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Introduction: Cervical cancer is amongst the leading causes of death in females. According to the World Cancer Statistics, the global incidence of cervical cancer is 6.5% and mortality related to it is 7.5%. The most effective way to screen and thus treat in early stages is achieved by screening the patients with Papanicolaou (Pap) smear. Aim: To assess the spectrum of cervical lesions in Pap smears, classify them as per the Bethesda System of reporting Cervical Cytology and compare the cytology results with histopathology where available. Materials and Methods: The present study was a cross-sectional study carried out for a period of two months from August 2022 to September 2022 in Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh, India. The slides of Pap smear were reported as per the 2014 Bethesda System of reporting cervical cytology. Comparison with the histopathological findings was done in cases whenever cervical biopsy or hysterectomy specimen was received. Data was collected, entered and compiled in Microsoft excel followed by analysis using software Statistical Package for the Social Sciences (SPSS) 23.0. The data was represented in frequency and validity was calculated in terms of sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV) and accuracy. The p-value was calculated using Chi-square test and significance was set at p

Objective: To evaluate the diagnostic yield of pancreatic cancer screening in individuals at risk (IAR) from familial pancreatic cancer (FPC) families with respect to the presence or absence of pathogenic germline variants predisposing to pancreatic adenocarcinoma (PDAC)., Design: In a 20 years period, IAR from FPC families were enrolled in a prospective screening program of the national case collection for FPC of Germany, including magnet resonance imaging (MRI) and endoscopic ultrasound (EUS). The diagnostic yield was analyzed regarding significant pancreatic lesions such as PDAC, high-grade pancreatic-intraepithelial-neoplasia (PanIN3) and intraductal-papillary-mucinous-neoplasia (IPMN) with high-grade dysplasia. Screening results were compared between carriers of pathogenic variants and variant-negative IAR., Results: 337 IAR, including 74 (22%) variant-carriers and 263 IAR of variant-negative FPC families (mean age 49; standard deviation [SD] + 8.9) were followed 64 (SD + 55) months. IAR underwent 5.1 (SD + 3.9) screening visits with 1733 MRI (5.1,SD + 3.9 per IAR) and 728 EUS (2.2,SD + 1.7 per IAR). In 12 (4%) cases, significant pancreatic lesions were detected, including 4 PDAC, 3 PanIN3 and 5 high-grade IPMN. Three of 4 IAR with PDAC died after a mean of 27 months postoperatively, and one IAR is alive without evidence of disease after 31 months. The diagnostic yield for significant lesions was 13.5% (10/74) for variant carriers compared to 0.8% (2/263) for IAR of variant-negative FPC families (p < 0.001). Logistic regression analysis revealed that a negative variant status was almost always accompanied by the absence of a significant lesion over time with a negative predictive value of 99.2% (95% CI 97.3%-99.9%)., Conclusion: The diagnostic yield seems to justify PDAC screening in IAR of FPC-families with pathogenic germline variants in PDAC predisposing genes, not in IAR of variant-negative families., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: The Japan Esophageal Society proposed the JES microvessel classification to assess eligibility of early esophageal squamous cell neoplasia (ESCN) for endoscopic resection based on intrapapillary capillary loop assessment. We aimed to assess its diagnostic reproducibility and accuracy in Western ESCN patients., Methods: Intrapapillary capillary loops on endoscopic images of Western ESCN lesions (n = 113) collected between 2010 and 2022 were assessed by nine endoscopists, including three Japanese expert endoscopists, three Western expert endoscopists, and three residents-in-training, and graded according to the JES microvessel classification where microvessel type A corresponds with normality or low-grade intraepithelial neoplasia, and microvessel types B1, B2, and B3 correspond with high-grade intraepithelial neoplasia or invasion into the lamina propria, muscularis mucosae or superficial submucosa, and deep submucosa, respectively. Outcomes included overall accuracy in predicting ESCN invasion depth and interobserver agreement., Results: Good interobserver agreement was observed among expert endoscopists (Krippendorf's alpha 0.64, 95% CI 0.57-0.70), while agreement was moderate among residents-in-training (Krippendorf's alpha 0.58, 95% CI 0.52-0.72). Overall accuracy of the JES microvessel classification was 53% (95% CI 42-63), 52% (95% CI 41-62), and 44% (95% CI 34-55) for Japanese endoscopists, Western endoscopists, and residents-in-training, respectively. Sensitivity and specificity for vessel type A, B1, B2, and B3 across assessors were 0%-50% and 89%-100%, 55%-64% and 66%-77%, 42%-71% and 60%-76%, and 10%-24% and 92%-97%, respectively. Negative predictive value ranged between 80% and 85% for B3 vessels., Conclusion: Overall accuracy of the JES microvessel classification in Western ESCN patients is low, though absence of B3 vessels as assessed by experienced endoscopists may predict superficial ESCN amenable to endoscopic resection., Trial Registry: www.trialregister.nl; NL8897 (6-9-2020)., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Serous tubal intraepithelial carcinoma is a precursor lesion for high-grade pelvic serous carcinoma. The incidence is 0.6%–6% in tubectomy specimens of women who are BRCA-1,2 positive or have a strong family history of breast or ovarian cancer. STIC in women who do not have BRCA-1,2 mutations or concomitant high-grade serous carcinoma is exceedingly rare. Ectopic tubal gestation coexisting with serous tubal intraepithelial carcinoma is very rarely reported. These lesions pose considerable difficulty in the diagnosis. A combination of histology and immunohistochemical expression p53 and ki67 substantially improves the reproducibility of the diagnosis. Diagnosing these lesions will help identify potential at risk patients and their families for carcinoma. Adequate prolonged follow-up for incidental serous tubal intraepithelial carcinoma is the mainstay. We report one such case of a 31-year-old female who was operated for the right tubal gestation and found to have serous tubal intraepithelial carcinoma.

