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Simple Summary: The Cancer Genome Atlas (TCGA) and more recent genome profiling recently revealed major intrinsic molecular subtypes in urothelial carcinoma (UC). Here we propose a fast and standardized immunophenotypical classification score (Piescore) that may discriminate between luminal, basal, or neu-like UC as a surrogate of molecular profile, and we describe, for the first time, an intratumoral phenotypical switch in tissue protein expression, from non-muscle to muscle-invasive progression. Our data show that a change from a luminal to a neu-like phenotype could worsen overall survival compared with a transition to a basal phenotype. In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be "non-real" luminal UC, which acquire nasal markers, such as CD44. [ABSTRACT FROM AUTHOR]

The adult Drosophila midgut epithelium is derived from a group of stem cells called adult midgut precursors (AMPs) that are specified during the migration of the endoderm in early embryogenesis. AMPs are maintained and expanded in AMP nests that lie on the basal side of the larval midgut throughout the larval development. During metamorphosis, the larval midgut undergoes histolysis and programmed cell death, while the central cells in the AMP nests form the future adult midgut and the peripheral cells form the transient pupal midgut. Here we review what is known about how cells polarise in the embryonic, larval, pupal and adult midgut, and discuss the open questions about the mechanisms that control the changes in cell arrangements, cell shape and cell polarity during midgut development.

Simple Summary: Although it is one disease, cancer of the urinary bladder occurs in several molecular subtypes that can be identified by laboratory tests. Tumors of advanced stages are treated with surgical removal of the urinary bladder with or without addition of chemotherapy. About 50% of patients are cured by surgery and this proportion is increased slightly by the addition of chemotherapy. Still, many patients do not benefit from chemotherapy, which also comes with significant toxicity. Recent advances in the field suggest that molecular subtypes can help identify patient categories that do or do not benefit from adding chemotherapy to surgery. In this article, we review the literature and conclude that molecular subtypes are likely to have such a role in the future but that there are differences between studies that make them challenging to compare. The current evidence is insufficient to guide clinical practice. There are no established biomarkers to guide patient selection for neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer. Recent studies suggest that molecular subtype classification holds promise for predicting chemotherapy response and/or survival benefit in this setting. Here, we summarize and discuss the scientific literature examining transcriptomic or panel-based molecular subtyping applied to neoadjuvant chemotherapy-treated patient cohorts. We find that there is not sufficient evidence to conclude that the basal subtype of muscle-invasive bladder cancer responds well to chemotherapy, since only a minority of studies support this conclusion. More evidence indicates that luminal-like subtypes may have the most improved outcomes after neoadjuvant chemotherapy. There are also conflicting data concerning the association between biopsy stromal content and response. Subtypes indicative of high stromal infiltration responded well in some studies and poorly in others. Uncertainties when interpreting the current literature include a lack of reporting both response and survival outcomes and the inherent risk of bias in retrospective study designs. Taken together, available studies suggest a role for molecular subtyping in stratifying patients for receiving neoadjuvant chemotherapy. The precise classification system that best captures such a predictive effect, and the exact subtypes for which other treatment options are more beneficial remains to be established, preferably in prospective studies. [ABSTRACT FROM AUTHOR]

The size and the weight of wheat grains vary across the length of each spike (Triticum aestivum L.). High temperature and water scarcity often reduce the single grain weight, and this reduction also varies across the spike length. Plants tend to cope with high temperature and drought stress through inherent mechanisms such ascanopy cooling through transpiration, which can contribute to yield stability. The effect of canopy cooling on the average grain weight at different positions in spike is still unknown. In this study, we planned to assess the role of canopy temperature, yield-related traits, and spike shape in final grain weight. For two years (2017–2018 and 2018–2019), fifteen diverse genotypes released for cultivation in different environmental conditions were grown in the field. They were examined for canopy temperature, spikelets spike−1, grain number spike−1, grain yield spike−1, and grain weight of the spike's basal, median, and distal regions. The Pearson correlation coefficient (r) was obtained for all pair-wise combinations of traits under different treatments and spike shapes. The results indicated that cooler canopy is correlated to grain weight in normal spike shape at all three positions within the spike irrespective of stress. The advantage of the cooler canopy in improving grain-filling at basal, median, and distal regions was more conspicuous in the high temperature stress conditions compared to non-stressed and drought conditions. [ABSTRACT FROM AUTHOR]

This study seeks to determine the effect of N fertilization method on ratoon lowland rice performance, to choose a fertilization method that provides high ratooned yield, and to assess its profitability adopting N fertilization method. The experiment lays out in a Randomized Complete Block Design with three replications and five N fertilization methods as treatments. Method of N application significantly affected the number of days to heading and maturity, plant height, leaf area index (LAI), number of productive tillers hill-1, panicle length and weight, number of filled and unfilled grains panicle-1. This method compensates cost of production of growing ratoon crop than those of the main crop. In fact, the highest profit (PhP25,564.80) was obtained in ratooned plants, which received 60 kg ha-1 N basal + 30 kg ha-1 N topdress application (T3) due to higher grain yield. Thereby, this is an appropriate option that provides high productivity and income for the ratoon growers.

