Magnetic resonance imaging-based radiomics analysis of the differential diagnosis of ovarian clear cell carcinoma and endometrioid carcinoma: a retrospective study.

PURPOSE: To retrospectively evaluate the diagnostic potential of magnetic resonance imaging (MRI)-based features and radiomics analysis (RA)-based features for discriminating ovarian clear cell carcinoma (CCC) from endometrioid carcinoma (EC). MATERIALS AND METHODS: Thirty-five patients with 40 ECs and 42 patients with 43 CCCs who underwent pretherapeutic MRI examinations between 2011 and 2022 were enrolled. MRI-based features of the two groups were compared. RA-based features were extracted from the whole tumor volume on T2-weighted images (T2WI), contrast-enhanced T1-weighted images (cT1WI), and apparent diffusion coefficient (ADC) maps. The least absolute shrinkage and selection operator (LASSO) regression with tenfold cross-validation method was performed to select features. Logistic regression analysis was conducted to construct the discriminating models. Receiver operating characteristic curve (ROC) analyses were performed to predict CCC. RESULTS: Four features with the highest absolute value of the LASSO algorithm were selected for the MRI-based, RA-based, and combined models: the ADC value, absence of thickening of the uterine endometrium, absence of peritoneal dissemination, and growth pattern of the solid component for the MRI-based model; Gray-Level Run Length Matrix (GLRLM) Long Run Low Gray-Level Emphasis (LRLGLE) on T2WI, spherical disproportion and Gray-Level Size Zone Matrix (GLSZM), Large Zone High Gray-Level Emphasis (LZHGE) on cT1WI, and GLSZM Normalized Gray-Level Nonuniformity (NGLN) on ADC map for the RA-based model; and the ADC value, spherical disproportion and GLSZM_LZHGE on cT1WI, and GLSZM_NGLN on ADC map for the combined model. Area under the ROC curves of those models were 0.895, 0.910, and 0.956. The diagnostic performance of the combined model was significantly superior (p = 0.02) to that of the MRI-based model. No significant differences were observed between the combined and RA-based models. CONCLUSION: Conventional MRI-based analysis can effectively distinguish CCC from EC. The combination of RA-based features with MRI-based features may assist in differentiating between the two diseases.

SRY-box Transcription Factor 6 Is Expressed Not Only in the Dorsal but Also in the Ventral Zone of the Neural Tube and Is Highly Expressed in the Notochord and Chordoma.

In the course of SRY-box transcription factor 6 (SOX6) expression profiling in human embryonic tissue, SOX 6 was found to be highly expressed in the notochord, based on the findings of immunohistochemistry (IHC). Sox6 is also expressed in the neural tube and the distribution of SOX6 is located in the ventral and dorsal zones of the neural tube. In contrast to the findings that SOX6-positive cells were located on the floor plate of the neural tube, OLIG2- and NKX2.2-expressing cells were lacking on the floor plate of the neural tube, and their expression was restricted only to the ventral zone of the neural tube. The expression patterns of SOX9 were similar to those of OLIG2 and NKX2.2 in the neural tube. NKX2.2 and OLIG2 are not expressed in the notochord, but SOX9 and SOX6 are. Because Sox6 is highly expressed in the notochord, the present study investigated whether or not SOX6 is an immunohistochemical marker for the pathologic diagnosis of chordoma, a neoplasm derived from the notochord. IHC revealed that chordoma was strongly positive for SOX6 in two cases of chordoma, one of which occurred in the sacrococcygeal region and another that developed at the base of the skull, suggesting that SOX6 is a useful marker for the histopathologic diagnosis of chordoma.

Small intestinal bleeding and stricture caused by Meckel's diverticulum.

A 44-year-old man presented to our hospital with lower gastrointestinal bleeding. We performed balloon-assisted enteroscopy, which revealed diverticulum and stricture at the ileum. The patient underwent segmental small bowel resection and diagnosed with Meckel's diverticulum. We should keep in mind the possibility of intestinal stricture due to Meckel's diverticulum.

