Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research.

PURPOSE: Inflammatory breast cancer is a deadly and aggressive type of breast cancer. A key challenge relates to the need for a more detailed, formal, objective definition of IBC, the lack of which compromises clinical care, hampers the conduct of clinical trials, and hinders the search for IBC-specific biomarkers and treatments because of the heterogeneity of patients considered to have IBC. METHODS: Susan G. Komen, the Inflammatory Breast Cancer Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to review the state of IBC and to propose initiatives to advance the field. After literature review of the defining clinical, pathologic, and imaging characteristics of IBC, the experts developed a novel quantitative scoring system for diagnosis. RESULTS: The experts identified through consensus several "defining characteristics" of IBC, including factors related to timing of onset and specific symptoms. These reflect common pathophysiologic changes, sometimes detectable on biopsy in the form of dermal lymphovascular tumor emboli and often reflected in imaging findings. Based on the importance and extent of these characteristics, the experts developed a scoring scale that yields a continuous score from 0 to 48 and proposed cut-points for categorization that can be tested in subsequent validation studies. CONCLUSION: To move beyond subjective 'clinical diagnosis' of IBC, we propose a quantitative scoring system to define IBC, based on clinical, pathologic, and imaging features. This system is intended to predict outcome and biology, guide treatment decisions and inclusion in clinical trials, and increase diagnostic accuracy to aid basic research; future validation studies are necessary to evaluate its performance.

Scoring of tumor-infiltrating lymphocytes: From visual estimation to machine learning.

The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.

Refined estimates of local recurrence risks by DCIS score adjusting for clinicopathological features: a combined analysis of ECOG-ACRIN E5194 and Ontario DCIS cohort studies.

PURPOSE: Better tools are needed to estimate local recurrence (LR) risk after breast-conserving surgery (BCS) for DCIS. The DCIS score (DS) was validated as a predictor of LR in E5194 and Ontario DCIS cohort (ODC) after BCS. We combined data from E5194 and ODC adjusting for clinicopathological factors to provide refined estimates of the 10-year risk of LR after treatment by BCS alone. METHODS: Data from E5194 and ODC were combined. Patients with positive margins or multifocality were excluded. Identical Cox regression models were fit for each study. Patient-specific meta-analysis was used to calculate precision-weighted estimates of 10-year LR risk by DS, age, tumor size and year of diagnosis. RESULTS: The combined cohort includes 773 patients. The DS and age at diagnosis, tumor size and year of diagnosis provided independent prognostic information on the 10-year LR risk (p ≤ 0.009). Hazard ratios from E5194 and ODC cohorts were similar for the DS (2.48, 1.95 per 50 units), tumor size ≤ 1 versus  > 1-2.5 cm (1.45, 1.47), age ≥ 50 versus < 50 year (0.61, 0.84) and year ≥ 2000 (0.67, 0.49). Utilization of DS combined with tumor size and age at diagnosis predicted more women with very low (≤ 8%) or higher (> 15%) 10-year LR risk after BCS alone compared to utilization of DS alone or clinicopathological factors alone. CONCLUSIONS: The combined analysis provides refined estimates of 10-year LR risk after BCS for DCIS. Adding information on tumor size and age at diagnosis to the DS adjusting for year of diagnosis provides improved LR risk estimates to guide treatment decision making.

Breast Cancer and Transplantation.

Breast cancer is an important cancer among solid organ transplant recipients. While the incidence of breast cancer in solid organ transplant recipients is comparable to the age-matched general population, the outcomes are generally poor. Interventions such as cancer screening that preclude the development of late-stage disease through early detection are not well studied, and clinical practice guidelines for cancer screening rely solely on recommendations from the general population. Among patients with a prior breast cancer history, disease recurrence after transplantation is a rare but fearful event. Once disease recurs, the risk of death is high. The focus of this review is to present the epidemiology of breast cancer in solid organ transplant recipients, screening and preventive strategies for those who may be at risk, novel genomic profiling for determining tumor progression, and the newer targeted interventions for recipients who have developed breast cancers after solid organ transplantation.

Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration.

Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. The information required to define pCR (ypT0/is ypN0 or ypT0 yp N0), residual ypT and ypN stage using the current AJCC/UICC system, and the Residual Cancer Burden system were recommended for quantification of residual disease in clinical trials.

The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.

BACKGROUND: The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC. DESIGN: A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches. CONCLUSIONS: The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies.

Prevalence and classification of spontaneous mammary intraepithelial lesions in dogs without clinical mammary disease.

Mammary intraepithelial lesions (IELs) are noninvasive epithelial proliferations that include ductal hyperplasia (DH), atypical DH (ADH), and ductal carcinoma in situ (DCIS). In women, IELs are associated with increased risk of invasive breast cancer and form a basis for therapeutic decisions. Similarly, in female dogs, IELs are common in tumor-bearing glands and in non-tumor-bearing glands. To determine the prevalence and types of spontaneous IELs, mammary glands from 108 female dogs without clinical mammary disease were evaluated histologically and immunohistochemically. Within this population, 56 dogs (52%) had at least one type of spontaneous IEL, including DH (49 dogs), ADH (14 dogs), low-grade DCIS (19 dogs), intermediate-grade DCIS (12 dogs), and high-grade DCIS (1 dog). Twenty-one dogs had two or more different IEL types. In 23 of 24 dogs with atypical IELs (ADH or DCIS), immunohistochemical expression was determined for estrogen receptor alpha (ER-alpha), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2/neu), and Ki-67. For all markers examined, low-grade DCIS had significantly lower scores than did adjacent nonlesional gland; PR expression was significantly decreased in low-grade DCIS compared to other atypical lesions. Sixty-one lesions were ER-alpha negative (12 ADH, 36 low-grade DCIS, 13 intermediate-grade DCIS), and no lesions overexpressed HER-2/neu. Based on the dog's prevalence of spontaneous mammary IELs that precede clinical mammary disease, the remarkable histologic similarity between canine and human IELs, and the loss of ER expression in certain IELs in both species, the dog shows promise as a model for human breast preneoplasia.

NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2.

The transcription factor nuclear factor kappa B (NF-kappaB) is constitutively active in both cancer cells and stromal cells of breast cancer; however, the precise role of activated NF-kappaB in cancer progression is not known. Using parental MCF10A cells and a variant that expresses the myoepithelial marker p63 stably overexpressing the constitutively active p65 subunit of NF-kappaB (MCF10A/p65), we show that NF-kappaB suppresses the expression of epithelial specific genes E-cadherin and desmoplakin and induces the expression of the mesenchymal specific gene vimentin. P65 also suppressed the expression of p63 and the putative breast epithelial progenitor marker cytokeratin 5/6. MCF10A/p65 cells were phenotypically similar to cells undergoing epithelial to mesenchymal transition (EMT). MCF10A/p65 cells failed to form characteristic acini in three-dimensional Matrigel. Analysis of parental and MCF10A/p65 cells for genes previously shown to be involved in EMT revealed elevated expression of ZEB-1 and ZEB-2 in MCF10A/p65 cells compared to parental cells. In transient transfection assays, p65 increased ZEB-1 promoter activity. Furthermore, MCF10A cells overexpressing ZEB-1 showed reduced E-cadherin and p63 expression and displayed an EMT phenotype. The siRNA against ZEB-1 or ZEB-2 reduced the number of viable MCF10A/p65 but not parental cells, suggesting the dependence of MCF10A/p65 cells to ZEB-1 and ZEB-2 for cell cycle progression or survival. MCF10A cells chronically exposed to tumor necrosis factor alpha (TNFalpha), a potent NF-kappaB inducer, also exhibited the EMT-like phenotype and ZEB-1/ZEB-2 induction, both of which were reversed following TNFalpha withdrawal.

Automated and continuous ambulatory peritoneal dialysis have similar outcomes.

