Validation of prostate and breast cancer detection artificial intelligence algorithms for accurate histopathological diagnosis and grading: a retrospective study with a Japanese cohort.

Prostate and breast cancer incidence rates have been on the rise in Japan, emphasising the need for precise histopathological diagnosis to determine patient prognosis and guide treatment decisions. However, existing diagnostic methods face numerous challenges and are susceptible to inconsistencies between observers. To tackle these issues, artificial intelligence (AI) algorithms have been developed to aid in the diagnosis of prostate and breast cancer. This study focuses on validating the performance of two such algorithms, Galen Prostate and Galen Breast, in a Japanese cohort, with a particular focus on the grading accuracy and the ability to differentiate between invasive and non-invasive tumours. The research entailed a retrospective examination of 100 consecutive prostate and 100 consecutive breast biopsy cases obtained from a Japanese institution. Our findings demonstrated that the AI algorithms showed accurate cancer detection, with AUCs of 0.969 and 0.997 for the Galen Prostate and Galen Breast, respectively. The Galen Prostate was able to detect a higher Gleason score in four adenocarcinoma cases and detect a previously unreported cancer. The two algorithms successfully identified relevant pathological features, such as perineural invasions and lymphovascular invasions. Although further improvements are required to accurately differentiate rare cancer subtypes, these findings highlight the potential of these algorithms to enhance the precision and efficiency of prostate and breast cancer diagnosis in Japan. Furthermore, this validation paves the way for broader adoption of these algorithms as decision support tools within the Asian population.

Substantial improvement of histopathological diagnosis by whole-slide image-based remote consultation.

Consultation by subspecialty experts is the most common mode of rendering diagnosis in challenging cases in pathological practice. Our study aimed to highlight the diagnostic benefits of whole-slide image (WSI)-based remote consultation. We obtained diagnostically challenging cases from two institutions from the years 2010 and 2013, with histological diagnoses that contained keywords "probable," "suggestive," "suspicious," "inconclusive," and "uncertain." A total of 270 cases were selected for remote consultation using WSIs scanned at 40 × . The consultation process consisted of three rounds: the first and second rounds each with 12 subspecialty experts and the third round with six multi-expertise senior pathologists. The first consultation yielded 44% concordance, and a change in diagnosis occurred in 56% of cases. The most frequent change was from inconclusive to definite diagnosis (30%), followed by minor discordance (14%), and major discordance (12%). Out of the 70 cases which reached the second round, 31 cases showed discrepancy between the two consultants. For these 31 cases, a consensus diagnosis was provided by six multi-expertise senior pathologists. Combining all WSI-based consultation rounds, the original inconclusive diagnosis was changed in 140 (52%) out of 266 cases. Among these cases, 80 cases (30%) upgraded the inconclusive diagnosis to a definite diagnosis, and 60 cases (22%) changed the diagnosis with major or minor discordance, accounting for 28 cases (10%) and 32 cases (12%), respectively. We observed significant improvement in the pathological diagnosis of difficult cases by remote consultation using WSIs, which can further assist in patient healthcare. A post-study survey highlighted various benefits of WSI-based consults.

Deep-Learning-Aided Detection of Mycobacteria in Pathology Specimens Increases the Sensitivity in Early Diagnosis of Pulmonary Tuberculosis Compared with Bacteriology Tests.

The histopathological diagnosis of mycobacterial infection may be improved by a comprehensive analysis using artificial intelligence. Two autopsy cases of pulmonary tuberculosis, and forty biopsy cases of undetected acid-fast bacilli (AFB) were used to train AI (convolutional neural network), and construct an AI to support AFB detection. Forty-two patients underwent bronchoscopy, and were evaluated using AI-supported pathology to detect AFB. The AI-supported pathology diagnosis was compared with bacteriology diagnosis from bronchial lavage fluid and the final definitive diagnosis of mycobacteriosis. Among the 16 patients with mycobacteriosis, bacteriology was positive in 9 patients (56%). Two patients (13%) were positive for AFB without AI assistance, whereas AI-supported pathology identified eleven positive patients (69%). When limited to tuberculosis, AI-supported pathology had significantly higher sensitivity compared with bacteriology (86% vs. 29%, p = 0.046). Seven patients diagnosed with mycobacteriosis had no consolidation or cavitary shadows in computed tomography; the sensitivity of bacteriology and AI-supported pathology was 29% and 86%, respectively (p = 0.046). The specificity of AI-supported pathology was 100% in this study. AI-supported pathology may be more sensitive than bacteriological tests for detecting AFB in samples collected via bronchoscopy.