A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death. PATIENTS CONCERNS: The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses. DIAGNOSIS: A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct. INTERVENTIONS: Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered. OUTCOMES: The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death. CONCLUSION: This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.

Whole-exome sequencing reveals a combination of extremely rare single-nucleotide polymorphism of DNAH9 and RSPH1 genes in a Japanese fetus with situs viscerum inversus.

Randomization of left-right body asymmetry, situs viscerum inversus (heterotaxy), is commonly associated with primary ciliary dyskinesia (PCD) resulting from an abnormal ciliary structure, with approximately 50% of PCD patients exhibiting organ laterality defects. I herein report an intrauterine fetal death case, in which an autopsy revealed two lobes of the bilateral lungs as well as heterotaxy of abdominal organs (right-sided spleen and inversion of the alimentary and biliary organs). Whole-exome sequencing (WES) identified a heterozygous single-nucleotide change (c.12775T>C) in exon 68 of the DNAH9 gene, which is a rare single-nucleotide polymorphism (SNP) of rs746081639 and results in the amino acid change of p.C4259R. WES also identified a rare SNP of rs763089682 (c.121G>A) in the RSPH1 gene that causes a heterozygous amino acid alteration of p.G41R. The frequencies of both SNPs, C in rs746081639 and A in rs763089682, are 0.00000824, and a polyphen-2 analysis predicted these amino acid changes to be probably damaging, with a score of 1.000. The combination of extremely rare SNPs in DNAH9 and RSPH1 genes might have been the possible mechanism underlying the development of the laterality defect in the present case.

Three cases of histologically proven hepatic epithelioid hemangioendothelioma evaluated using a second-generation microbubble contrast medium in ultrasonography: case reports.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is rare; it is reported in < 1 person in 1,000,000 individuals. For accurate diagnosis, information regarding multiple graphic modalities in HEH is required. However, there is very little information concerning Sonazoid® contrast enhanced ultrasonography (CEUS) in HEH. CASE PRESENTATION: The present report describes the histologically proven three HEH cases evaluated using Sonazoid® CEUS. Case 1 was a 33-year-old female patient with no relevant past medical history, who experienced right upper quadrant pain. Conventional abdominal US revealed multiple low echoic liver nodules with vague borderlines. In CEUS, the vascularity of the nodules was similar to that seen in the neighboring normal liver. Later in the portal venous and late phases (PVLP) and post vascular phase, washout of Sonazoid® was detected in the nodules. Case 2 was a 93-year-old female patient with a previous medical history including operations for breast cancer and ovary cancer in her 50's. Conventional abdominal US revealed multiple low echoic nodules, some of which contained cystic lesions. In the early vascular phase of CEUS, nodules excluding the central anechoic regions were enhanced from peripheral sites. Although the enhancement inside the nodules persisted in both the PVLP and post vascular phase, anechoic areas in the center of some nodules were not enhanced at all. Case 3 was a 39-year-old male patient presented with right upper-quadrant pain, without any relevant past medical history. Conventional abdominal US revealed multiple low echoic liver nodules. In the early vascular phase of CEUS, nodules were gradually enhanced from the peripheral sites as ringed enhancement. Sonazoid®was washed out from the nodules in the PVLP and post vascular phase. CONCLUSIONS: The most important feature was peripheral enhancement in the early vascular phase. In case 2, the enhancement of the parenchyma of liver nodules persisted even in the PVLP; indicating the lower degree of malignant potential than others. Actually, the tumors did not extend without any treatment in case 2. Since case 2 is the first case report of HEH with cystic lesions, in patients with liver nodules including cystic lesions, HEH is a potential diagnosis.

Analysis of YAP1 and TAZ expression by immunohistochemical staining in malignant mesothelioma and reactive mesothelial cells.

[This retracts the article DOI: 10.3892/ol.2018.8225.].

Analysis of YAP1 and TAZ expression by immunohistochemical staining in malignant mesothelioma and reactive mesothelial cells.