Philip R Cohen,1 Antoanella Calame2 1San Diego Family Dermatology, National City, CA, USA; 2Compass Dermatopathology, San Diego, CA, USACorrespondence: Philip R Cohen Email mitehead@gmail.comAbstract: Multiple skin neoplasms at one site (MUSK IN A NEST), initially referred to as a collision tumor, describes the occurrence of two or more benign or malignant neoplasms that are adjacent or intermingled at the same cutaneous site. A mononeoplastic cutaneous tumor refers to a single tumor at any cutaneous site. Two, three, four, five, and six tumors at the same site are described as dineoplastic, trineoplastic, tetraneoplastic, pentaneoplastic, and hexaneoplastic cutaneous tumors, respectively; the prefixes are based on the numerical multiplier used by the International Union of Pure and Applied Chemistry (IUPAC). MUSK IN A NEST can be classified based upon their mechanism of pathogenesis–either being composed of mixed clones of cells (clonalium, which has three subtypes: collision, colonization, and combination) or the same clone of cells that has undergone clonal evolution (clonalidem, which has one subtype: biphenotypic). Basal cell carcinoma (BCC)-associated MUSK IN A NEST can be observed with either benign tumors, malignant tumors, or both. Nevi and seborrheic keratoses are the most common benign tumors associated with BCC; melanoma in situ and invasive melanoma are the most commonly reported malignant tumors associated with BCC. The definitive etiology of BCC-associated MUSK IN A NEST remains to be established–whether the development of the BCC at that site occurs as a direct or indirect consequence of the coexisting neoplasm or whether the occurrence of the BCC and the other neoplasm is merely the result of a coincidental juxtaposition of the tumors.Keywords: basal, carcinoma, cell, collision, neoplasm, tumor

Abstract Background Bladder cancer (BlCa) taxonomy has proved its impact in patient outcome and selection for targeted therapies, but such transcriptomic-based classification has not yet translated to routine practice. Moreover, epithelial-to-mesenchymal transition (EMT) has shown relevance in acquisition of more aggressive BlCa phenotype. We aimed to test the usefulness of the molecular classification, as defined by immunohistochemistry (a routinely performed and easy-to-implement technique), in a well-defined BlCa cohort of both non-muscle invasive (NMIBC) and muscle invasive (MIBC) disease. Also, we aimed to assess the additional prognostic value of the mesenchymal marker vimentin to the stratification strategy. Methods A total of 186 samples were available. Immunohistochemistry/RT-qPCR for luminal markers GATA3/FOXA1, basal markers KRT5/KRT6A and vimentin were performed. Results mRNA expression levels of the markers positively correlated with immunoexpression scores. We found substantial overlapping in immunoexpression of luminal and basal markers, evidencing tumor heterogeneity. In MIBC, basal tumors developed recurrence more frequently. NMIBC patients with higher vimentin immunoexpression endured poorer disease-free survival, and increased expression was observed from normal bladder-NMIBC-MIBC-metastases. Conclusions The classification has the potential to be implemented in routine, but further adjustments in practical scoring should be defined; focusing on additional markers, including those related to EMT, may further refine BlCa molecular taxonomy.

Introduction Prostatic basal cell carcinoma is an extremely rare tumor, exhibiting various histopathological features and clinical spectrums of disease. Case presentation A 69‐year‐old male presented to our department with 2 years of voiding difficulty and intermittent macroscopic hematuria. With a presumed diagnosis of benign prostatic hyperplasia, he underwent a transurethral resection of the prostate. Pathological examination revealed atypical basaloid cells forming solid nests. Robot‐assisted radical prostatectomy was subsequently performed, confirming a diagnosis of basal cell carcinoma with coexisting acinar adenocarcinoma. Conclusion Although more cases of basal cell carcinoma are indolent than aggressive, there is no reliable method of differentiation between these presentations. Thus, we recommend radical surgery and 6‐monthly disease surveillance until more is discovered about this very rare malignancy.

Background: Human mammary epithelial cell (HMEC) cultures encounter a stress-associated barrier termed stasis, during which most cells adopt a senescence-like phenotype. From these cultures, rare variants emerge from the basal epithelial population, re-initiating growth. Variants exhibit pre-malignant properties, including an aberrant epigenetic program that enables continued proliferation and acquisition of genetic changes. Following oncogenic transformation, variants produce tumors that recapitulate the histopathological characteristics of metaplastic breast cancer (MBC), a rare subtype characterized by squamous and mesenchymal differentiation., Methods: Using the conventional serum-free HMEC culture system, we probed the capacity for phenotypic plasticity inherent to basal epithelial cell populations from human breast tissue as they navigated stasis and emerged as variant populations., Results: We observed robust activation of a TGF-β-dependent epithelial-mesenchymal transition (EMT) program in basal epithelial cells during stasis, followed by subsequent attenuation of this program in emerging variants. Inhibiting the TGF-β pathway or depleting the EMT regulators Snail or Slug allowed basal epithelial cells to collectively bypass stasis, demonstrating that cellular dysfunction and arrest resulting from TGF-β and EMT activation are central to this in vitro barrier. The spontaneous emergence of variants from stasis cultures was associated with a restricted EMT trajectory, which diverted cells away from a complete mesenchymal state characterized by irreversible growth arrest, and instead limited variants to epithelial and intermediate EMT states associated with greater proliferative capacity and stemness. Epigenetic mechanisms, which contributed to the dysregulated growth control characteristic of the variant phenotype, also contributed to the constrained EMT program in variants. By overcoming the cellular dysfunction and growth arrest resulting from TGF-β and EMT activation, variants exhibited increased oncogenic transformation efficiency compared to pre-stasis basal epithelial cells. Inhibiting the TGF-β pathway prior to stasis significantly reduced EMT in the basal epithelial population, alleviated selective pressure driving variant emergence, and enhanced oncogenic transformation efficiency, resulting in tumors with markedly diminished metaplastic differentiation., Conclusions: This study reveals how adaptive EMT reprogramming governs basal epithelial cell fate decisions and contributes to the development of MBC progenitors by restricting access to terminal mesenchymal states that induce growth arrest and, instead, favoring intermediate states with enhanced tumorigenic potential., Competing Interests: Competing interests: The authors declare no competing interests.