Combined Extensive Esophageal Squamous Papillomas and Florid Cardiac Gland Hyperplasia in a Patient with Adenocarcinoma.

We report a rare case of extensive esophageal squamous papillomas (ESPs) involving the entire esophagus and florid cardiac gland hyperplasia involving only the lower esophagus in a 39-year-old woman with heartburn and epigastric distress for the past 2 years. Previous esophagogastroduodenoscopy showed multiple ESPs involving the entire esophagus extending 38 cm from the esophageal orifice to the esophagogastric junction (EGJ). Additionally, prominent cardiac gland hyperplasia over the esophageal posterior wall was exhibited extending 12 cm from the mid-esophagus to the EGJ. A biopsy obtained from the ESP area showed typical squamous papillomas and cardiac gland hyperplasia with no evidence of koilocytosis or malignancy. Polymerase chain reaction was negative for a variety of human papilloma virus DNAs. Subsequently, Siewert type II gastric cancer with submucosal elevation of the stomach was detected at the EGJ. Endoscopy showed a 20-mm-thick lesion appearing to extend to the muscularis propria; subsequent biopsy showed invasive adenocarcinoma. Total gastrectomy with D2 lymph node dissection, splenectomy, and Roux-en-Y reconstruction were performed for the EGJ cancer. The patient died from widespread multiorgan metastasis within 2 years following surgery.

Descrevemos um caso raro de extensos papilomas escamosos esofágicos (PEEs) envolvendo todo o esófago associados a uma florida hiperplasia glandular do cárdia envolvendo apenas o esófago distal, numa mulher de 39 anos com quadro de 2 anos de pirose e dispepsia. Endoscopias altas prévias mostraram múltiplos PEEs envolvendo todo o esófago desde o cricofaríngeo até à junção esofagogástrica (JEG). Adicionalmente, verificou-se também uma proeminente hiperplasia glandular do cárdia na parede posterior esofágica com uma extensão de cerca de 12 cm, desde o esófago médio até à JEG. Biopsias destas áreas evidenciaram os típicos PEEs e hiperplasia glandular do cárdia sem evidência de coilocitose ou malignidade. A análise por polymerase chain reaction foi negativa para o DNA de vários vírus do papiloma humano. Subsequentemente foi diagnosticado um cancro juncional tipo Siewert II com elevação da submucosa a nível da vertente gástrica da junção. A endoscopia mostrou uma lesão de 20 mm de espessura que parecia já estender-se para a muscular própria; biopsias confirmaram o diagnóstico de adenocarcinoma invasor. Foi realizada gastrectomia total com dissecção ganglionar D2, esplenectomia e reconstrução em Y de Roux para cancro da junção esofagogástrica. O doente morreu dois anos após a cirurgia com metástases multi-orgânicas.

Application of microscope-based scanning software (Panoptiq) for the interpretation of cervicovaginal cytology specimens.