Gene mutations are involved in the development of malignant mesothelioma. Important mutations have been identified in the genes for cyclin-dependent kinase inhibitor 2A (p16) alternative reading frame, breast cancer-associated protein 1 (BAP1) and neurofibromatosis type 2 (NF2). Previously, the utility of detecting the loss of BAP1 by immunohistochemistry (IHC) and p16-deletion by fluorescence in situ hybridization has been identified in several studies. However, NF2-associated examinations have not been performed. The present study aimed to evaluate the expression of yes-associated protein 1 (YAP1) and tafazzin (TAZ) protein, which are associated with NF2 gene mutations, in malignant mesothelioma (MM) and reactive mesothelial cells (RMCs). Formalin-fixed paraffin-embedded tissues from 31 MM and 33 RMC samples were analyzed. The expression of YAP1 and TAZ protein were examined by IHC. Positivity for YAP1 was identified 27/31 MM and 15/33 RMC samples. Positivity for TAZ was identified in 28/31 MM and 18/33 RMC samples. Using the optimal cutoff points determined by the receiver operating characteristic curve, a positive IHC result for YAP1 and TAZ was 74% sensitive and 94% specific for detecting MM. The results indicate that increased expression of YAP1 and TAZ may be associated with mesothelial tumorization, and aid in the diagnosis of MM.

Expression of matrix metalloproteinase-7 correlates with the invasion of T1 colorectal carcinoma.

T1 colorectal carcinomas (CRCs) are an initial site of metastatic spread. Various risk factors for lymph node metastasis have been investigated in T1 CRCs. However, the major step in the entire process of metastasis remains unclear. In terms of carcinoma invasion and metastasis, matrix metalloproteinases (MMPs) have recently gained increasing attention. Notably, MMP-7 is frequently overexpressed in CRCs, but its implication has not been determined in T1 CRCs yet. The present study aimed to clarify the associations between the pathological risk factors of T1 CRCs and MMP-7. In the current study, 211 lesions of T1 CRC that were resected endoscopically or surgically at Showa University Northern Yokohama Hospital (Yokohama, Japan) between April 2008 and December 2009 were retrospectively analyzed. MMP-7 was immunostained and evaluated by its frequency of expression. Pathological factors of T1 CRCs were analyzed in association with MMP-7 expression. Furthermore, the ultrastructural alterations of carcinoma invasion were examined using low vacuum-scanning electron microscopy (LV-SEM). MMP-7 expression was associated with venous invasion (P=0.005), and LV-SEM revealed the disappearance of the normal structure of collagen and elastic fibers of veins invaded by tumor cells expressing MMP-7. At the invasive front, MMP-7 has a vital role in carcinoma invasion, correlating with venous invasion of T1 CRCs.

Increased expression of interleukin-17 is associated with macrophages in chronic immune thrombocytopenia.

Objectives: Interleukin-(IL-)17-mediated cells contribute to the imbalance of cellular immunity in the pathogenesis of immune thrombocytopenia (ITP). We examined samples of bone marrow (BM) clots to determine if IL-17-mediated immunological changes involve the BM and to identify clinical predictors of treatment response. Methods: We enrolled 33 patients with chronic ITP. BM clots were obtained before treatment and stained with the following markers: CD3, CD4, CD8, CD20, CD25, CD68, CD163, and IL-17. Pathological findings and clinical information, including laboratory data, were compared between the patients and 11 control subjects and between IL-17-high and -low-expression groups. Results: Univariate analysis revealed increased cells expressing CD68, CD163, and IL-17 in the patients with ITP than in the control subjects (P = 0.02, 0.001, and 0.001, respectively). The expression of both CD68 and CD163 showed correlation with IL-17 expression (r = 0.60 and 0.48, respectively). Responses to Eltrombopag were better in the IL-17-low-expression group than in the IL-17-high-expression group (P = 0.056). Conclusions: Macrophages and monocytes were associated with IL-17 expression in patients with ITP. We demonstrated that ITP is associated with IL-17-expressing monocytes/macrophages and might be more difficult to treat.