Cutaneous basal cell carcinoma (BCC) in situ is a recently recognized subtype of the skin neoplasm in which the abnormal cells are confined to the epidermis. BCC in situ of the skin was previously referred to as a superficial BCC. A review of the world literature has revealed 10 cutaneous BCCs in situ that have been described in nine patients but likely reflect a more general phenomenon. The neoplasm typically presents as an asymptomatic red plaque on the abdomen, upper extremity, back, and chest. Pathologic changes frequently show confluent tumor cells along the epidermal basal layer or superficial aggregates of neoplastic cells that are contiguous with the epidermis and extend into the dermis. Genomic evaluation has been performed in neoplasms from one individual with cutaneous BCC in situ and metastatic BCC; like other variants of BCC, an aberration of the PTCH1 gene was observed. In contrast to his liver metastasis, the in situ carcinoma had a lower tumor mutational burden, lacked programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) amplification and had a distinct PTCH1 mutation, suggesting that the in situ BCC of his skin and the metastatic BCC of his liver were derived from different clones of cells., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Razelle Kurzrock declare(s) personal fees from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant. Razelle Kurzrock has received research funding from these companies. Razelle Kurzrock declare(s) personal fees from X-Biotech, Caris, Datar Cancer Genomics, Neomed, Pfizer, Actuate Therapeutics, and Roche, . Razelle Kurzrock has been a consultant and/or speaker fees and/or advisory board of these companies. Razelle Kurzrock declare(s) non-financial support from IDbyDNA and CureMatch Inc. Razelle Kurzrock has an equity interest in these companies. Razelle Kurzrock declare(s) non-financial support from CureMatch and CureMetrix. Razelle Kurzrock serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Cohen et al.)

The surgeon involved in the management of breast disease must work as part of an effective multidisciplinary team. The surgeon must work with all team members communicating effectively and working together. Histopathology provides diagnostic, prognostic and predictive information. The surgeon must understand the implications of the histopathology report for effective patient management. Improvements in core biopsy techniques have provided additional information resulting in lower open biopsy rates and improved preoperative diagnostic rates for facilitating surgical planning. Assessment of margin status, lymph node status and prognostication are continually evolving and shaping surgical practice towards less surgical intervention in the field of breast disease. Molecular testing is becoming an increasingly important aspect of breast cancer management in the era of precision medicine. [ABSTRACT FROM AUTHOR]

Background: Using a population‐based database, this study investigates the risk factors, epidemiology, and outcomes of basal cell adenocarcinoma (BCAC) of the head and neck. Methods: The Surveillance, Epidemiology, and End Results database was analyzed for all patients with BCAC of the head and neck from 1973 to 2015. Results: Three hundred and twenty‐two cases of BCAC of the head and neck were identified. Mean age of diagnosis was 64.1 years. 52.5% were male and 77.3% were white. The most common primary site was the parotid gland (71.7%). Most patients underwent surgery alone (51.9%). Five‐year disease‐specific survival (5Y‐DSS) was 95.6%, and 10Y‐DSS was 90.3%. Highest survival was seen with surgery alone followed by combined surgery and radiation (10Y‐DSS: 93.9% vs. 88.9%, p = 0.001). Age, primary site, T‐classification, grade, and treatment type significantly affected survival. Conclusions: BCAC of the head and neck presents most frequently in the parotid glands. Surgery alone is associated with highest survival. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma and basal cell carcinoma are two types of neoplasms that rarely affect the perianal region, and their etiology is still a matter for debate. We present the case of a 75 year old patient with a 26 year history of perianal fistula, who presents with purulent and fecal perianal discharge and swelling at this level. Physical examination and anoscopy detected low transsphincteric fistula. The biopsy revealed the diagnosis of squamous cell carcinoma, for which a local excision was performed followed by adjuvant radiotherapy. Two years after this event, the patient presented with another perianal lession, which according to the histopathological result was a basal cell carcinoma; local excision was the only treatment performed for this malignancy.

Introduction: Prostatic basal cell carcinoma (PBCC) with concurrent acinar adenocarcinoma and ductal adenocarcinoma is an extremely rare tumor that can exhibit various morphological features, as well as clinical spectrums of the disease. Case presentation: A 59-year-old male presented to the Department of Urology with two years of lower urinary tract symptoms. The ultrasound examination in Minqin County people's Hospital exhibited benign prostatic hyperplasia with calcification. After administration of ineffective medication, the patient underwent transurethral resection of the prostate (TURP). Pathological examination revealed a diagnosis of PBCC. Subsequently, robot-assisted radical prostatectomy was performed, which confirmed a diagnosis of prostatic basal cell carcinoma with coexisting acinar adenocarcinoma and ductal adenocarcinoma. Conclusion: Although most cases of prostatic basal cell carcinoma are indolent, rather than aggressive, there are no reliable methods that are able to distinguish these presentations. Furthermore, an optimal treatment has not yet been established. Radical surgery is recommended if PBCC is diagnosed at an early stage.

Urothelial carcinoma is subdivided into luminal (L), basal (B), and p53-wild-type (WT) molecular subtypes, with basal and p53-WT groups showing more aggressive course and poor treatment response, respectively. The literature on molecular subtypes of UC includes a mixture of different stages. We investigated the molecular profile and outcome of pure cohort of muscle invasive bladder carcinoma (MIBC) considering two distinct patterns of muscularis propria (MP) invasion. Forty-three cystectomies harboring stage pT2 were retrospectively identified in 18 years. MP invasion was subclassified into patterns 1 (tumor encasing intact detrusor muscle bundles) and 2 (tumor dissecting/replacing detrusor muscle). Using IHC, B/L phenotypes, p53, and Ki67 were assessed, and survival data was collected. Pattern 1 invasion was noted in 16 (37%) and pattern 2 in 27 (63%), with mean age of pattern 1 being 10 years younger. B/L phenotypes were successfully determined in 83.7%; 48.8% and 34.8% revealed L and B phenotypes, respectively (indeterminate phenotype in 16.4%). Pattern 1 was associated with L phenotype (GATA3 and HER-2 expressions: p = 0.02 & p = 0.04, respectively). Ki67 ≥ 5/10HPF was noted in pattern 2 and B phenotype (p = 0.03). B phenotype showed association with p53-WT (p = 0.007). In median follow-up of 60.7 months, 63.6% of pattern 1 cases were alive without disease compared to 32% of pattern 2 (not significant). A panel of CK20 and GATA3 for luminal and CK5/6 and CK14 for basal subtypes can provide reliable molecular classification in UC. Also, morphology of MIBC can predict the molecular phenotype and the behavior of the UC. [ABSTRACT FROM AUTHOR]