Novianti Qurnia Putri,1 Tiara Bunga Mayang Permata,1 Ni Ayu Wulandari,1 Handoko,1 Endang Nuryadi,1 Gatot Purwoto,2 Soehartati Argadikoesoema Gondhowiardjo1 1Department of Radiation Oncology, Dr. Cipto Mangunkusumo National General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia; 2Department of Obstetrics and Gynecology, Dr. Cipto Mangunkusumo National General Hospital, Faculty of Medicine universitas Indonesia, Jakarta, IndonesiaCorrespondence: Soehartati Argadikoesoema Gondhowiardjo Tel/Fax +62 21-3926288Email gondhow@gmail.comAbstract: Cervical cancer is the one of the most common gynecology malignancies in the world. National Comprehensive Cancer Network (NCCN) guidelines on cervical cancer are widely adopted as national guidelines and clinical practice guidelines. These guidelines are constantly being updated but their effectiveness has not been questioned. Therefore, we conducted a systematic review to assess outcomes with/without guideline adherence in the published studies. This systematic review was conducted according to PRISMA statement. Searching with strategy on PubMed, ProQuest, Scopus, and Wiley databases resulted in three studies that met all criteria, thus assessed further with Newcastle-Ottawa scale, and assessed qualitatively. All three studies adopt NCCN guidelines. We found that the proportion of adherence to cervical cancer treatment guidelines was low, ranging from 42% to 54%, with violations occurring at various clinical stages. One study stated that early stage cervical cancer was more likely to receive guideline adherence (adjusted OR=5.48; 95%CI: 1.94– 15.5; p=0.001) than advanced stage. There was a higher five-year survival of cervical cancer patients in the guideline-adhering group than in the nonadhering group. In all three studies, survival in the adherent group was reported as big as 88%, 79%, and 93%, respectively, compared to nonadherent group with 56%, 78%, and 88.1%respectively (p< 0.05). One study stated that adherence to guidelines could reduce cervical cancer mortality on stage I and II by 0.22 times (p< 0.05). As the conclusion, adherence to guidelines increases survival rates. In the early stages, there are differences in survival.Keywords: intraepithelial, neoplasia, squamous, cell, recommendation

Serous tubal intraepithelial carcinoma is a precursor lesion for high-grade pelvic serous carcinoma. The incidence is 0.6%-6% in tubectomy specimens of women who are BRCA-1,2 positive or have a strong family history of breast or ovarian cancer. STIC in women who do not have BRCA-1,2 mutations or concomitant high-grade serous carcinoma is exceedingly rare. Ectopic tubal gestation coexisting with serous tubal intraepithelial carcinoma is very rarely reported. These lesions pose considerable difficulty in the diagnosis. A combination of histology and immunohistochemical expression p53 and ki67 substantially improves the reproducibility of the diagnosis. Diagnosing these lesions will help identify potential at risk patients and their families for carcinoma. Adequate prolonged follow-up for incidental serous tubal intraepithelial carcinoma is the mainstay. We report one such case of a 31-year-old female who was operated for the right tubal gestation and found to have serous tubal intraepithelial carcinoma. [ABSTRACT FROM AUTHOR]

Giant ovarian cysts are rare and usually pose significant diagnostic challenges especially in adolescents and young adults. There is limited report of such cases reported in existing literature with hardly any cases published from the Sub-Sharan African region. We present the case of a 24-year-old young woman who reported to our gynaecology clinic on the 23rd of January 2023 with a year's history of a progressively increasing abdominopelvic mass. She was successfully managed surgically and made smooth recovery. Based on the history and examination findings, confirmed the diagnosis clinically with abdomino-pelvic ultrasound scan, removed the tumour surgically and undertook histopathological studies to confirm a benign disease. To the best of our knowledge, our successful management of this patient is the first case of such a huge borderline ovarian tumour reported in Ghana and the Sub-Saharan African region to inform clinicians on safe surgical management in our context. Our successful management of this giant mucinous BOT reiterates the fact that in the absence of precise prognostic marker of malignancy, clinicians should always balance the oncologic safety of the patient against less radical treatment modality. • Giant ovarian cysts have become rare due early presentation and availability of modern imaging modalities. • They pose significant diagnostic challenges especially in adolescents and young adults. • Data is limited especially from Sub-Sharan African region. • We successfully managed the giant mucinous borderline ovarian tumour with about 25litres in a 24year old woman. • Clinicians should balance the oncologic safety of the patient against less radical treatment modality. [ABSTRACT FROM AUTHOR]

The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα+ T lymphocytes, and CD49a+ liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46−CD8αα−Ly49E+ cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.

Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.

Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ+CD8αβ+ and TCRαβ+CD8αα+ intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development. [Display omitted] • Low-fiber diet changes the microbiota and impair the development of intestinal T cells • Mice fed low-fiber diet over generations have persistent defects in intestinal T cells • Low-fiber diet reduces the abundance and impairs the vertical transmission of SFB • Dietary fiber and SFB are needed for the development of CD8αβ intraepithelial T cells Royer et al. show that low-fiber diets change the small intestinal microbiota and impairs the development of intestinal T cells. This defect becomes persistent over generations of mice fed low-fiber diets due to impaired vertical transmission of SFB. This study demonstrates the importance of fiber for microbiota transmission and immune system development. [ABSTRACT FROM AUTHOR]

Primary fallopian tube carcinomas (PFTC) are rare tumors with non-specific clinical presentations. The current case was unique since the tumor was first detected on endometrial curettage and clinicoradiologically was misdiagnosed as endometrial carcinoma. A 48-year-old, post-menopausal female presented with one episode of vaginal bleeding. Endometrial curettage showed poorly differentiated carcinoma, while cervicovaginal Papanicolaou (Pap) smear was negative for malignant cells. Right sided fallopian tube carcinoma in-situ was diagnosed on histopathological examination of surgical hysterectomy with B/L salpingo-oophorectomy specimen. As observed in the current case, unusual tumor histology with broad papillary fronds lined by pleomorphic cells showing nuclear stratification and focal involvement of endometrial curettage specimen may be considered a useful pointer for tubal malignancy. [ABSTRACT FROM AUTHOR]