We compared survival and death-censored technique survival in patients on automated peritoneal dialysis (automated dialysis) or on continuous ambulatory peritoneal dialysis. All 4128 patients from the Australia and New Zealand Dialysis and Transplant Registry who started peritoneal dialysis over a 5-year period through March 2004 were included. Times to death and death-censored technique failure were analyzed by Cox proportional hazards models while a conditional risk set model computed technique failure. Compared to patients treated entirely with continuous ambulatory peritoneal dialysis, automated peritoneal dialysis patients were more likely to be young, Caucasian, have marginally lower body mass index, and were less likely to have baseline cardiovascular disease or diabetes. Using univariate and multivariate analysis, our study showed there were no significant differences in patient survival and death-censored technique failure between the two types of peritoneal dialysis modalities.

Amplified in breast cancer 1 expression in breast cancer.

AIMS: The amplified in breast cancer 1 (AIB1), steroid receptor co-activator family member, acts as an oestrogen receptor (ER) co-activator. Acting with HER-2, it is thought to play a role in endocrine resistance by facilitating ER-growth factor crosstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. METHODS: A tissue microarray comprising tumours from 438 patients with 15.4 years' median follow-up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. RESULTS: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER-2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. CONCLUSIONS: AIB1 expression correlates with HER-2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER-growth factor interactions.

Subjective global assessment of nutritional status of patients with chronic renal insufficiency and end stage renal disease on dialysis.

OBJECTIVES: (1)To assess the nutritional status of chronic renal insufficiency (CRI) and dialysis patients using the subjective global assessment (SGA) method. (2) To validate SGA in assessing the nutritional status of this group of patients. PARTICIPANTS: The nutritional status of 81 patients was evaluated using dietary recall, anthropometry, biochemical parameters and SGA. There were 51 males and 30 females. Their mean +/- SD age was 53.8 +/- 14.3 years. There were 27 patients with (CRI) on conservative management, 38 patients with end stage renal disease (ESRD) on maintenance hemodialysis (HD) and 16 patients with ESRD on continuous ambulatory peritoneal dialysis (CAPD). METHODS: SGA was done using seven variables derived from medical history and physical examination. Each variable was scored from 1-7 depending on the severity. The SGA scores were correlated with the standard methods. RESULTS: Thirteen (48%) patients with CRI, 22 (58%) patients on HD and 8 (50%) patients on CAPD were malnourished. It was seen that the dietary protein & calorie intake and serum albumin level did not correlate well with the SGA scores. The anthropometric measures correlated with the SGA scores (Skinfolds and SGA r = 0.2, MAC and SGA r = 0.5 and MAMC and SGA r = 0.5). CONCLUSION: Malnutrition is an important complication in CRI patients and ESRD patients on dialysis. SGA is a reliable method of assessing nutritional status. Most important is the fact that it can detect the changing trend of nutritional status, which may be missed by one-time anthropometry and biochemical methods.

Phase II study of continuous infusion fluorouracil and interferon alfa-2b in the palliation of malignant neuroendocrine tumors.

PURPOSE AND METHODS: Twenty-four patients with rapidly progressive neuroendocrine tumors were treated with a new regimen of continuous infusion fluorouracil for 20 weeks (200 mg/m2/d) together with interferon alfa-2b (5 MU three times per week). Maintenance interferon alfa at the same dose was continued after the initial 20-week period. RESULTS: Of 15 patients with carcinoid tumors, seven (47%) had an objective response, with a median duration of 20.5 months (range, 8.5 to 41), and five (33%) had stabilization of disease for between 3.5 and 42 months. Improvement in symptoms was reported by 10 patients (67%). Three early deaths occurred, all in patients with advanced disease. Of nine patients with neuroendocrine tumors other than carcinoid, three (33%) had an objective response that lasted 2.5 to 24.5 months, and five had disease stabilization for between 2.5 and 16 months. CONCLUSION: These data, particularly in respect to carcinoid tumors, are encouraging, especially since serious complications from treatment were limited. This regimen is not generally toxic, is well tolerated, and offers useful palliation and symptom control in patients with disease that does not respond to simple pharmacologic manipulations.

NF-κB-dependent and -independent epigenetic modulation using the novel anti-cancer agent DMAPT.

