectin-3 is expressed by various immune cells, including mast cells, histiocytes and macrophages, and plays an important role in diverse physiological functions. Since galectin-3 is readily expressed on the cell surface, and is readily secreted by injured and inflammatory cells, it has been suggested that cardiac galectin-3 could be a marker for cardiac disorders such as cardiac inflammation and fibrosis, depending on the specific pathogenesis. Thus, galectin-3 may be a novel candidate biomarker for the diagnosis, analysis and prognosis of various cardiac diseases, including heart failure. The goals of heart disease treatment are to prevent acute onset and to predict their occurrence by using the ideal molecular biomarkers. In this review, we discuss and summarize recent developments of galectin-3 as a next-generation molecular biomarker of heart disease. Furthermore, we describe how galectin-3 may be useful as a diagnostic marker for detecting the early stages of various heart diseases, which may contribute to improved early therapeutic interventions.

Spur cell anemia related to alcoholic liver cirrhosis managed without liver transplantation: a case report and literature review.

Spur cell anemia is an acquired hemolytic anemia associated with liver cirrhosis and is characterized by the presence of increased large red blood cells, which are covered with spike-like projections that vary in width, length, and distribution. A 26-year-old man was referred to our hospital presenting with jaundice, lower limb edema, and dyspnea. The patient was subsequently diagnosed with spur cell anemia related to alcoholic liver cirrhosis. Spur cell anemia is an independent predictor of mortality in liver cirrhosis and has been associated with extremely poor prognosis. The most effective treatment for spur cell anemia is liver transplantation. As seen in the literature, the treatment of spur cell anemia without liver transplantation is quite challenging. This report highlights the importance of management and treatment strategies, including control of fluid retention, blood transfusion, plasma diafiltration, and administration of diuretics. Our treatment strategies might be useful in patients who are not candidate of liver transplantation or patients waiting for liver transplantation.

Molecular Trajectory of BRCA1 and BRCA2 Mutations.

Every cancer carries genomic mutations. Although almost all these mutations arise after fertilization, a minimal count of cancer predisposition mutations are already present at the time of genesis of germ cells. Of the cancer predisposition genes identified to date, BRCA1 and BRCA2 have been determined to be associated with hereditary breast and ovarian cancer syndrome. Such cancer predisposition genes have recently been attracting attention owing to the emergence of molecular genetics, thus, affecting the strategy of cancer prevention, diagnostics, and therapeutics. In this review, we summarize the molecular significance of these two BRCA genes. First, we provide a brief history of BRCA1 and BRCA2, including their identification as cancer predisposition genes and recognition as members in the Fanconi anemia pathway. Next, we describe the molecular function and interaction of BRCA proteins, and thereafter, describe the patterns of BRCA dysfunction. Subsequently, we present emerging evidence on mutational signatures to determine the effects of BRCA disorders on the mutational process in cancer cells. Currently, BRCA genes serve as principal targets for clinical molecular oncology, be they germline or sporadic mutations. Moreover, comprehensive cancer genome analyses enable us to not only recognize the current status of the known cancer driver gene mutations but also divulge the past mutational processes and predict the future biological behavior of cancer through the molecular trajectory of genomic alterations.