Intestinal eosinophils are implicated in homeostatic and disease-associated processes, yet the phenotype of intestinal tissue-dwelling eosinophils is poorly defined and their roles in intestinal health or disease remain enigmatic. Here we probed the phenotype and localization of eosinophils constitutively homed to the small intestine of naive mice at baseline, and of antigen-sensitized mice following intestinal challenge. Eosinophils homed to the intestinal lamina propria of naive mice were phenotypically distinguished from autologous blood eosinophils, and constitutively expressed antigen-presenting cell markers, suggesting that intestinal eosinophils, unlike blood eosinophils, may be primed for antigen presentation. We further identified a previously unrecognized resident population of CD11chi eosinophils that are recovered with intraepithelial leucocytes, and that are phenotypically distinct from both lamina propria and blood eosinophils. To better visualize intestinal eosinophils in situ, we generated eosinophil reporter mice wherein green fluorescent protein expression is targeted to both granule-delimiting and plasma membranes. Analyses of deconvolved fluorescent z-section image stacks of intestinal tissue sections from eosinophil reporter mice revealed eosinophils within intestinal villi exhibited dendritic morphologies with cellular extensions that often contacted the basement membrane. Using an in vivo model of antigen acquisition in antigen-sensitized mice, we demonstrate that both lamina propria-associated and intraepithelium-associated eosinophils encounter, and are competent to acquire, lumen-derived antigen. Taken together these data provide new foundational insights into the organization and functional potential of intestinal tissue-dwelling eosinophils, including the recognition of different subsets of resident intestinal eosinophils, and constitutive expression of antigen-presenting cell markers. [ABSTRACT FROM AUTHOR]

This study was aimed at investigating the clinicopathological characteristics of tubal metastases originating from primary endometrial, cervical, and nongynecological malignancies. We performed a 4-year retrospective study in which fallopian tube tissues obtained from 60 patients with tubal metastases were examined. In addition, we compared the number of tubal metastasis cases detected during periods of representative or whole tubal sampling. Twenty-three and 37 tubal metastases were found in cases examined after representative and whole tubal sampling techniques, respectively. Four cases of microscopic tubal metastases were detected via whole sampling, whereas no microscopic lesions were identified via representative sampling. The metastatic lesions originated from 14 uterine (10, endometrium; 4, cervix) and 46 nongynecological tumors (21, colon; 15, stomach; 5, biliary; 3, appendix; 2, breast). Tumors were most commonly involved in the muscle and lamina propria (n = 17). We noted distinctive histopathological features according to the extent of mural involvement: fibromyxoid stromal reaction and lymphohistiocytic infiltration in tumors involving the muscle and subepithelial connective tissue, architectural alterations of plicae in those involving the subepithelial connective tissue, and intraluminal mucinous and inflammatory exudate adjacent to intraepithelial tumors. We observed distinctive histopathological features associated with tubal metastases according to the extent of mural involvement. In addition, we demonstrated that the sampling method used in the routine microscopic examination of the fallopian tube affects the detection of tubal metastases. Our data support the notion that it is more logical to thoroughly sample both the fimbrial ends and the nonfimbriated portions of fallopian tubes for all salpingectomy specimens in the setting of cancer surgery. [ABSTRACT FROM AUTHOR]

Summary The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα + T lymphocytes, and CD49a + liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46 − CD8αα − Ly49E + cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity. [ABSTRACT FROM AUTHOR]

Background This research is dedicated to investigating the effects and potential mechanism of action of the aryl hydrocarbon receptor on the intestinal mucosal immune system in dextran sulfate sodium (DSS)-induced colitis. Methods Colitis was induced by the administration of 3% DSS to wild-type C57BL/6J mice for 7 days. 6-formylindolo(3, 2-b)carbazole (FICZ), an endogenous agonist of the aryl hydrocarbon receptor (AhR), was given intraperitoneally on a daily basis beginning 2 days after the start of DSS administration. The mice were weighed and assessed, and colon tissues were measured. Intraepithelial lymphocytes (IELs) were isolated from the colon and examined by flow cytometry and quantitative real-time PCR. Results FICZ ameliorated DSS-induced colitis, resulting in a reduced disease activity index and improvement in the histology and length of the colon. Colitis reduced the percentage and number of CD8αα + TCRαβ + IELs. FICZ prevented the reduction in the numbers of CD8αα + TCRαβ + IELs by upregulating the expression of the IL-15 receptor and the aryl hydrocarbon receptor (AhR), and attenuating the apoptotic rate of CD8αα + TCRαβ + IELs. Finally, IL-10 was increased and IFN-γ was decreased in CD8αα + TCRαβ + IELs by FICZ administration in DSS-induced colitis. Conclusions The results suggest that AhR activation ameliorated DSS-induced acute colitis, in a manner that is associated with the local expansion and functions of CD8αα + TCRαβ + IELs in acute colitis. The findings indicate that AhR-related ligands might be targeted as novel drug targets for IBD. [ABSTRACT FROM AUTHOR]

Aims Differentiated squamous intraepithelial neoplasia ( DSIN) has been described in several sites, including the upper aerodigestive tract and vulva, so this study investigated whether it also occurred in the anal canal. Methods and results All cases of squamous cell carcinoma ( SCC) involving the anal canal diagnosed between 2009 and 2015 at our institution were reviewed. Eighty-six cases were included, and 13 (15%) showed features consistent with DSIN: 10 were 'pure' DSIN, and three were 'mixed' DSIN and squamous intraepithelial lesion. DSIN was characterized by atypical keratinocytes limited to the basal/parabasal layers, acanthosis, and a 'cobblestone' appearance. Among specimens with pure DSIN, the surface was flat in eight cases. In five cases, the DSIN was extensive, and associated with deeply invasive SCC requiring radical surgical resection. Immunohistochemically, the epithelia showing changes consistent with DSIN were p16-negative, whereas the invasive component was p16-positive in 12 cases. Both Ki67 and p53 showed strong nuclear positivity in the basal/parabasal layers of DSIN. Conclusions Invasive SCC associated with DSIN often presents at an advanced stage of disease, requiring radical surgical treatment. The neoplastic changes in DSIN are limited to the basal/parabasal layers, which may account for the negative diagnoses by anal cytopathology and late clinical diagnosis. The recognition of anal DSIN is important in order to avoid underdiagnosis in superficial biopsies. [ABSTRACT FROM AUTHOR]