The transcription factor nuclear factor-kappaB (NF-κB) is constitutively active in several cancers and is a target of therapeutic development. We recently developed dimethylaminoparthenolide (DMAPT), a clinical grade water-soluble analog of parthenolide, as a potent inhibitor of NF-κB and demonstrated in vitro and in vivo anti-tumor activities in multiple cancers. In this study, we show DMAPT is an epigenetic modulator functioning in an NF-κB-dependent and -independent manner. DMAPT-mediated NF-κB inhibition resulted in elevated histone H3K36 trimethylation (H3K36me3), which could be recapitulated through genetic ablation of the p65 subunit of NF-κB or inhibitor-of-kappaB alpha super-repressor overexpression. DMAPT treatment and p65 ablation increased the levels of H3K36 trimethylases NSD1 (KMT3B) and SETD2 (KMT3A), suggesting that NF-κB directly represses their expression and that lower H3K36me3 is an epigenetic marker of constitutive NF-κB activity. Overexpression of a constitutively active p65 subunit of NF-κB reduced NSD1 and H3K36me3 levels. NSD1 is essential for DMAPT-induced expression of pro-apoptotic BIM, indicating a functional link between epigenetic modification and gene expression. Interestingly, we observed enhanced H4K20 trimethylation and induction of H4K20 trimethylase KMT5C in DMAPT-treated cells independent of NF-κB inhibition. These results add KMT5C to the list NF-κB-independent epigenetic targets of parthenolide, which include previously described histone deacetylase 1 (HDAC-1) and DNA methyltransferase 1. As NSD1 and SETD2 are known tumor suppressors and loss of H4K20 trimethylation is an early event in cancer progression, which contributes to genomic instability, we propose DMAPT as a potent pharmacologic agent that can reverse NF-κB-dependent and -independent cancer-specific epigenetic abnormalities.

A comparison of microanatomic basis for coupling between bone formation and bone resorption in man and the rat.

The trabecular bone of the secondary spongiosa of mature rats shows a coupling of bone formation to resorption. In adult man the coupling of formation and resorption involves a site-specific sequence of events, in which bone resorption is normally followed, at the same site, by bone formation. Whether the coupled processes of bone resorption and formation also occur at the same site in the rat is unknown. To elucidate the spatial relationship between bone formation and resorption in the rat, we compared the percentage of crenated and non-crenated cement lines with the percentage of crenated and non-crenated bone surfaces in the proximal tibia of adult rats aged 16 weeks-two years. A similar comparison was also made using bone from adult human iliac crest. We found that the trabecular bones of 16-week and seven-month-old rats exhibited a low percentage of crenated cement lines. In contrast, the surfaces of rat bone trabeculae showed a similar low proportion of crenated surface to human bone. However, in older (two years) rats, in which bones have ceased to grow in length, the percentage of cement lines that were crenated increased to towards human levels. These results imply that most of the bone formed in the secondary spongiosa of growing rats occurs on non-resorbed surfaces. Thus, although there is substantial evidence that bone formation is coupled to resorption in the rat, such that increased resorption is associated with increased formation, and suppression of resorption suppresses bone formation, bone formation does not necessarily occur on a previously resorbed site.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue distribution of the lipocalin alpha-1 microglobulin in the developing human fetus.

Alpha-1 microglobulin (alpha(1)m), a lipocalin, is an evolutionarily conserved immunomodulatory plasma protein. In all species studied, alpha(1)m is synthesized by hepatocytes and catabolized in the renal proximal tubular cells. alpha(1)m deficiency has not been reported in any species, suggesting that its absence is lethal and indicating an important physiological role for this protein To clarify its functional role, tissue distribution studies are crucial. Such studies in humans have been restricted largely to adult fresh/frozen tissue. Formalin-fixed, paraffin-embedded multi-organ block tissue from aborted fetuses (gestational age range 7-22 weeks) was immunohistochemically examined for alpha(1)m reactivity. Moderate to strong reactivity was seen at all ages in hepatocytes, renal proximal tubule cells, and a subset of pancreatic islet cells. Muscle (cardiac, skeletal, or smooth), adrenal cortex, a scattered subset of intestinal mucosal cells, tips of small intestinal villi, and Leydig cells showed weaker and/or variable levels of reactivity. Connective tissue stained with variable location and intensity. The following cells/sites were consistently negative: thymus, spleen, hematopoietic cells, lung parenchyma, glomeruli, exocrine pancreas, epidermis, cartilage/bone, ovary, seminiferous tubules, epididymis, thyroid, and parathyroid. The results underscore the dominant role of liver and kidney in fetal alpha(1)m metabolism and provide a framework for understanding the functional role of this immunoregulatory protein.