BACKGROUND: Digital pathology increasingly has been gaining the attention of pathologists worldwide. However, the application of digital cytology by Panoptiq (ViewsIQ, Vancouver, Canada) microscope-based scanning software is relatively unexplored. Panoptiq enables the operator to combine low-power panoramic digital images with z-stacks at regions of interest with a significantly smaller image size than that obtained by whole-slide scanning. The current study aimed to evaluate the feasibility of the use of Panoptiq in the digital interpretation of cervicovaginal cytology specimens in comparison with conventional light microscopy. METHODS: A total of 100 liquid-based cytology slides were selected sequentially. The dotted slides were reviewed and scanned, in which all dotted areas were scanned further by the ×20 objective with z-stacks. The cases were reviewed by 4 pathologists and a cytotechnologist using conventional light microscopy and digital cytology images acquired by Panoptiq and interpreted based on the Bethesda classification system. The washout time was set as 3 weeks. The Cohen kappa coefficient was calculated to measure the agreement between the 2 modalities. RESULTS: Digital cytology demonstrated an intermodality agreement among 3 observers who had sufficient training in digital pathology at concordance rates between 81% and 90% with kappa values between 0.76 and 0.86, whereas the other 2 observers who did not have sufficient training in digital pathology had lower agreement at a concordance rate of between 56% and 57%, with kappa values between 0.41 and 0.44. CONCLUSIONS: Panoptiq appears to be feasible for the interpretation of cervicovaginal cytology specimens but requires adequate training in digital pathology. Cancer Cytopathol 2017;125:918-25. © 2017 American Cancer Society.

Does flat epithelial atypia have rounder nuclei than columnar cell change/hyperplasia? A morphometric approach to columnar cell lesions of the breast.

Columnar cell lesions of the breast encompass columnar cell change/hyperplasia (CCC/CCH) and flat epithelial atypia (FEA). These have attracted researchers because emerging data suggest that FEA may represent the earliest histologically detectable non-obligate precursor of breast cancer. However, it is occasionally difficult to distinguish FEA from CCC/CCH because of similar histology. Although the nuclei of FEA are frequently described as relatively round compared with those of CCC/CCH, there are few morphometric studies to support this statement. The aim of this study was to provide objective data as to the nuclear shape in columnar cell lesions. As a shape descriptor, we adopted ellipticity that is defined by the formula 2b/2a, where a is the length of the long axis of the ellipse and b is the length of the short axis. Contrary to circularity, ellipticity reflects the overall configuration of an ellipse irrespective of surface irregularity. Our image analysis included generating whole slide images, extracting glandular cell nuclei, measuring nuclear ellipticity, and superimposing graded colors based on execution of results on the captured images. A total of 7917 nuclei extracted from 22 FEA images and 5010 nuclei extracted from 13 CCC/CCH images were analyzed. There was a significant difference in nuclear roundness between FEA and CCC/CCH with mean ellipticity values of 0.723 and 0.679, respectively (p < 0.001, Welch's t test). Furthermore, FEA with malignancy had significantly rounder nuclei than FEA without malignancy (p < 0.001). Our preliminary results suggest that nuclear ellipticity is a key parameter in reproducibly classifying columnar cell lesions of the breast.

MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a "Genetic Switch" Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma.

Melanoma is a very aggressive neoplasm with a propensity to undergo progression and invasion early in its evolution. The molecular pathways underpinning invasion in melanoma are now just beginning to be elucidated, but a clear understanding of the transition from non-invasive to invasive melanoma cells remains elusive. Microphthalmia-associated transcription factor (MITF), is thought to be a central player in melanoma biology, and it controls many aspects of the phenotypic expression of the melanocytic lineage. However, recently the paired box transcription factor PAX3 was shown to transcriptionally activate POU3F2/BRN2, leading to direct repression of MITF expression. Here we present a theory to explain melanoma phenotype switching and discuss the predictions that this theory makes. One prediction is that independent and opposing roles for MITF and PAX3 in melanoma would be expected, and we present empirical evidence supporting this: in melanoma tissues PAX3 expression occurs independently of MITF, and PAX3 does not play a key role in melanoma cell proliferation. Furthermore, we show that knockdown of PAX3 inhibits cell migration in a group of "lower MITF" melanoma cell lines, while knockdown of MITF promotes cell migration in a complementary "higher MITF" group of melanoma cell lines. Moreover, the morphological effects of knocking down PAX3 versus MITF in melanoma cells were found to differ. While these data support the notion of independent roles for MITF and PAX3, additional experiments are required to provide robust examination of the proposed genetic switch theory. Only upon clear delineation of the mechanisms associated with progression and invasion of melanoma cells will successful treatments for invasive melanoma be developed.