Aim. To evaluate clinical peculiarities and prognostic value of abdominal syndrome in adult patients with systemic vascular purpura (SVP). Material and methods. Incidence, clinical picture, complications of abdominal syndrome, its relations with principal extraintestinal manifestations of SVP were studied in 125 SVP patients. Absorption and barrier functions of the small intestine, their correlations with clinical activity of the disease were investigated in 32 SVP patients with no clinical signs of intestinal affection. Computer-assisted morphometry of duodenal mucosa biopsies was conducted and the results were compared to those of intestinal permiability and clinical activity of SVP. Results. Negative correlation was found between the occurrence of abdominal syndrome and the patients' age. The gastrointestinal tract suffered more frequently in men. 21% patients had abdominal complications, association of abdominal syndrome with higher frequency of glomerulonephritis. In the absence of abdominal symptoms, the barrier function of the small intestine for protein macromolecules was impaired. This correlated with exacerbations of skin purpura. Increased intestinal permeability and activity of skin purpura correlated with severity of inflammation in the duodenal mucosa. Conclusion. Abdominal syndrome in SVP is an unfavourable prognostic factor indicating possible severe complications and high risk of glomerulonephritis. Subclinical intestinal involvement presenting as barrier dysfunction may contribute to aggravation of skin vasculitis.

Introduction: We investigated the occurrence of differentiated oral intraepithelial neoplasia (DOIN) that met the criteria for differentiated intravulvar neoplasia, associated with invasive squamous cell carcinoma (SCC) of the anterior oral cavity, and its clinicopathologic significance. Materials and Methods: Sixty-nine consecutive cases of SCC of the anterior oral cavity were categorized into 2 groups: group A comprised SCC associated with DOIN; Group B consisted of cases associated with classical SCC in situ. Results: Fifty-five cases (80%) were classified as group A, or DOIN lesions, with only 14 (20%) as group B. All cases were associated with invasive SCC, except 2 cases in group B. Squamous epithelium continuous or adjacent to invasive SCC displayed consistent changes in the parabasal and basal layers with (1) cytologic atypia with proliferation of parabasal cells in downward expansion causing reactive proliferation of the basal cell layer in early stage and invading the basal layer in late stage, (2) disordered nuclear/cytoplasmic arrangement, and (3) a “cobblestone” appearance characterized by prominent intercellular spaces and cytoplasmic density involving the entire cell (dyskeratosis) of the parabasal layer. p53 and Ki67 immunostaining revealed linear reactivity mainly in the parabasal layer. Conclusions: DOIN lesions are frequently associated with invasive SCC of anterior oral cavity. Due to the subtle histopathologic changes, DOIN lesions pose potential diagnostic difficulty with differentiation from mild dysplasia or reactive atypia. [ABSTRACT FROM PUBLISHER]

Allergen immunotherapy has been used to treat allergic diseases, such as asthma, allergic rhinitis, and venom allergy, since first described over a century ago. The current standard of care in the United States involves subcutaneous administration of clinically relevant allergens for several months, building up to eventual monthly injections for typically 3 to 5 years. Recent advances have improved the safety and efficacy of immunotherapy. The addition of omalizumab or Toll-like receptor agonists to standard subcutaneous immunotherapy has proved beneficial. Altering the extract itself, either through chemical manipulation producing allergoids or directly producing recombinant proteins or significant peptides, has been evaluated with promising results. The use of different administration techniques, such as sublingual immunotherapy, is common in Europe and is on the immediate horizon in the United States. Other methods of administering allergen immunotherapy have been studied, including epicutaneous, intralymphatic, intranasal, and oral immunotherapy. In this review we focus on new types and routes of immunotherapy, exploring recent human clinical trial data. The promise of better immunotherapies appears closer than ever before, but much work is still needed to develop novel immunotherapies that induce immunologic tolerance and enhanced clinical efficacy and safety over that noted for subcutaneous allergen immunotherapy. [Copyright &y& Elsevier]

Abstract: The Hedgehog signaling pathway regulates embryo patterning and progenitor cell homeostasis in adult tissues, including epidermal appendages. A role for the Hh pathway in mammary biology and breast cancer has also been suggested. The aim of this study was to analyze Hh signaling in the mouse mammary gland through the generation of transgenic mice that express Sonic Hedgehog (Shh) under the control of the mammary-specific WAP promoter (WAP-Shh mice). To identify mammary cells capable of activating the Hh pathway we bred WAP-Shh mice to Ptch1-lacZ knock-in mice, in which the expression of a nuclear-targeted β-galactosidase reporter protein (β-gal) is driven by the endogenous Patched 1 gene regulatory region. After two cycles of induction of transgenic Shh expression, we detected areas of X-gal reactivity. Immunohistochemical analysis showed nuclear β-gal staining in clusters of mammary cells in WAP-Shh/Ptch1-lacZ bitransgenic mice. These were epithelial cells present in a basal location of displastic ducts and alveoli, adjacent to Shh-expressing luminal cells, and overexpressed epithelial basal markers keratin 5, 14 and 17 and transcription factor p63. Absence of smooth muscle actin expression and a cuboidal morphology differentiated Hh-responding cells from flat-shaped mature myoepithelial cells. Groups of cells expressing stem cell markers integrin β3 and keratins 6 and 15 were also detected within Hh-responding areas. In addition, we found that Hh-responding cells in the mammary glands of WAP-Shh/Ptch1-lacZ mice were ciliated and exhibited a low proliferation rate. Our data show the paracrine nature of hedgehog signaling in the epithelial compartment of the mouse mammary gland, where a subset of basal cells that express mammary progenitor cell markers and exhibit primary cilia is expanded in response to secretory epithelium-derived Shh. [Copyright &y& Elsevier]