BackgroundNormal, healthy human breast tissue from a variety of volunteer donors has become available for research thanks to the establishment of the Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center (KTB). Multiple epithelial (K-HME) and stromal cells (K-HMS) were established from the donated tissue. Explant culture was utilized to isolate the cells from pieces of breast tissue. Selective media and trypsinization were employed to select either epithelial cells or stromal cells. The primary, non-transformed epithelial cells, the focus of this study, were characterized by immunohistochemistry, flow cytometry, and in vitro cell culture.ResultsAll of the primary, non-transformed epithelial cells tested have the ability to differentiate in vitro into a variety of cell types when plated in or on biologic matrices. Cells identified include stratified squamous epithelial, osteoclasts, chondrocytes, adipocytes, neural progenitors/neurons, immature muscle and melanocytes. The cells also express markers of embryonic stem cells.ConclusionsThe cell culture conditions employed select an epithelial cell that is pluri/multipotent. The plasticity of the epithelial cells developed mimics that seen in metaplastic carcinoma of the breast (MCB), a subtype of triple negative breast cancer; and may provide clues to the origin of this particularly aggressive type of breast cancer. The KTB is a unique biorepository, and the normal breast epithelial cells isolated from donated tissue have significant potential as new research tools.

We derive the surface and basal radar reflectance and backscatter coefficients of the southern McMurdo Ice Shelf (SMIS) and part of the nearby Ross Ice Shelf (RIS), Antarctica, from radar statistical reconnaissance using a 60-MHZ airborne survey. The surface coefficients are further inverted in terms of snow density and roughness, providing a spatial distribution of the processes contributing to the surface boundary conditions. We disentangle the basal coefficients from surface transmission losses, and we provide the basal coherent content, an indicator of the boundary geometric disorder that is also self-corrected from englacial attenuation. The basal radar properties exhibit sharp gradients along specific iso-depths, suggesting an abrupt modification of the ice composition and geometric structure. We interpret this behavior as locations where the pressure-melting point is reached, outlining fields of freezing and melting ice. Basal steps are observed at both SMIS and RIS, suggesting a common geometric expression of widespread basal processes. This technique offers a simultaneous view of both the surface and basal boundary conditions to help investigate the ice-shelf stability, while its application to airborne data significantly improves coverage of the difficult-to-observe ice–ocean boundary. It also provides constraints on thermohaline circulation in ice shelves cavities, which are analogs for ice-covered ocean worlds.

Cytokeratin 5 is a marker of basal molecular subtypes of muscle‐invasive bladder cancer (MIBC), which correlates with worse overall survival compared to luminal subtypes. Our observations have not confirmed CK5 as a marker of high‐grade (HG) disease in Ta non‐muscle‐invasive bladder cancer (NMIBC). Therefore, to understand the basal‐luminal immunohistochemistry profile in Ta NMIBC, we performed immunohistochemistry for CK5, P40, P63 (basal), GATA3 and CK20 (luminal) and studied the correlation with HG and clinical outcome in 109 patients with Ta NMIBC. HG and low‐grade (LG) diseases were scored in each patient. Four different CK5 patterns were evaluated: absent (median 41.3%), normal (72.5%), rising (84.4%) and full thickness (23.9%). The median percentage of GATA3 was 100%. HG disease and CK5 expression and rising CK5 pattern had a significant inverse correlation, whereas HG disease and CK20 expression had a significant positive correlation. We also found a significant inverse correlation between CK5 expression and CK20 expression. Quantitative PCR confirmed that the presence of CK5 correlated with up‐regulation of CK5 RNA. None of the markers could differentiate patients with regard to clinical outcome. Our results suggest a role for CK5 and CK20 in differentiating between LG and HG disease in Ta NMIBC. [ABSTRACT FROM AUTHOR]

Background: Basal cell carcinoma of the axilla, an area that is not usually exposed to the sun, is rare. Individuals with basal cell nevus syndrome, a disorder associated with a mutation in the patch 1 (PTCH1) gene, develop numerous basal cell carcinomas.Purpose: To describe a woman with basal cell nevus syndrome who developed a pigmented basal cell carcinoma in each of her axilla and to review the features of axillary basal cell carcinoma patients with Goltz-Gorlin syndrome.Methods: Pubmed was used to search the following terms: axillary basal cell carcinoma and basal cell nevus syndrome. The papers and their citations were evaluated.Results: Basal cell nevus syndrome patients with basal cell carcinoma of the axilla were observed in two women; this represents 2.5% (2 of 79) of the patients with axillary basal cell carcinoma. Both women had pigmented tumors that were histologically nonaggressive. The cancers did not recur after curettage or excision.Conclusions: Basal cell carcinoma of the axilla has only been described in 79 individuals; two of the patients were women with pigmented tumors who had basal cell nevus syndrome. Similar to other patients with axillary basal cell carcinoma, the tumors were histologically nonaggressive and did not recur following treatment. Whether PTCH1 gene mutation predisposes basal cell nevus patients to develop axillary basal cell carcinomas remains to be determined.