Metastases to the oral region from pleural mesothelioma: Clinicopathologic review.

BACKGROUND: Malignant mesothelioma is a rare neoplasm that usually develops after exposure to asbestos and particularly involves the pleural cavity. It has a poor prognosis with aggressive local invasion and metastatic spread. METHODS: The literature relating to malignant mesothelioma metastatic to the oral region was reviewed. RESULTS: In all, 14 cases of malignant mesothelioma metastatic to the oral cavity were found. All were from pleural mesotheliomas, the tongue was the most common site of metastasis (8/14), and most metastases (9/13) were of the epithelioid type. The newly reported case is only the second report of a mesothelioma metastasizing to the buccal mucosa. It showed strong immunopositivity for keratin markers, vimentin, calretinin, and Wilms tumor product-1. CONCLUSIONS: The incidence of mesothelioma is predicted to continue to increase for at least another decade. Clinicians and pathologists should be aware of this lesion and its propensity to metastasize to the oral cavity.

A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria.

PURPOSE: We investigated whether the RNA assay uRNA® and its derivative Cxbladder® have greater sensitivity for the detection of bladder cancer than cytology, NMP22™ BladderChek™ and NMP22™ ELISA, and whether they are useful in risk stratification. MATERIALS AND METHODS: A total of 485 patients presenting with gross hematuria but without a history of urothelial cancer were recruited prospectively from 11 urology clinics in Australasia. Voided urine samples were obtained before cystoscopy. The sensitivity and specificity of the RNA tests were compared to cytology and the NMP22 assays using cystoscopy as the reference. The ability of Cxbladder to distinguish between low grade, stage Ta urothelial carcinoma and more advanced urothelial carcinoma was also determined. RESULTS: uRNA detected 41 of 66 urothelial carcinoma cases (62.1% sensitivity, 95% CI 49.3-73.8) compared with NMP22 ELISA (50.0%, 95% CI 37.4-62.6), BladderChek (37.9%, 95% CI 26.2-50.7) and cytology (56.1%, 95% CI 43.8-68.3). Cxbladder, which was developed on the study data, detected 82%, including 97% of the high grade tumors and 100% of tumors stage 1 or greater. The cutoffs for uRNA and Cxbladder were prespecified to give a specificity of 85%. The specificity of cytology was 94.5% (95% CI 91.9-96.5), NMP22 ELISA 88.0%, (95% CI 84.6-91.0) and BladderChek 96.4% (95% CI 94.2-98.0). Cxbladder distinguished between low grade Ta tumors and other detected urothelial carcinoma with a sensitivity of 91% and a specificity of 90%. CONCLUSIONS: uRNA and Cxbladder showed improved sensitivity for the detection of urothelial carcinoma compared to the NMP22 assays. Stratification with Cxbladder provides a potential method to prioritize patients for the management of waiting lists.

Laparoscopic adrenalectomy for a rare 14-cm adrenal schwannoma.