Partial duplication of DHH causes minifascicular neuropathy: A novel mutation detection of DHH.

Minifascicular neuropathy (MN) is an extremely rare developmental malformation in which peripheral nerves are composed of many small fascicles. Only one patient with MN with 46XY gonadal dysgenesis (GD) was found to carry a mutation affecting the start codon in desert hedgehog (DHH). We identified an identical novel rearrangement mutation of DHH in two consanguineous families with MN, confirming mutations in DHH cause MN with 46XY GD. The patients with the 46XY karyotype developed GD, whereas a patient with the 46XX karyotype did not. These findings further support that DHH has important roles in perineural formation and male gonadal differentiation.

The role of microvessel density, lymph node metastasis, and tumor size as prognostic factors of distant metastasis in colorectal cancer.

Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per ×400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welch's t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.

A novel mutation of the FAT2 gene in spinal meningioma.

Meningiomas may be classified as neurofibromin 2 (NF2)-associated and non-NF2 meningiomas depending on the presence or absence of molecular alterations in the NF2 gene. One of the characteristic histological features of meningiomas is the whorl formation of neoplastic arachnoid cells. NF2 is a human homolog of the Drosophila gene, Merlin (Mer). In humans, NF2 is the gene responsible for the disease neurofibromatosis type II, which results in the development of brain tumors, including acoustic neurinoma and meningioma. The present study aimed to investigate the molecular pathogenesis of spinal meningioma. It was hypothesized that the whorl formation of meningiomas may occur as a result of a disturbance in the planar cell polarity (PCP) of arachnoid cells, thus, genes understood to govern PCP signaling were analyzed for alterations. Whole exome sequencing followed by Sanger sequencing validation was performed for the analysis of spinal meningioma tissue obtained from a 42-year-old Japanese female. The sequencing identified a nonsynonymous mutation of c.3597G>C, resulting in p.Q1199H, in the FAT atypical cadherin 2 (FAT2) gene. FAT2 is homologous to the Drosophila Fat (Ft) gene, which belongs to the cadherin superfamily. Drosophila Fat is involved in PCP, tumor suppression and Hippo (Hpo) signaling, which is associated with Mer. Taken together, the results of the present study concluded that human FAT2 may function as a key molecule that governs not only PCP, but also NF2-Hpo signaling in arachnoid cells; thus, a mutation in this gene may result in spinal meningioma.

Biallelic alterations of the large tumor suppressor 1 (LATS1) gene in infiltrative, but not superficial, basal cell carcinomas in a Japanese patient with nevoid basal cell carcinoma syndrome.

The present study was conducted to address the molecular pathogenesis underlying the progression of basal cell carcinoma (BCC) in a nevoid basal cell carcinoma syndrome (NBCCS) patient. We analyzed infiltrative BCCs that invaded the subcutaneous tissue of the scalp and penetrated the skull in a 61-year-old Japanese female. Whole-exome sequencing validated by Sanger sequencing was applied to assess the subcutaneously infiltrative BCCs. Differences in genetic alterations between the superficial and infiltrative BCCs were also examined. Of particular note, the infiltrative BCCs showed a nonsense mutation, c.943C>T, resulting in p.Q315X in the large tumor suppressor 1 (LATS1) gene, as well as the loss of the wild-type allele of LATS1 (6q25.1), thus indicating that the LATS1 gene was biallelically disrupted. In contrast, no alterations in the LATS1 gene were observed in the superficial BCCs. Additionally, a loss of heterozygosity analysis revealed that the distal region of chromosome 6q where LATS1 locates was deleted in a heterozygous manner. The present results imply that the biallelic disruption of LATS1 is a progressive factor of the infiltrative BCCs observed in this NBCCS patient and suggest that the Hippo pathway is a potential therapeutic target in cases of infiltrative BCC.

CD200 Expression on Plasma Cell Myeloma Cells is Associated with the Efficacies of Bortezomib, Lenalidomide and Thalidomide.