Red dot basal cell carcinoma is a distinctive clinical subtype of basal cell carcinoma. It has been reported in eight individuals with a male to female ratio of 1:1; and the patients' ages ranged from 50 to 74 years. All patients had prior history of actinic keratoses and basal cell carcinoma. In addition, some patients also had prior squamous cell carcinoma, malignant melanoma, and/or dysplastic nevus. The tumor was usually of recent onset, asymptomatic, and on sun-exposed skin. It was most commonly located on the nose (five patients); other sites were the upper lip, the mid back, or thigh—each in one patient. The red dot basal cell carcinoma was solitary and small—usually 4 mm or less in diameter. It typically presented as a red macule or papule; however, it sometimes appeared as a flesh-colored or pink to light-red papule with a bright-red central area. Microscopic features showed basaloid tumor cells (arranged as either nodular aggregates or superficial buds or both). In the central portion of the lesion, there was a proliferation of erythrocyte-containing vascular spaces between the epidermis and the neoplasm. The basal cell carcinoma pathology subtype was either nodular and superficial (three patients), nodular (two patients), or superficial (one patient). The clinical differential diagnosis of red dot basal cell carcinoma included not only benign vascular lesions (such as hemangioma and telangiectasia) but also inflammatory conditions and adnexal tumors. Other basaloid cell neoplasms were in the pathologic differential diagnosis. The pathogenesis of red dot basal cell carcinoma is similar to that of other basal cell carcinoma clinical subtypes. Mohs surgery is the treatment of choice for red dot basal cell carcinomas. Red dot basal cell carcinoma has two categories of biologic behavior based on the ratio of the postoperative wound size as compared with the size of the preoperative tumor: nonaggressive (for which the ratio was 5:1 or less for three patients) and aggressive (for which the ratio was greater than 12:1 for three patients). There was no recurrence of the red dot basal cell carcinoma after treatment. In conclusion, the incidence of red dot basal cell carcinoma—a unique morphologic variant of basal cell carcinoma—may be higher than suggested by the number of reported patients with this basal cell carcinoma subtype. [ABSTRACT FROM AUTHOR]

Objectives: The nested variant of urothelial carcinoma (NVUC) is a rare bladder tumor that may possess a luminal molecular phenotype. We sought to determine whether a small immunohistochemical (IHC) panel using common surrogates for molecular phenotypes would reliably classify a cohort of pure NVUC cases.Methods: IHC staining with a panel composed of markers for basal subtypes (CK5/6, CK14) and luminal subtypes (FOXA1, GATA3) was performed on pure small NVUC cases (n = 23) and 5 large NVUC cases (n = 5). Scoring of IHC stains was performed semiquantitatively. Individual cases were analyzed using previously reported IHC-based surrogates for molecular subtype.Results: The phenotype of NVUC was classified as luminal from 60.1% (FOXA1+/CK5/6-) to 100% (GATA3+/CK14-) of cases using composite phenotypes. No cases possessed a basal or squamous cell carcinoma-like phenotype. The majority of small NVUC cases (69.5%) showed subset CK5/6 expression distinctly localized to the basal layers of tumor cell nests. Intratumoral heterogeneity was also noted in CK5/6 (21.7% of small NVUC cases) but no other markers.Conclusions: NVUC appears to express markers of both basal and luminal bladder tumors. Definitive gene expression profiling may be valuable to further characterize this unique histologic variant. [ABSTRACT FROM AUTHOR]

Pyramidal neurons are the most common neurons in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. We compared human temporal cortex and mouse visual cortex pyramidal neurons from the Allen Cell Types Database in terms of their electrophysiology and dendritic morphology. We found that, among other differences, human pyramidal neurons had a higher action potential threshold voltage, a lower input resistance, and larger dendritic arbors. We learned Gaussian Bayesian networks from the data in order to identify correlations and conditional independencies between the variables and compare them between the species. We found strong correlations between electrophysiological and morphological variables in both species. In human cells, electrophysiological variables were correlated even with morphological variables that are not directly related to dendritic arbor size or diameter, such as mean bifurcation angle and mean branch tortuosity. Cortical depth was correlated with both electrophysiological and morphological variables in both species, and its effect on electrophysiology could not be explained in terms of the morphological variables. For some variables, the effect of cortical depth was opposite in the two species. Overall, the correlations among the variables differed strikingly between human and mouse neurons. Besides identifying correlations and conditional independencies, the learned Bayesian networks might be useful for probabilistic reasoning regarding the morphology and electrophysiology of pyramidal neurons.

During physiological epithelial-mesenchymal transition (EMT), which is important for embryogenesis and wound healing, epithelial cells activate a program to remodel their structure and achieve a mesenchymal fate. In cancer cells, EMT confers increased invasiveness and tumor-initiating capacity, which contribute to metastasis and resistance to therapeutics. However, cellular plasticity that navigates between epithelial and mesenchymal states and maintenance of a hybrid or partial E/M phenotype appears to be even more important for cancer progression. Besides other core EMT transcription factors, the well-characterized Snail-family proteins Snail (SNAI1) and Slug (SNAI2) play important roles in both physiological and pathological EMT. Often mentioned in unison, they do, however, differ in their functions in many scenarios. Indeed, Slug expression does not always correlate with complete EMT or loss of E-cadherin (CDH1). For example, Slug plays important roles in mammary epithelial cell progenitor cell lineage commitment and differentiation, DNA damage responses, hematopoietic stem cell self-renewal, and in pathologies such as pulmonary fibrosis and atherosclerosis. In this Perspective, we highlight Slug functions in mammary epithelial cells and breast cancer as a “non-EMT factor” in basal epithelial cells and stem cells with focus reports that demonstrate co-expression of Slug and E-cadherin. We speculate that Slug and E-cadherin may cooperate in normal mammary gland and breast cancer/stem cells and advocate for functional assessment of such Slug+/E-cadherinlow/+ (SNAI2+/CDH1low/+) “basal-like epithelial” cells. Thus, Slug may be regarded as less of an EMT factor than driver of the basal epithelial cell phenotype.