Marked involvement of bronchial epithelium by malignant cells with a neuroendocrine immunophenotype was observed in a pulmonary lobectomy specimen containing combined small cell lung carcinoma (SCLC). Review of the medical literature reveals scant information on malignant neuroendocrine cells in bronchial epithelium accompanying SCLC and no documentation of an SCLC precursor. We discuss the possibility that the intraepithelial neoplastic lesion that we have described may be a primary lesion and possibly a precursor of SCLC and the alternative possibility that it represents invasion by underlying invasive SCLC. The need for further comprehensive study of the morphology and immunophenotype of bronchial mucosal abnormalities accompanying SCLC utilizing lung resection specimens is emphasized. [ABSTRACT FROM PUBLISHER]

Background: Lymphocytic bronchiolitis (LB) is the strongest risk factor for subsequent allograft loss due to bronchiolitis obliterative syndrome (BOS); however, it is poorly assessed by transbronchial biopsy (TBBx) because of sampling error, interpretation error and the presence of non-alloimmune airway inflammation. We hypothesized that flow cytometric evaluation of bronchiolar brushings (transbronchial brush, TBBr) may be a better approach. Methods: Transbronchial brushings (2 to 3 cm from the pleural surface under radiologic guidance) were obtained prior to TBBx in 32 patients and analyzed by flow cytometry. We assessed the proportion of nucleated cells that were CD3+CD103+ (epithelial-specific T cells). Results: No adverse events occurred; 0.5% (0.27 to 0.84) of the cells were epithelial-specific T cells and numbers increased with episodes of Grade A1 rejection (p < 0.01) and in patients with BOS (p = 0.02). Viral and invasive fungal infection were associated with marked infiltration with CD103− T cells (p < 0.01). Conclusion: TBBr is simple to obtain, low risk, quantitative, and can discriminate between infective and alloimmune LB. It may be a valuable addition to current lung allograft assessment. [ABSTRACT FROM AUTHOR]

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Proliferative inflammatory atrophy (PIA) belongs to the atrophic lesions that frequently occur in the prostate. The location of PIA in the periphery of the gland near to prostate carcinoma or even showing direct transition to malignant or pre-malignant epithelia suggested a connection between PIA and prostate cancer. Further findings in PIA, such as imbalance between proliferation and apoptosis and detection of molecular-biological abnormalities specific for oxidative stress or malignancy, supported this hypothesis. Recently, epidemiological studies including large cohorts of patients have been undertaken in order to investigate the causal connection between PIA and prostate carcinoma. The current understanding of PIA allows us to consider it as a benign lesion with certain genetic instability which can degenerate into prostate intraepithelial neoplasia or carcinoma, provided that the balance between anti-carcinogens and carcinogens is perturbed. To evaluate the role of PIA as a precursor lesion of prostate cancer, further examinations of genetic or epigenetic aberrations are required. [ABSTRACT FROM AUTHOR]

Most pancreatic neoplasia are of ductal lineage, characterized by tubule (gland), cyst, papilla, or mucin formation and expression of mucin-related glycoproteins and oncoproteins (eg, MUC1, CA19-9, CEA, DUPAN), as well as some subsets of cytokeratin (eg, CK19). Mutations of k-ras oncogene and DPC4 are also common in ductal neoplasia and generally not seen in nonductal tumors. A variety of pancreatic neoplasia fall under the heading of ductal neoplasia. Invasive ductal adenocarcinoma (DA) is the most important and constitutes the vast majority (>85%) of pancreatic tumors. DA is characterized by insidious infiltration and rapid dissemination, despite its relatively well-differentiated histologic appearance. In some variants of DA such as undifferentiated or sarcomatoid, evidence of ductal differentiation may be lacking or only focal. The presumed precursors of DA are microscopic intraductal proliferative changes that are now termed pancreatic intraepithelial neoplasia (PanIN). PanINs comprise a neoplastic transformation ranging from early mucinous change (PanIN-1A) to frank CIS (PanIN-3). A similar (in situ) neoplastic spectrum also characterizes intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, which are cystic ductal-mucinous tumors with varying degrees of papilla formation, and may be associated with invasive carcinoma. As such, these can be regarded as mass-forming preinvasive neoplasia. Some intraductal papillary mucinous neoplasms are associated with invasive carcinoma of the colloid type. Colloid carcinoma of the pancreas appears to be a clinicopathologically distinct tumor with indolent behavior. Whereas most ductal pancreatic neoplasia are characterized by some degree of mucin formation, serous tumors, of which serous (microcystic) adenoma is the sole example, lack mucin formation, presumably because they recapitulate centroacinar ducts. They are typically benign tumors. It is recognized now that pancreatic carcinoma, like other malignant processes, is a genetic disease produced by progressive mutations in cancer-related genes. These alterations can be categorized as “early” such as k-ras mutation, HER-2/neu, PSCA, MUC5, and fascin overexpression; “intermediate” such as p16 inactivation, MUC1, and cyclin D1 overexpression; and finally as “late” such as p53 and DPC4 inactivation, BRCA2 mutation, and overexpression of ki-67, 14-3-3σ, and mesothelin. Ductal neoplasia is the most important category among pancreatic tumors. It is important to appreciate the different types of ductal tumors because they vary greatly in their clinicopathologic characteristics and prognosis. Understanding the molecular mechanisms of ductal carcinogenesis will help develop more efficient prevention and therapy of these tumors. [Copyright &y& Elsevier]

Although γδ T cells compose a small proportion of lymphocytes in lymphoid compartments and peripheral blood, they are the major T-cell population present in epithelial tissues. However, the role played by γδ TCR expressing intraepithelial lymphocytes (IEL) has been enigmatic. The location of tissue-resident I EL suggests that they are important members of the first line of defense against insult for organs exposed to the environment, including the skin, gut, lungs, and reproductive system. Dendritic epidermal T cells (DETC) are the skin-resident γδ IEL and serve as a model system for γδ IEL in other locations. DETC have demonstrated importance in the modulation of immune responses, surveillance and repair of tissue, and resistance to infection. This work discusses recent developments in understanding DETC activation. [ABSTRACT FROM AUTHOR]