Laparoscopic surgery for adrenal tumors is the gold standard for benign tumors; however, its role for adrenal cancer, metastases, and large suspicious lesions remains controversial. This aspect becomes clinically more important as larger incidentaloma are being detected with increasing frequency. Here, we discuss a rare case of a giant 14-cm adrenal schwannoma, which presented as an incidentaloma and was excised laparoscopically. Epidemiology, histology, and surgical treatment options were reviewed. An abdominal computerized tomography scan of a 30-year-old female weighing 130 kg revealed a large left adrenal mass. Preoperative biochemical and endocrine workup confirmed that it was nonfunctioning. The patient had a laparoscopic adrenalectomy without complication. The nodular tumor measured 145 × 100 × 80 cm in size and weighed 312 g. Histopathology showed myxoid areas and spindle cells arranged in a palisading manner. Mitoses were not observed. Tumor cells were immunohistochemically strongly positive for S-100, but negative for CD117, desmin, and muscle-specific actin. There was no evidence of malignancy. The diagnosis was of a benign schwannoma. Adrenal schwannoma is an extremely rare entity and can grow considerably in size. So far, this is the largest adrenal schwannoma reported in literature. In agreement with a growing number of publications, laparoscopic adrenalectomy can also be used for potentially malignant tumors larger than 10 cm in diameter provided the tumor does not infiltrate into other organs, conversion to open surgery is carefully considered, and resection occurs within the anatomic planes, thus ensuring the intactness of the tumor capsule.

T cell subpopulations in lymph nodes may not be predictive of patient outcome in colorectal cancer.

BACKGROUND: The immune response has been proposed to be an important factor in determining patient outcome in colorectal cancer (CRC). Previous studies have concentrated on characterizing T cell populations in the primary tumour where T cells with regulatory effect (Foxp3+ Tregs) have been identified as both enhancing and diminishing anti-tumour immune responses. No previous studies have characterized the T cell response in the regional lymph nodes in CRC. METHODS: Immunohistochemistry was used to analyse CD4, CD8 or Foxp3+ T cell populations in the regional lymph nodes of patients with stage II CRC (n = 31), with (n = 13) or without (n = 18) cancer recurrence after 5 years of follow up, to determine if the priming environment for anti-tumour immunity was associated with clinical outcome. RESULTS: The proportions of CD4, CD8 or Foxp3+ cells in the lymph nodes varied widely between and within patients, and there was no association between T cell populations and cancer recurrence or other clinicopathological characteristics. CONCLUSIONS: These data indicate that frequency of these T cell subsets in lymph nodes may not be a useful tool for predicting patient outcome.

Prognostic association of YB-1 expression in breast cancers: a matter of antibody.

The literature concerning the subcellular location of Y-box binding protein 1 (YB-1), its abundance in normal and cancer tissues, and its prognostic significance is replete with inconsistencies. An explanation for this could be due in part to the use of different antibodies in immunohistochemical and immunofluorescent labeling of cells and tissues. The inconsistencies could also be due to poor resolution of immunohistochemical data. We analyzed two cohorts of breast tumours for both abundance and subcellular location of YB-1 using three different antibodies; two targeting N-terminal epitopes (AB-a and AB-b) and another (AB-c) targeting a C-terminal epitope. We also investigated stress-induced nuclear translocation of YB-1 in cell culture. We report that both AB-a and AB-c detected increased YB-1 in the cytoplasm of high-grade breast cancers, and in those lacking estrogen and progesterone receptors; however the amount of YB-1 detected by AB-a in these cancers is significantly greater than that detected by AB-c. We confirm our previously published findings that AB-b is also detecting hnRNP A1, and cannot therefore be used to reliably detect YB-1 by immunohistochemistry. We also report that AB-a detected nuclear YB-1 in some tumour tissues and stress treated cells, whereas AB-c did not. To understand this, cancer cell lines were analyzed using native gel electrophoresis, which revealed that the antibodies detect different complexes in which YB-1 is a component. Our data suggest that different YB-1 antibodies show different staining patterns that are determined by the accessibility of epitopes, and this depends on the nature of the YB-1 complexes. It is important therefore to standardize the protocols if YB-1 is to be used reproducibly as a prognostic guide for different cancers.

Loss of epidermal Langerhans cells occurs in human papillomavirus alpha, gamma, and mu but not beta genus infections.