Pyramidal neurons are the most common neurons in the cerebral cortex. Understanding how they differ between species is a key challenge in neuroscience. We compared human temporal cortex and mouse visual cortex pyramidal neurons from the Allen Cell Types Database in terms of their electrophysiology and dendritic morphology. We found that, among other differences, human pyramidal neurons had a higher action potential threshold voltage, a lower input resistance, and larger dendritic arbors. We learned Gaussian Bayesian networks from the data in order to identify correlations and conditional independencies between the variables and compare them between the species. We found strong correlations between electrophysiological and morphological variables in both species. In human cells, electrophysiological variables were correlated even with morphological variables that are not directly related to dendritic arbor size or diameter, such as mean bifurcation angle and mean branch tortuosity. Cortical depth was correlated with both electrophysiological and morphological variables in both species, and its effect on electrophysiology could not be explained in terms of the morphological variables. For some variables, the effect of cortical depth was opposite in the two species. Overall, the correlations among the variables differed strikingly between human and mouse neurons. Besides identifying correlations and conditional independencies, the learned Bayesian networks might be useful for probabilistic reasoning regarding the morphology and electrophysiology of pyramidal neurons. [ABSTRACT FROM AUTHOR]

Gene expression profiling has reshaped our understanding of breast cancer by identifying four molecular subtypes: (1) luminal A, (2) luminal B, (3) human epidermal growth factor receptor 2 (HER2)-enriched, and (4) basal-like, which have critical differences in incidence, response to treatment, disease progression, survival, and imaging features. Luminal tumors are most common (60%-70%), characterized by estrogen receptor (ER) expression. Luminal A tumors have the best prognosis of all subtypes, whereas patients with luminal B tumors have significantly shorter overall and disease-free survival. Distinguishing between these tumors is important because luminal B tumors require more aggressive treatment. Both commonly present as irregular masses without associated calcifications at mammography; however, luminal B tumors more commonly demonstrate axillary involvement at diagnosis. HER2-enriched tumors are characterized by overexpression of the HER2 oncogene and low-to-absent ER expression. HER2+ disease carries a poor prognosis, but the development of anti-HER2 therapies has greatly improved outcomes for women with HER2+ breast cancer. HER2+ tumors most commonly present as spiculated masses with pleomorphic calcifications or as calcifications alone. Basal-like cancers (15% of all invasive breast cancers) predominate among "triple negative" cancers, which lack ER, progesterone receptor (PR), and HER2 expression. Basal-like cancers are frequently high-grade, large at diagnosis, with high rates of recurrence. Although imaging commonly reveals irregular masses with ill-defined or spiculated margins, some circumscribed basal-like tumors can be mistaken for benign lesions. Incorporating biomarker data (histologic grade, ER/PR/HER2 status, and multigene assays) into classic anatomic tumor, node, metastasis (TNM) staging can better inform clinical management of this heterogeneous disease. [ABSTRACT FROM AUTHOR]

Neuroscientists based at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour in London, Danbee Kim and Adam R Kampff study how the brain builds a mental model of its environment. Here, they imagine 'built environments' derived from these mental models. Their proposed designs may be ugly and they will likely fall over, but they hope they will distil insights from neuroscientific research in a form that facilitates discussion with the architects and planners responsible for creating environments in which the brain thrives. [ABSTRACT FROM AUTHOR]

Background: Bladder cancer (BlCa) taxonomy has proved its impact in patient outcome and selection for targeted therapies, but such transcriptomic-based classification has not yet translated to routine practice. Moreover, epithelial-to-mesenchymal transition (EMT) has shown relevance in acquisition of more aggressive BlCa phenotype. We aimed to test the usefulness of the molecular classification, as defined by immunohistochemistry (a routinely performed and easy-to-implement technique), in a well-defined BlCa cohort of both non-muscle invasive (NMIBC) and muscle invasive (MIBC) disease. Also, we aimed to assess the additional prognostic value of the mesenchymal marker vimentin to the stratification strategy.Methods: A total of 186 samples were available. Immunohistochemistry/RT-qPCR for luminal markers GATA3/FOXA1, basal markers KRT5/KRT6A and vimentin were performed.Results: mRNA expression levels of the markers positively correlated with immunoexpression scores. We found substantial overlapping in immunoexpression of luminal and basal markers, evidencing tumor heterogeneity. In MIBC, basal tumors developed recurrence more frequently. NMIBC patients with higher vimentin immunoexpression endured poorer disease-free survival, and increased expression was observed from normal bladder-NMIBC-MIBC-metastases.Conclusions: The classification has the potential to be implemented in routine, but further adjustments in practical scoring should be defined; focusing on additional markers, including those related to EMT, may further refine BlCa molecular taxonomy. [ABSTRACT FROM AUTHOR]

Objectives: Data on the predictive values of parameters included in the diagnostic work-up for precocious puberty (PP) remain limited. We detected the diagnostic value of basal sex hormone levels, pelvic ultrasound parameters and bone age assessment for activation of the hypothalamic-pituitary-gonadal axis in girls with PP, in order to help in the decision to perform GnRH testing. Patients and methods: We retrospectively considered 177 girls with PP. According to puberty evolution, the girls were divided into two groups: rapid progressive central precocious puberty (RP-CPP) and non/slowly progressive/transient forms (SP-PP). In all patients we considered Tanner stage, basal luteinizing hormone (LH) and estradiol (E2) values, bone age, and pelvis examination. We assessed the diagnostic value of each variable and identified the number of pathological parameters that best identify patients with RP-CPP. Results: Basal LH ≥ 0.2IU/L, E2 level ≥ 50 pmol/L, uterine longitudinal diameter ≥ 3.5 cm, transverse uterine diameter ≥ 1.5 cm, endometrial echo and ovarian volume ≥ 2 cm3 were significantly associated with RP-CPP (p ≤ 0.01). The ability to diagnose RP-CPP was enhanced with increasing number of pathological hormonal and instrumental parameters (p < 0.001). With more than three parameters detected, sensitivity and specificity reached 58% (95%CI 48–67) and 85% (95%CI 74–92), respectively, with a PPV = 86% (95%CI 76–93) and PPN = 54% (95%CI 43–54); the area under the ROC curve was 0.71 (95%CI 0.65–0.78). Conclusion: Despite the availability of different tests, diagnosing RP-CPP remains difficult. A diagnosis model including at least three hormonal and/or ultrasound parameters may serve as a useful preliminary step in selecting patients who require GnRH testing for early detection of RC-PP. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) development in the context of a piercing is a rare phenomenon, reported in the literature in only six instances. We present a 55-year-old woman with nodular BCC involving her auricular piercing and extending clinically onto the Posteroinferior right ear lobule and right postauricular crease. Histological analysis revealed spread of the BCC through the piercing onto the anterior lobule, with evidence that the cancer utilized the piercing as a low resistance pathway for this microscopic invasion. This case is, to our knowledge, the first report of microscopic BCC present within an auricular piercing itself. Chronic inflammation related to repeated trauma from the embedded jewelry may have played a role in its formation. A piercing may provide a path of least resistance for BCC tumor cells to invade, providing a nidus for recurrence. Careful histological examination with possible complete excision of the piercing is prudent to prevent cancer return. [ABSTRACT FROM AUTHOR]