Israeli Jewish women are at low risk for cancer of the uterine cervix. In view of absent screening programs in Israel, there are only scarce data available with regard to results of PAP smears. The aim of this study was to assess the incidence of premalignant cervical lesions in the largest sample of PAP smears reported so far from Israel. We retrospectively analyzed the results of 297,849 PAP smears, which had been examined in a single laboratory, during 9 years (1991–1999). The incidence of low- and high-grade squamous intraepithelial was 0.69% and 0.29%, respectively. Our data indicate similar incidence rates for premalignant lesions in Jewish Israeli women as observed in Western countries, but no increase during the study period. In spite of relatively high incidence rates for premalignant lesions of the uterine cervix, the incidence rate for invasive cervical cancer remains conspicuously low. For unknown reason the conversion rate from premalignant cervical lesions to invasive cancer is lower in Israeli Jewish women than in European and North American women. We discuss possible reasons for this phenomenon and suggest that at this time mass screening for cervical cancer in Israel may probably not be justified. [ABSTRACT FROM AUTHOR]

It is now accepted that there is a strong association between vulval intraepithelial neoplasia (VIN) and human papillomavirus (HPV) skin infection. HPV oncogenic subtype infection and altered p53 tumour suppressor function contribute to risk of malignant transformation of VIN, but other factors may be important such as HLA class 1 status and cellular immune mechanisms.The long-term cumulative risk of developing vulval squamous carcinoma following the diagnosis of high grade VIN diagnosis is thought to be approximately 6% per decade, but observational data supporting this is mostly non-population-based and retrospective. Unifocal asymptomatic VIN in younger women may have a lower malignant potential than in older women. Immunocompromised women with multifocal or multicentric squamous intraepithelial neoplasia of the lower genital tract may be at greater risk.Surgical treatments of VIN may reduce the risk of malignant transformation, but recurrence rates are high, and treatment related morbidity is common. Although the standard of care is considered to be excisional surgery, conservative management of asymptomatic high grade VIN in sexually active younger women may be a sensible option if disease involves the forchette or periclitoral areas. Fully informed consent should be documented if conservative management is chosen and surgery should be performed subsequently if lesions become symptomatic or if visual progressive changes occur whilst under surveillance.New treatments being researched include photodynamic therapy (PDT), human papillomavirus vaccines, immunotherapy, and immune modulators. The advantages of these new modalities over surgery is the potential to preserve body image and sexual functioning whilst targeting cellular dysfunction. [Copyright &y& Elsevier]

Conflicting results regarding the association of a polymorphism at codon 72 of the p53 tumour suppressor gene and susceptibility to develop human papilloma virus (HPV)-associated cervical cancer have been published over the last year, implicating differences in ethnic background, sample origin, sample size and/or detection assay. The material for this study was collected in the identical geographical region as for 2 previous reports with contradictory results regarding the association of codon 72 genotype with squamous cell cancer (SCC). We have used an alternative detection assay, based on pyrosequencing technology, that interrogates the variable position by the accuracy of DNA polymerase. Inaddition to cervical clinical specimens fromSCC, HPV16- and HPV18-infected adenocarcinoma cases as well as cervical intraepithelial neoplasia (CIN) were investigated. No significant associationwas foundbetween p53 codon72 genotype and the risk to develop adenocarcinoma, SCC or CIN in the Swedish population. [ABSTRACT FROM AUTHOR]

The normal human intestinal mucosa contains clonal T cell expansions. Clonal populations of T cells can be determined through evaluation of the idiotypic, hypervariable region of their T cell receptor (TCR). We have previously reported that there exists a highly conserved TCR pattern among intestinal CD8+ T cells in the majority of ulcerative colitis (UC) patients undergoing colectomy that was not present in normal control individuals. This TCR pattern, or motif, was characterized by particular β-chain usage (TCRBV3 and TCRBJ1S6) and a defined length in the hypervariable third complementarity determining region (CDR3). The aim of this study was to assess the motif's relationship to disease activity. Subjects were 66 with UC, 19 with Crohn's disease, 14 inflammatory controls, and 6 normal controls. cDNA and gDNA were prepared from colonic biopsies and paraffin blocks, respectively, obtained from study subjects and used to assess TCRBV CDR3 region length and usage, as well as for cloning and sequencing of TCRs. The TCRBV CDR3 region was present in 25 of a series of 48 UC subjects but only 3 of 19 Crohn's disease patients and 3 of 14 inflammatory controls. The motif was more common in UC than either Crohn's disease or inflammatory controls (χ2 = 7.5, P = 0.006, and χ2 = 4.1, P = 0.04, respectively). The motif's presence was not dependent upon histologic disease activity (either active or inactive UC). Clinical UC disease activity was also not significantly associated with an increased presence of the motif in 14 paired biopsies, which were taken during times of clinical activity or inactivity. There was a trend toward persistence of the motif, as it was present in 6 of 14 subjects over a 3- to 6-month time period. The previously described UC-associated TCRBV CDR3 region motif located in the intestinal CD8+ T-cell subset is found in a significant proportion of UC subjects. The TCR motif does not significantly discriminate active from inactive disease states. The persistent and diffuse nature of this TCR-associated motif in UC suggests that an ongoing T-cell response to a particular antigen(s) is occuring in this disorder. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 30 year old lesbian, in which she was diagnosed with cervical neoplasia. It is widely thought that lesbian women do not need Papanicolaou (Pap) smear testing. Lesbian women who have never had heterosexual intercourse may not be at as low a risk of developing cervical neoplasia as is often assumed, if human papillomavirus (HPV) DNA can be sexually transmitted between female partners. The woman presented for a routine physical examination and Pap smear. The patient's gynecologic history was unremarkable. Before performing colposcopy, two samples were obtained from the cervix for HPV DNA testing. The cervical biopsy sample was diagnosed as CIN 2. A high oncogenic risk HPV was detected in this patient using the Hybrid Capture method. HPV DNA was also detected in the cervicovaginal lavage by PCR. This is one of the first reports of a cervical high grade CIN associated with a high oncogenic risk HPV type in a lesbian woman who had no history of heterosexual intercourse.