Prediction of local recurrence of ductal carcinoma in situ of the breast using five histological classifications: a comparative study with long follow-up.

The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening and the more widespread use of breast-conserving surgery have led to a search for histological features associated with the risk of recurrence. In a case control study of 141 patients with long follow-up, we compared the ability of five morphological classifications to predict recurrence after local excision. A significant correlation was not found between recurrence and growth pattern when a traditional classification based on architecture was used nor with necrosis when a scheme based principally on this feature was employed. A correlation was, however, found between recurrence and "differentiation" as defined by nuclear features and cell polarization in a classification recently formulated by the European Pathologists Working Group (EPWG), but this failed to reach statistical significance at the 5% level. A stronger and statistically significant correlation was found between nuclear grade as defined by the EPWG and recurrence when cell polarization was disregarded, using the classification currently employed by the UK National Health Service and European Commission-funded Breast Screening Programmes. This was attributable to a small number of recurring cases being downgraded as a consequence of exhibiting polarized cells. A significant correlation between histology and recurrence was also observed using the Van Nuys classification, which is based on nuclear grade and necrosis. Whether the tumor recurred as in situ or invasive carcinoma was unrelated to histological classification, as was the time course over which it occurred. These findings strongly support the use of nuclear grade to identify cases of DCIS at high risk of recurrence after local excision, but further work is necessary to determine whether nuclear grade or necrosis is more appropriate to subdivide the non-high-grade cases.

Non-hodgkin malignant lymphoma with tissue neutrophilia: a report of 3 cases.

CONTEXT: Neutrophils, in the absence of necrosis, are uncommon in non-Hodgkin malignant lymphoma. Recently, a neutrophil-rich type of Ki-1 (CD30)-positive, anaplastic large cell lymphoma was described. OBJECTIVES: We report 3 cases of nonanaplastic large cell lymphoma with an abundance of tissue neutrophils; 2 cases were associated with breast carcinoma and possible infection. RESULTS: Peripheral blood neutrophilia was noted in only 1 of these 3 patients. Neutrophilia in the lymph nodes occurred in either a sinusoidal or interstitial pattern. Multiple biopsies were available for review in 2 patients; however, tissue neutrophilia was present in only 1 biopsy each. CONCLUSION: These findings suggest that nonanaplastic large cell lymphoma-related tissue neutrophilia is a transient phenomenon.

Intraductal hepatocellular carcinoma with normal liver--case report.

Hepatocellular carcinoma commonly invades the portal vein but is rarely seen in the bile duct. When seen, a minor intraductal component usually accompanies a prominent hepatic involvement. We report a case of hepatocellular carcinoma that entirely involved the common bile duct, the hepatic involvement was undiscernible at operation or ultrasonography. The patient had obstructive jaundice both at first presentation and at recurrence. The liver was normal at both explorations. The elevated AFP levels returned to normal after second resection. The diagnosis was confirmed by electron microscopy.

Uraemia--a rare presentation of non-Hodgkin's lymphoma.

Kidney involvement by Non-Hodgkin's lymphoma is very common microscopically but rarely a cause of uraemia even when the parenchymatous involvement is considerable. Renal failure in cases of lymphoma is secondary to ureteral obstruction, hypercalcaemia, urate nephropathy, gammopathy or immunologically mediated nephrosis. This is a case where the patient presented to the ophthalmic O.P.D. with blurring of vision and admitted with full blown uraemia. He could not be saved and at autopsy, a gastrointestinal lymphoma was found in the caecum. His uraemia was due to massive parenchymatous involvement of the kidney, there being no ureteral obstruction, hypercalcaemia, urate or immunologically mediated nephropathy. Very few cases are reported in literature with such a presentation.