Plasma cell myeloma (PCM) is a devastating disease with a highly heterogeneous outcome, with survival ranging from a few months to longer than 10 years. Treatment of multiple myeloma has changed markedly in the past decade due to the development of new drugs such as bortezomib, lenalidomide and thalidomide, which have greatly improved the outcome of PCM. The clinical and prognostic value of immunophenotyping in PCM remains questionable. The aim of this study was to determine the diagnostic and prognostic significance of CD200 expression in newly diagnosed PCM. We retrospectively reviewed the records of 107 patients newly diagnosed with PCM at Showa University Hospital between January 2004 and September 2013. Expression of CD200 was studied by immunohistochemistry. Clinical and pathological parameters were compared between CD200-positive and CD200-negative cases. CD200-positive PCM cases had lower serum albumin (p = 0.0001) compared to those without CD200 expression. Our results showed no significant difference in median overall survival between patients with CD200-positive and CD200-negative PCM. However, there was a strong correlation between CD200 expression and serum albumin level. In the CD200-negative group, median overall survival was significantly longer in patients who received new drug treatment. These findings suggest that CD200 expression is a useful marker for evaluation of the severity of PCM and that lack of CD200 expression may improve the sensitivity of PCM to therapy with new drugs.

A novel mutation of the axonemal dynein heavy chain gene 5 (DNAH5) in a Japanese neonate with asplenia syndrome.

Asplenia syndrome (Ivemark syndrome) is a complex disorder composed of asplenia, malpositioning of the visceral organs and congenital heart defects. To elucidate the underlying molecular mechanism of asplenia syndrome, we herein analyzed the fatal case of a male neonate who exhibited three lobes of the left lung, asplenia and complex heart anomalies and died 6 hours after delivery. A whole-exome sequence (WES) analysis followed by Sanger sequence identified a heterozygous single nucleotide change (c.7829A>G) in exon 47 of the axonemal dynein heavy chain gene 5 (DNAH5), which results in the missense mutation of p.Glu2610Gly. This mutation was found only in the neonate, but not in his parents, implying de novo mutation of DNAH5 that codes dynein heavy chain, a component of outer dynein arm. The WES analysis also identified a heterozygous single nucleotide substitution (c.3697C>T) in the axonemal dynein heavy chain gene 7 (DNAH7), resulting in p.Arg1233Cys, and a rare SNP (c.2029G>A, p.Gly677Ser) of the axonemal dynein intermediate chain gene 1 (DNAI1) in the patient and his mother, but not in his father. The mutation of p.Glu2610Gly in DNAH5 is novel and we here present a first Japanese case of asplenia syndrome who exhibited a DNAH5 mutation.

[A case of esophageal squamous cell carcinoma with an adenocarcinoma component that dedifferentiated after chemotherapy].

CASE: A 69-year-old man was diagnosed with advanced esophageal cancer(well-differentiated squamous cell carcinoma). Neoadjuvant chemotherapy consisting of nedaplatin and 5-fluorouracil(5-FU)was initiated. After two courses of chemotherapy, the patient was judged to have achieved a clinical complete response. The patient then decided against undergoing surgery and opted instead to continue with the chemotherapy, receiving five courses in total. However, the esophageal cancer recurred, and subtotal esophagectomy was performed in January 2011. Squamous cell carcinoma with an adenocarcinoma component, which consisted of poorly differentiated squamous cell carcinoma and tubular adenocarcinoma cells, was observed at the primary site. Metastasis of the cancer to the liver was detected 2 months after surgery. The subsequent administration of four courses of docetaxel to the patient did not result in any beneficial effects, and the patient developed carcinomatous pleurisy and died of this complication in November 2011. The patient survived for a total of 21 months after starting chemotherapy. In this case, the chemotherapy itself may have resulted in the dedifferentiation of a well differentiated squamous cell carcinoma to result in a poorly differentiated squamous cell carcinoma with an adenocarcinoma component.

Gastric mixed adenoneuroendocrine carcinoma occurring 50 years after a gastroenterostomy with braun anastomosis.