Human intestinal intraepithelial lymphocytes (IEL) demonstrate target cell-restricted spontaneous cytotoxic (SC) activity that is due to CD2+CD3+CD8+CD16- CD56- effector cells: they kill epithelial ceil (EC) tumours (such as DLD-1 colon cancer cells), but not natural killer (NK)-sensitive K-562 cells. The present study shows that the measured levels of SC activities by IEL correlated with those of autologous lamina propria lymphocytes (LPL), but not with those of peripheral blood lymphocytes (PBL). Also, the susceptibilities of DLD-1 cell clones to lysis by IEL and PBL effector cells did not correlate, suggesting different mechanisms of lysis. Antibody blocking experiments showed that the main surface molecules involved in lysis depended on the effector cell type: αEβ7 (HML-1) on IEL and CD16 on PBL. No antibody-dependent cell-mediated cytotoxicity (ADCC) was demonstrated by IEL, even after stimulation with interferon-gamma (IFN-γ). Few IEL expressed Fc receptors for IgG. This study describes further differences between the SC activities of IEL and PBL. [ABSTRACT FROM AUTHOR]

Immunohistological analysis of the cellular composition of the small intestinal mucosa in a group of untreated and treated coeliac patients and non-coeliac control subjects was performed using monoclonal antibodies and an immunoperoxidase technique. A characteristic cellular distribution was observed within the normal mucosa. The intraepithelial and lamina propria compartments were occupied mainly by T suppressor/ cytotoxic and T helper/inducer cells respectively. Further subdivision of lamina propria T helper/inducer cells with the Leu 8 antibody revealed that these were of the Leu 3a+ Leu 8+ phenotype. Macrophages, defined by the RFD7 antibody, were seen to occupy the same microenvironment its T helper/inducer cells. T cells expressing the T cell activation antigen defined by anti-Ta1 were found with the normal lamina propria, although few cells were identified by the anti-Tae antibody, HLA-Dr antigens were expressed by stellate cells within the lamina propria, and also by the epithelial cells of the villi, but not by normal crypt epithelial cells, in untreated coeliac patients the distribution of the various cell types was essentially unchanged, although the number of these cells was markedly increased, including those which expressed the Ta1 antigen. A significant deviation from normal in the expression of HLA-DR antigens was found in the coeliac small bowel: these antigens were expressed not only on the villous epithelial cells but also on the epithelial cells of the crypts. Immunohistological findings in the treated coeliac patients were intermediate between the normal and untreated coeliac groups, and were completely normal in those patients with complete histological resolution of their disease. These results suggest that coeliac disease is accompanied by an enhanced stimulation of the normal mucosal immune response and do not imply a primary pathogenic role for the immune system in this disease. [ABSTRACT FROM AUTHOR]

The objective of this study was to define the colposcopic features of the normal anal canal and of anal human papillomavirus (HPV)-associated lesions, including anal intraepithelial neoplasia (AIN), and to correlate the colposcopic impression with the final histopathologic diagnosis. A controled colposcopic screening study of women considered at risk for HPV-associated anal epithelial abnormalities was carried out. All colposcopic assessments included a biopsy with matching histopathologic diagnosis. The study group consisted of 213 women who were considered at risk of anal HPV infection and AIN. A further group of 50 women, who had no previous history of ano-genital HPV infection or AIN and whose recent cervical smear was negative were recruited as controls. Informed consent was obtained from all patients, and the study was approved by the local ethical committee. In the control group of 50 women no AIN was detected. Normal histology was obtained in 45/50 (90%) biopsies where normality had been predicted on colposcopy. Histologic diagnosis in the at-risk group was normal in 143 (67%), subclinical papillomarvirus infection (SPI) in 24 (11%), and AIN of all grades (including three cases of early invasive squamous cancer in a field change of AIN III) in 46 (22%) patients. Nineteen of 24 (79%) cases of SPI were incorrectly predicted as normal on colposcopy, and another one (4%) as AIN I-II. Only four (17%) cases of SPI were correctly predicted at colposcopy. Of the 46 cases of histologically proven AIN, 26 (56%) were AIN I-II, and 20 (44%) were AIN III. Some 50% of AIN I-II were incorrectly predicted as SPI on colposcopy. Of the 20 AIN III lesions, 15 (75%) were correctly predicted by colposcopy. Three (20%) of these lesions contained foci of early invasion, of which in only one case (33.3%) was invasive disease suspected at colposcopy. Some 25% (5/20) of AIN III lesions were incorrectly diagnosed as AIN I-II at colposcopy. As is the experience with colposcopic assessment of the cervix, anal colposcopy predictions correlated well with the final histologic diagnosis, at the normal and high-grade AIN ends of the spectrum. The colposcopic predictive distinction between SPI and low-grade AIN (I-II) was less accurate. It was difficult to distinguish early invasive lesions within a field change of AIN III, from pure AIN III. In these studies there were three cases of early anal squamous carcinoma arising in AIN III lesions, two of which were unsuspected clinically. [ABSTRACT FROM AUTHOR]

Nineteen specimens of normal tissue were obtained from the duodenum, upper jejunum and terminal ileum. Specimens were fixed with periodatelysine-paraformaldehyde and then frozen sections were made. Lymphoid cell subsets were identified by indirect immunoperoxidase staining using mouse anti-human monoclonal antibodies. Results: 1) There was a remarkable variation in the distribution of positive cells among individuals and even within single sections. 2) Lymphoid cell subsets of the three parts of the small intestine were almost identical except for the difference in IgA subclasses of IgA-containing cells. IgAl predominated over IgA2 in the jejunum while IgA2 predominated over IgAl in the ileum. The subsets in the lamina propria (LP) and in the epithelium were clearly distinct; Leu 3 + (helper/inducer T) predominated in LP while Leu 2 + (suppressor/cytotoxic T) predominated in the epithelium and no Ig-containing cells were found in the epithelium. In LP the mean ratio of Leu 1 + (pan T): IgA (IgAl + IgA2) containing cells: IgM: IgG: IgD: IgE: HNK-1 + was 48.9: 36.6: 9.0: 1.8: 1.0: 0.3: 2.4. 3) The staining patterns of HLA-DR + and Leu 10 + were similar; dense in the top in LP of the villi. In some individuals the apical portion of epithelial cells was stained by anti-HLA-DR. 4) A few positive cells were observed in only two out of 19 cases by anti IL-2R. [ABSTRACT FROM AUTHOR]