Human papillomaviruses (HPVs), which are contained in the alpha, beta, gamma, mu, and nu genera, differ in their oncogenic potential and their tropism for cutaneous or mucosal epidermis. Langerhans cells (LC), the only epidermal professional antigen-presenting cells, are readily detected in normal mucosal and cutaneous epithelium. The aim of this study is to determine whether LC loss, which has been reported for HPV16, occurs in other HPV genera and establish its significance in viral pathology. We found that, as for HPV16, LCs were reduced in lesions infected with high-risk mucosal (alpha7 and alpha9 species) and low-risk cutaneous (gamma and mu) types. Lesions infected with alpha10 low-risk genital types had reduced LC but contained epidermal LC patches, coincident with dermis-localized regulatory T cells (T-regs). In contrast to other genera, LCs were common in the epidermis, and T-regs occupied the dermis of the potentially high-risk cutaneous beta-HPV type infected lesions. Therefore, LC loss in the infected lesions occurred irrespective of tropism or oncogenic potential of the HPV type. LC depletion in the HPV-infected epidermis may create an environment that is permissive for viral persistence and in HPV lesions in which LCs are found, the presence of typically immunosuppressive T-regs may compensate for their continued presence.

Increased levels of active c-Src distinguish invasive from in situ lobular lesions.

INTRODUCTION: Mounting molecular evidence suggests that invasive lobular carcinoma (ILC) is developing from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). However, little is known about the mechanisms promoting the progression of lobular breast cancer (LBC) to invasive disease. Here, we investigated whether c-Src kinase, an established inducer of invasive states, contributes to the progression from ALH/LCIS to ILC. METHODS: Immunochemistry for c-Src and other cancer-related molecules was performed on archived tissue specimens from 57 LBC patients. Relative c-Src activity was estimated by comparing fluorescence intensity of ILC with that of adjacent ALH/LCIS and nonneoplastic epithelia after staining with an antibody against active c-Src. Expression of active c-Src was correlated with markers of invasion and malignancy and with relapse among LBC patients. RESULTS: Levels of activated c-Src were increased in ILC relative to ALH/LCIS (1.63-fold +/- 0.24 SD) and nonneoplastic epithelia (1.47 +/- 0.18 SD). Increased c-Src levels correlated with the activation of c-Src downstream targets (Fak, Stat-3) and the expression of mesenchymal markers. ILC cells with activated c-Src co-expressed metastatic markers (Opn, Cxcr4) and included cells positive for the cancer stem cell marker Aldh1. A tendency for high c-Src levels (P = 0.072) was observed among the seven LBC patients with relapsed disease. CONCLUSIONS: Our data indicate elevated c-Src activity in ILC relative to noninvasive neoplastic tissue. The associated molecular changes suggest that c-Src promotes LBC invasiveness by inducing an epithelial-mesenchymal transition. Therefore, c-Src antagonists might counteract the acquisition of invasiveness during LBC progression. Inhibition of c-Src may also affect ILC cells thought to have a high metastatic potential and to be capable of initiating/maintaining tumor growth. Together with the possible association between high c-Src levels and disease recurrence, our findings encourage the evaluation of c-Src antagonists for the treatment of LBC.

Epigenetic silencing in non-neoplastic epithelia identifies E-cadherin (CDH1) as a target for chemoprevention of lobular neoplasia.

Invasive lobular carcinoma (ILC) of the breast is believed to develop from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Down-regulation of the cell-cell adhesion protein E-cadherin is a defining feature of lobular breast cancer (LBC) and already occurs in ALH and LCIS. Apart from mutational mechanisms, epigenetic silencing of the E-cadherin gene (CDH1) is thought to be involved in E-cadherin down-regulation and has been observed at a high frequency in ILC. Whether CDH1 promoter methylation is already present in in situ lesions and thus contributes to the initiation of LBC is not established. We thus examined microdissected archived tissue from 20 LBCs by methylation-specific PCR to determine the CDH1 methylation status of lobular lesions. Nineteen of the 20 LBCs had a hypermethylated CDH1 promoter, including 13/14 ILCs and 13/13 ALHs or LCIS. Bisulphite sequencing indicated that methylation was complete within the investigated promoter fragment. Intriguingly, CDH1 methylation was likewise present in 8/8 adjacent non-neoplastic epithelia, but not in 6/6 mammary epithelia from healthy subjects. E-cadherin protein and mRNA were down-regulated in in situ lesions relative to adjacent epithelia. Together, these results indicate that CDH1 promoter methylation occurs in LBC prior to E-cadherin down-regulation and neoplastic formation. We thus propose that epigenetic silencing represents the first of the two hits required to silence both CDH1 alleles for LBC to develop. Because promoter methylation is in principle reversible, our findings suggest that chemoprevention of LBC by epigenetic drugs should be feasible. Furthermore, the presence of CDH1 methylation in pre-neoplastic epithelia suggests the existence of mammary regions with increased disease susceptibility, providing an explanation for the often multifocal presentation of LBC.