Cellular and molecular heterogeneity within tumors has long been associated with the progression of cancer to an aggressive phenotype and a poor prognosis. However, how such intratumoral heterogeneity contributes to the invasiveness of cancer is largely unknown. Here, using a tumor bioengineering approach, we investigate the interaction between molecular subtypes within bladder microtumors and the corresponding effects on their invasiveness. Our results reveal heterogeneous microtumors formed by multiple molecular subtypes possess enhanced invasiveness compared to individual cells, even when both cells are not invasive individually. To examine the molecular mechanism of intratumoral heterogeneity mediated invasiveness, live single cell biosensing, RNA interference, and CRISPR-Cas9 gene editing approaches were applied to investigate and control the composition of the microtumors. An agent-based computational model was also developed to evaluate the influence of NOTCH1 variation on DLL4 expression within a microtumor. The data indicate that intratumoral variation in NOTCH1 expression can lead to upregulation of DLL4 expression within the microtumor and enhancement of microtumor invasiveness. Overall, our results reveal a novel mechanism of heterogeneity mediated invasiveness through intratumoral variation of gene expression.

Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative clonal mapping with 3D reconstruction of adult human prostates, we show that multipotent basal stem cells, confined to discrete niches in juxta-urethral ducts, generate bipotent basal progenitors in directed epithelial migration streams. Basal progenitors are then dispersed throughout the entire glandular network, dividing and differentiating to replenish the loss of apoptotic luminal cells. Rare lineage-restricted luminal stem cells, and their progeny, are confined to proximal ducts and provide only minor contribution to epithelial homeostasis. In situ cell capture from clonal maps identified delta homolog 1 (DLK1) enrichment of basal stem cells, which was validated in functional spheroid assays. This study establishes significant insights into niche organization and function of prostate stem and progenitor cells, with implications for disease.

Mitophagy, the clearance of surplus or damaged mitochondria or mitochondrial parts by autophagy, is important for maintenance of cellular homeostasis. Whereas knowledge on programmed and stress-induced mitophagy is increasing, much less is known about mechanisms of basal mitophagy. Recently, we identified SAMM50 (SAMM50 sorting and assembly machinery component) as a receptor for piecemeal degradation of components of the sorting and assembly machinery (SAM) complex and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 interacts directly with Atg8-family proteins through a canonical LIR motif and with SQSTM1/p62 to mediate basal piecemeal mitophagy. During a metabolic switch to oxidative phosphorylation (OXPHOS), SAMM50 cooperates with SQSTM1 to mediate efficient piecemeal mitophagy. [ABSTRACT FROM AUTHOR]

Prostate epithelial basal cells are highly plastic in their luminal differentiation capability. Basal stem cells actively produce luminal cells during organogenesis, but become restricted in the adult prostate unless receiving oncogenic or inflammatory stimuli. Given that the number of luminal cells increases relative to basal cells through development and that equilibrium is reached in the adulthood, we hypothesize that a negative-feedback mechanism exists to inhibit basal-to-luminal differentiation. We provide evidence supporting this hypothesis by comparing murine prostatic growth in a tissue reconstitution assay with cell recombinants of different basal-to-luminal ratios. Additionally, in organoid culture, hybrid organoids derived from adjacent basal and luminal cells showed reduced basal stem cell activities, suggesting contact inhibition. Importantly, removal of adult luminal cells in vivo via either an inducible Cre/loxP-Dre/rox dual-lineage-tracing system or orthotopic trypsin injection led to robust reactivation of basal stem cell activities, which acts independent of androgen. These data illustrate the prostate organ as a distinctive paradigm where cell contact from differentiated daughter cells restricts adult stem cell multipotency to maintain the steady-state epithelial architecture.

Introduction and objectives. Basal cell carcinoma is the most common locally invasive malignant epidermal neoplasm in humans and its incidence has increased over the last decades worldwide, especially among the Caucasian population. Basal cell carcinoma accounts for about 75% of all skin cancers. Incidence data on basal cell carcinoma is sparse because traditional cancer registries often do not register these tumours. In Lithuania, patients with skin cancer and melanoma were traditionally treated in centralized oncological institutes. From 2006, the Centre of Dermatovenereology at Vilnius University Hospital Santaros Klinikos (Vilnius, Lithuania) provides modern diagnostic and treatment facilities to oncodermatological patients. The objective of the study was to evaluate epidemiological and clinical data of basal cell carcinoma at the Centre of Dermatovenereology during the last 15 years. Materials and methods. Medical documentation of the cases of histologically-proven basal cell carcinoma diagnosed between 2000 and 2015 was analyzed. Epidemiological and clinical evaluation according to the patients’ age, sex, and place of residence, as well as tumour localization, its histological type, and treatment options was performed. Results. After the skin lesion biopsy and histopathological examination, a total of 847 basal cell carcinomas were confirmed to 782 patients. During the study period, the total annual number of newly diagnosed basal cell carcinomas rose steadily in our centre: 2.7% between 2000 and 2003, 6.5% between 2004 and 2006, 13.6% between 2007 and 2009, 27.6% between 2010 and 2012, and 49.6% between 2013 and 2015. The biggest part of patients (28.4%) were 70–79 years old, 4.6% – younger than 40, 7.3% – 40–49, 17.1% – 50–59, 27.2% – 60–69, 14.1% – 80–89, and 1.3% ≥90 years old. The average patient age was 66.0 (±13.6). Of these patients, 62.0% were female and 38.0% male; 63.6% were from the capital city, 18.3% from other cities, and 18.2% from rural areas. Basal cell carcinomas occurred most often in the face region 49.0%, followed by the trunk – 29.4%, the scalp and neck – 10.9%, arms and legs – 7.7%, in 2.9% location was not specified and the whole body – 0.1%. The predominant histological type of basal cell carcinomas was nodular (60.6%), other diagnosed types were superficial (22.9%), infiltrative/morpheaform (8.0%), mixed nodular and infiltrative (1.7%), pigmented (0.2%), rare types (micronodular, infundibulocystic, ductal and mixed) – 0.6%; the type was not specified in 6.0% of cases. Nodular, superficial, and infiltrative types were the most common morphological types in all body sites: respectively, in the face – 67.5%, 12.5%, 9.4%; in the scalp and neck region – 77.2%, 14.1%, 5.4%; in the trunk – 49.8%, 37.3%, 7.2%; in extremities – 41.5%, 43.1%, 7.7%. The nodular type was more common among the elderly and its incidence increased with age (p = 0.009), meanwhile, superficial basal cell carcinomas prevailed among younger patients (