Previously 2D cable analysis has been performed with two microelectrodes, one for passing intraepithelial current and the other for measuring the voltage response in multiple cells along the distance scale. This requires that the epithelium must be in a stable state for a considerably long period because of the multiple impalements. To follow changes of intraepithelial resistances in chambered Necturus antral mucosa with good temporal resolution, four/five electrodes were used to impale cells in the same preparation and the intraepithelial current (6.5–20 nA) was conducted sequentially to three/four of the electrodes, one at a time, to obtain six/ten independent voltage response measurements along the distance scale. The solution to the 2D cable equations was fitted to results and apical, basolateral and shunt resistances were calculated. It was found that an incorrect distance configuration can ruin the precision of the measurement. The distance configuration can, however, be optimized. The resistance values calculated with the 2D cable analysis were very close to those obtained by the amiloride exposure technique in the same tissues. The improvement gained with this work is better temporal resolution (even <10 s) when measuring epithelial resistances. [ABSTRACT FROM AUTHOR]

We have investigated the involvement of adhesion molecules in the lymphocyte infiltration associated with acute intestinal graft-versus-host disease (GVHD) induced by injection of C3H lymph node cells into irradiated (C3H × DBA/2)F mice. First we analyzed the expression profile of adhesion molecules including α1, α2, α4, α5, α6, αL and β7 integrins, CD44 and L-selectin of lymphocytes from lymph nodes and gut mucosa in normal mice. In normal mice, intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) uniquely showed increased expression of α1, α2 and β7 integrins, and decreased expression of L-selectin compared with that of lymphocytes of the lymph nodes and Peyer's patches. In mice with GVHD, IEL and LPL of donor lymph node cells origin underwent phenotyplc changes characterized by the increased expression of α1, αL and β7 integrins, and the loss of L-selectin. The expression profile of adhesion molecules on IEL and LPL of GVHD mice resembled that of normal mice except for the lack of α2 integrin. Treatment of GVHD mice with anti-α1,-α4 or-β7 integrin antibody alone partially prevented the mucosal pathology of intestinal GVHD, whereas only mice treated with anti-α1 showed reduced donor lymphocytic infiltration into the intestinal mucosa. In contrast, treatment with anti-αL or anti-CD44 antibody did not affect the intestinal GVHD. Furthermore, dual blockade of both α1 and α4 integrins completely inhibited the mucosal pathology and donor lymphocyte infiltration of intestinal GVHD. These results indicate that α1 and α4 integrins play an important role in the pathology of intestinal GVHD. [ABSTRACT FROM PUBLISHER]

An extensive comparison of TCR V-reglon usage by CD8CD4CD8 intraepithelial lymphocytes (IEL), CD4CD8 IEL, and lymph node (LN) T cell subsets in three minor lymphocyte stimulating (MIs)-disparate, MHC-ldentical mouse strains revealed novel TCR selection patterns. In cases where forbidden V regions were expressed by CD8 CD4CD8 IEL, the same TCRs were deleted from CD8β CD4CD8 IEL, Indicating that lack of CD8β expression was not solely responsible for forbidden V-region expression. These results also suggested that CD4 may be involved in negative selection of CD4CD8 IEL TCRs. In C57BR/cdJ (Mls-12) mice, a major increase in V3CD4CD8 IEL but not in other IEL or LN subsets was noted suggesting a subset-specific expansion of V3 cells. Negative selection of V14 cells in only the CD4CD8 IEL subset further supported the existence of intestine-specific TCR selection processes. Analysis of V-reglon expression of CD8 and CD8CD4CD8 IEL subsets revealed that forbidden V-region expression was not strictly confined to the CD8 subset in all cases. Overall, the data point to a dynamic, gut-specific TCR selection process that may be antigen driven. [ABSTRACT FROM PUBLISHER]

Intraepithelial lymphocytes (IEL) of the mouse small intestine were examined for their potential to respond to TCR signalling . Purified IEL subsets were activated using mAbs specific for CD3, TCRor TCRγ&. Thy-1IEL, regardless of TCR type, proliferated equally well in response to anti-TCR mAb with or without exogenous IL-2. In contrast, Thy-1 TCR, CD8 IEL required exogenous IL-2 for proliferation. No such requirement was observed for Thy-1 TCRγ& IEL proliferation. IEL proliferation in the absence of added IL-2 was due to an IL-2 secretion/IL-2 receptor (IL-2R) autocrine pathway, since mAbs specific for IL-2 and IL-2R inhibited IEL proliferation. Thy-1 CD8 CD4CD8 IEL were unresponsive to TCR-induced proliferation but exhibited high levels of cytolytic activity upon TCR-triggerlng. Thy-1 non-cytolytic IEL were induced to express Thy-1 and cytolytlc activity following activation . In addition, the involvement of the co-stimulatory molecule CD28 in IEL activation was tested. CD28 was weakly expressed by fresh IEL and anti-CD28 mAb had no effect on TCR-triggered proliferation. However, anti-TCR stimulation increased CD28 expression on a subset of TCR IEL and the addition of anti-CD28 mAb resulted in increased IL-2 production, but not in increased proliferation. Our results indicate that IEL, including the purported extrathymlc CD8 subset, can respond to TCR-driven signals via proliferation and/or cytolytlc activity. [ABSTRACT FROM PUBLISHER]

• PIN is characterized with higher recurrence rates after single surgical excision or other approaches. • PDT combined with circumcision is an effective treatment option for PIN, especially for the patient with an excessively long foreskin. • Circumcision before PDT application is very important. Penile intraepithelial neoplasia(PIN) is a premalignant lesion that can effect any part of the penile surface. Approximately 10–30 % of PIN patients are at risk of progression to squamous cell carcinoma (SCC), with metastatic potential of 3%–5%.. The use of photodynamic therapy (PDT) for PIN is currently controversial. Here, we performed circumcision in combination with PDT and successfully cured 3 cases of PIN. We considered that circumcision is very important before PDT. We recommend the treatment of circumcision combined with PDT to treat patients with PIN, especially for those who have failed previous treatment, or with an excessively long foreskin. [ABSTRACT FROM AUTHOR]