A novel Cys1638Tyr NC1 domain substitution in alpha5(IV) collagen causes Alport syndrome with late onset renal failure without hearing loss or eye abnormalities.

BACKGROUND: Mutations in the type IV collagen gene, COL4A5, are associated with Alport syndrome, characterized by ultrastructural abnormalities of the glomerular basement membrane (GBM), with or without progressive loss of renal function, characteristic ophthalmic signs and/or high tone sensorineural deafness. More than 300 sequence variants in type IV collagen have been identified, including alterations in the non-collagenous NC1 domain. METHODS: We performed linkage analysis and sequencing to identify the mutation in a New Zealand family with Alport glomerulonephritis and late onset renal failure without hearing loss or eye abnormalities. RESULTS: We report a novel c.4913G>A (p.Cys1638Tyr) alteration in the NC1 domain of COL4A5, identified in a moderately large family, eight of whom were confirmed by renal biopsy to have renal abnormalities. Only three of eight mutant male members of the pedigree progressed to end-stage renal failure. The remaining five mutant males exhibit either chronic renal disease at age 36, 46 and 72, or as yet show no renal disease at ages 39 and 39. Extra-renal manifestations such as sensorineural deafness or ocular changes were absent from all family members carrying the mutation. CONCLUSION: This variant is the first reported to affect the tenth of 12 cysteine residues in the NC1 domain. We conclude that the cysteine to tyrosine substitution in the NC1 domain of the alpha5(IV) collagen chain in this family leads to a mild form of Alport syndrome, including absence of extra-renal features.

Multiple gene expression classifiers from different array platforms predict poor prognosis of colorectal cancer.

PURPOSE: This study aimed to develop gene classifiers to predict colorectal cancer recurrence. We investigated whether gene classifiers derived from two tumor series using different array platforms could be independently validated by application to the alternate series of patients. EXPERIMENTAL DESIGN: Colorectal tumors from New Zealand (n = 149) and Germany (n = 55) patients had a minimum follow-up of 5 years. RNA was profiled using oligonucleotide printed microarrays (New Zealand samples) and Affymetrix arrays (German samples). Classifiers based on clinical data, gene expression data, and a combination of the two were produced and used to predict recurrence. The use of gene expression information was found to improve the predictive ability in both data sets. The New Zealand and German gene classifiers were cross-validated on the German and New Zealand data sets, respectively, to validate their predictive power. Survival analyses were done to evaluate the ability of the classifiers to predict patient survival. RESULTS: The prediction rates for the New Zealand and German gene-based classifiers were 77% and 84%, respectively. Despite significant differences in study design and technologies used, both classifiers retained prognostic power when applied to the alternate series of patients. Survival analyses showed that both classifiers gave a better stratification of patients than the traditional clinical staging. One classifier contained genes associated with cancer progression, whereas the other had a large immune response gene cluster concordant with the role of a host immune response in modulating colorectal cancer outcome. CONCLUSIONS: The successful reciprocal validation of gene-based classifiers on different patient cohorts and technology platforms supports the power of microarray technology for individualized outcome prediction of colorectal cancer patients. Furthermore, many of the genes identified have known biological functions congruent with the predicted outcomes.