The Research Society for the Study of Diabetes in India (RSSDI) has regularly updated its Clinical Practice Guidelines on various aspects of diabetes. The pharmacotherapeutic management of diabetes involves a plethora of agents targeting different aetiopathogenic mechanisms administered orally or via injections as well as insulin. While most people with type 1 diabetes need complete insulin replacement therapy with multiple-daily subcutaneous injections of insulin or a continuous subcutaneous insulin infusion pump, patients with type 2 diabetes may also need insulin as and when needed, especially owing to the declining beta cell function due to the progressive nature of their diabetes. To date, various insulin regimens including basal-bolus, split-mixed, premix, and prandial therapy are available which can be individualized based on the patient profile though their prescription is often perceived as complex for management of diabetes, forming a major barrier in the acceptability of insulin. In order to provide physicians with a simple guidance on different aspects of insulin use including choosing the right insulin and regime to match the individual patient, the RSSDI for the first time has formulated this guideline on insulin therapy using simple algorithms for insulin initiation as well as titrations based on a systematic literature search of new clinical evidences on all aspects of insulin use. Insulin therapy is hereby proposed as easy to initiate and maintain, efficacious, and a safer option which when administered appropriately can almost mimic physiological insulin secretion in diabetic patients and help them achieve target glucose control and minimize complications while improving their quality of life. [ABSTRACT FROM AUTHOR]

It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC. • The pCR rate was higher with FEC-D than with TC6 (P = 0.265). • For basal BC, the pCR rate was higher with FEC-D than with TC6 (P = 0.033). • For TNBC, DFS and OS were better with FEC-D than with TC6 (P = 0.016 and P = 0.034). [ABSTRACT FROM AUTHOR]

Bladder cancer tumors can be divided into two molecular subtypes referred to as luminal or basal. Each subtype may react differently to current chemotherapy or immunotherapy. Likewise, the technology required for comprehensive molecular analysis is expensive and not yet applicable for routine clinical diagnostics. Therefore, it has been suggested that the immunohistochemical expressions of only two markers, luminal (CK20+, CK5/6-) and basal (CK5/6+, CK20-), is sufficient to identify the molecular subtypes of bladder cancer. This would represent a molecular grade that could be used in daily practice. Molecular classification is done using immunohistochemistry to assess luminal-basal phenotype based on tissular expression of CK20 and CK5/6 as surrogate for luminal or basal subtypes, respectively. A series of 147 non-muscle-invasive bladder carcinoma cases was selected, and the tumors were divided into four subgroups based on the presence of CK20 and/or CK5/6, that is, null (CK20-, CK5/6-), mixed (CK20+, CK5/6+), basal (CK20-, CK5/6+), and luminal (CK20+, CK5/6-) categories. Survival analysis was estimated using the Kaplan-Meier method and the log-rank test. Hazard ratios were calculated by Cox multivariate analysis. The molecular grade included cases with null (n = 89), mixed (n = 6), basal (n = 20), and luminal (n = 32) phenotypes with differences in recurrence-free, progression-free and cancer-specific survival associated with molecular-grade categories in patients with low- or high-grade Ta, or high-grade T1 tumors. The multivariate analysis identified the luminal phenotype as a predictor of more aggressive neoplasms. Our findings provide a rationale to investigate luminal and basal subtypes of bladder cancer using two gene expression signatures as surrogate markers and show that non-muscle-invasive bladder carcinoma can be stratified into biologically and clinically different subgroups by using an immunohistochemical classifier. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify predictors of long‐term response to the initiation of basal‐supported oral therapy (BOT) with insulin glargine (IGlar‐100). Patients from the observational TOP registry were grouped based on those who had achieved (responders) and those who had not achieved (non‐responders) their HBA1c target and/or FBG ≤110 mg/dL 12 months after IGlar‐100 initiation. Independent predictors of treatment response were identified by regression analysis. Data for 2444 patients were analysed (responders, n = 1610; non‐responders, n = 834). Although the IGlar‐100 dose increase over 12 months was larger for non‐responders (+12.83 vs +9.46 U/d; P < 0.0001), the corresponding decrease in HbA1c was smaller (−0.88% vs −1.57%). Independent predictors of response included lower BMI (OR, 0.97; 95% CI, 0.95‐1.00), lower FBG (OR, 0.98; 95% CI, 0.97‐0.98) and HbA1c values at baseline (OR, 0.24; 95% CI, 0.18‐0.31), a less ambitious HbA1c target (OR, 5.07; 95% CI, 3.37‐7.63) and bedtime administration of IGlar‐100 (OR, 1.55; 95% CI, 1.12‐2.14). In conclusion, HbA1c was the clinically most significant baseline characteristic predictive of response to BOT. This may suggest an advantage of IGlar‐100 initiation prior to excessive hyperglycaemia escalation. [ABSTRACT FROM AUTHOR]