A 75-year-old man was diagnosed with gastric cancer. Fifty years previously, he had undergone gastroenterostomy with a Braun enteroenterostomy. At present, a distal gastrectomy and small intestinal partial resection were performed. Intraoperatively, the tumor was localized to the previous stomal site. HE staining showed that the tumor comprised two elements: a tubular adenocarcinoma on the gastric side and a neuroendocrine carcinoma (NEC) on the jejunal side. The final pathologic diagnosis was mixed adenoneuroendocrine carcinoma based on an immunohistochemical analysis of endocrine markers and an elevated Ki-67 labeling index. The risk of later cancer development cancer recurrence near the gastrojejunostomy site is well known. Potentially, chronic enterogastric bile reflux may irritate the gastric mucosa and act as a promoter. Gastric NEC has a strong malignant potential. We suspect that, in the present case, the constant exposure to secondary bile may have induced a gastric mucosal adenocarcinoma, which finally differentiated into a NEC.

Biallelic disruption of the PTCH1 gene in multiple basal cell carcinomas in Japanese patients with nevoid basal cell carcinoma syndrome.

The aim of the present study is to address whether the molecular pathogenesis is identical among multiple basal cell carcinomas (BCCs) present in the same nevoid basal cell carcinoma syndrome (NBCCS) patient. Patient 1 is a 61-year-old (yo) Japanese female whose clinical characteristics and findings of a genetic analysis of PTCH1 have been previously described. Patient 2 is patient 1's 64-yo sister who also suffered from NBCCS with a single base deletion at nucleotide 2613 in exon 16 (c.2613delC) in one PTCH1 allele. Thirteen and 3 independent specimens of BCC were applied for a molecular analysis of loss of heterozygosity (LOH) in PTCH1 in patients 1 and 2, respectively. Of particular note is that all BCC specimens examined showed a loss of the wild-type allele of exon 16 in PTCH1, thus indicating that LOH results in the biallelic disruption of PTCH1 in multiple BCCs that develop in an age- and location-independent manner in the same patient. These results indicate that the germline single base deletion of PTCH1 (c.2613 delC) is a first hit and the LOH of the wild-type allele is a second hit, implying that all 16 BCCs detected in these NBCCS sisters fit the standard two-hit model.

Dynamic morphologic change and differentiation from fetal to mature pancreatic acinar cells in rats.

BACKGROUND/AIMS: Because of the notion that pancreatic and duodenal homeobox 1 (PdX-1)-positive cells are pancreatic stem cells that contribute to the differentiation and proliferation of exocrine cells, we examined PdX-1-associated changes in the morphology of rat pancreatic acinar cells that occur between the late fetal and early neonatal periods. METHODS: Light and electron microscopy and PdX-1 and MIB-5 immunohistochemistry were used to examine pancreatic tissues obtained from fetal rats 22 days postconception (dpc), from newborn rats 48 and 72 hours after natural birth, and from rats 7 days after natural birth. RESULTS: At 22 dpc, the cytoplasm of the acinar cells was large and eosinophilic due to accumulation of dense and numerous zymogen granules. Zymogen granules, rough endoplasmic reticulum, and other organelles were distributed throughout the cytoplasm. At 48 hours, i.e., just after feeding, the cytoplasm appeared smaller, less eosinophilic, and vacuolated. Electron microscopic examination showed cleaved nuclei and fewer zymogen granules. Expression of both PdX-1 and MIB-5 was increased at 48 hours. At 72 hours, acinar cell cytoplasm was decreased in size. At 7 days, the acinar cells were larger, biphasic distribution of zymogen granules was seen on the eosinophilic apical side, and rough endoplasmic reticulum and other ergastoplasms were seen on the basophilic basal side, typical of mature pancreatic acinar cells. Expression of PdX-1 and MIB-5 was markedly decreased in acinar cells. CONCLUSION: Our findings indicate dynamic PdX-1-associated morphologic change from fetal to mature pancreatic acinar cells between 48 and 72 hours after birth.