Comparison of Ki-67 labeling index measurements using digital image analysis and scoring by pathologists

Abstract

Background

Routine analysis of Ki-67 is not widely recommended for clinical decision-making because of poor reproducibility. Furthermore, counting numerous cells can be laborious for pathologists. Digital image analysis for immunohistochemical analysis was recently developed; however, the clinical efficacy of the Ki-67 index obtained using image analysis is unknown.

Methods

We retrospectively identified female patients with breast cancer with immunohistochemical Ki-67 and survival data using the pathology database at the Tokai University, Japan. Ki-67 expression was scored by three pathologists. Slides were scanned and converted to virtual slides; Ki-67-positive cells were counted using image analysis. Ki-67 indices obtained by the pathologist's scoring and image analysis were evaluated by 2 × 2 analysis. Relationships between Ki-67 index and survival outcomes were evaluated using the Kaplan–Meier method and compared using the log-rank test.

Results

Based on the 2 × 2 analysis, Ki-67 index obtained using image analysis was moderately correlated with the pathologist's scoring for all patients (κ 0.41; sensitivity, 0.573; specificity, 0.878). Poorer relapse-free survival was associated with high Ki-67 index than with low Ki-67 index for estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and stage I or II patients scored by pathologists (p < 0.001) and obtained using image analysis (p = 0.031).

Conclusions

The Ki-67 indices obtained using image analysis were moderately correlated with those scored by pathologists. Digital image analysis can be effective for measuring Ki-67 values, because they are associated with relapse-free survival in estrogen receptor-positive, human epidermal growth factor receptor 2-negative, and patients at stage I or II.

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Association between pre-operative biological phenotypes and postoperative pulmonary complications: An unbiased cluster analysis

BACKGROUND Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. OBJECTIVE To assess whether distinct biological phenotypes exist within surgical patients, and whether development of postoperative pulmonary complications (PPCs) and subsequent dependence of intra-operative positive end-expiratory pressure (PEEP) differ between such phenotypes. SETTING Operating rooms of six hospitals in Europe and USA. DESIGN Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. PATIENTS Adult patients scheduled for abdominal surgery who are at risk of PPCs. INTERVENTIONS Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. MAIN OUTCOME MEASURES We applied unbiased cluster analysis to identify biological phenotypes. We then compared the proportion of patients developing PPCs within each phenotype, and associations between intra-operative PEEP levels and development of PPCs among phenotypes. RESULTS In total, 242 patients were included. Unbiased cluster analysis clustered the patients within two biological phenotypes. Patients with phenotype 1 had lower plasma concentrations of TNF-α (3.8 [2.4 to 5.9] vs. 10.2 [8.0 to 12.1] pg ml−1; P 

https://ift.tt/2Kvp5Pz

Radiotherapy dose–volume parameters predict videofluoroscopy-detected dysphagia per DIGEST after IMRT for oropharyngeal cancer: Results of a prospective registry

Our primary aim was to prospectively validate retrospective dose–response models of chronic radiation-associated dysphagia (RAD) after intensity modulated radiotherapy (IMRT) for oropharyngeal cancer (OPC). The secondary aim was to validate a grade ≥2 cut-point of the published videofluoroscopic dysphagia severity (Dynamic Imaging Grade for Swallowing Toxicity, DIGEST) as radiation dose-dependent.

https://ift.tt/2lE2vJI

Response to Spartalis et al

We would like to thank Spartalis et al. [1] for their valuable comments about our report from Jumeau et al. on stereotactic body radiotherapy (SBRT) for ventricular tachycardia (VT) substrates [2].

https://ift.tt/2tKV2Mw

Randomized controlled study comparing simultaneous modulated accelerated radiotherapy versus simultaneous integrated boost intensity modulated radiotherapy in the treatment of locally advanced head and neck cancer

Publication date: Available online 28 June 2018
Source:Journal of the Egyptian National Cancer Institute
Author(s): Sarthak Tandon, Munish Gairola, Parveen Ahlawat, Sheh Rawat, Archana Aggarwal, Kanika Sharma, Sandeep Tiwari, Ahmad M. Karimi, Vinayakumar Muttagi, Nishtha Sachdeva, Manindra Bhushan
ObjectivesComparison of two fractionation schedules of intensity modulated radiotherapy (IMRT) for locally advanced head and neck cancer – simultaneous integrated boost (SIB-IMRT) and simultaneous modulated accelerated radiotherapy (SMART) boost in terms of toxicity and survival end-point measures.Patients and methodsSixty patients with locally advanced head and neck cancer were randomized in two treatment arms (SIB-IMRT [control arm] and SMART boost arm [study arm]). In the control arm, patients received 70, 63 and 56 Gy in 35 fractions to clinical target volumes (CTV) 1, 2 and 3, respectively. In the study arm, patients received 60 and 50 Gy to CTV 1 and CTV 3, respectively. Toxicities, progression free survival (PFS) and overall survival (OS) were compared between both arms.ResultsBaseline patient-related characteristics were comparable between the arms except for primary site of tumour. No significant differences were noted in acute toxicities between the arms except for fatigue which was statistically higher for control arm. No significant differences in 2-year late toxicities were observed. The median follow-up duration was 25.5 (range, 1.8–39.9) months. The 2-year PFS was 53.3% and 80.0% (p = 0.028) for control and study arm, respectively. The 2-year OS was 60.0% and 86.7% (p = 0.020) in control and study arms, respectively. Multivariate analysis showed clinical stage and site to be significant predictors for OS and PFS, respectively.ConclusionsThe SMART boost technique can be a feasible alternative fractionation schedule that reduces the overall treatment time, maintaining comparable toxicity and survival compared with SIB-IMRT.



https://ift.tt/2Kwp5if

SH2B3 aberrations enriched in iAMP21 B lymphoblastic leukemia

Publication date: October 2018
Source:Cancer Genetics, Volumes 226–227
Author(s): LB Baughn, MM Meredith, L Oseth, TA Smolarek, B Hirsch
Acute lymphoblastic leukemia (ALL) represents the most common childhood malignancy. Although survival for pediatric B-ALL has approached 90%, variability in outcome among and within cytogenetically defined subgroups persists. While G-banding and fluorescence in situ hybridization (FISH) have been used to characterize leukemic clones, there is added value of chromosomal microarray and next generation sequencing in screening genome-wide for copy number aberrations, copy neutral loss of heterozygosity and nucleotide variations. Evaluation of novel genetic aberrations can provide information about the biologic mechanisms of cytogenetically defined subgroups associated with poor prognosis, explain heterogeneity in patient outcome and identify novel targets for therapeutic intervention. The high risk B-ALL intrachromosomal amplification of chromosome 21, (iAMP21), subtype is characterized by amplification of a region of chromosome 21 that typically encompasses the RUNX1 gene and is associated with poor prognosis. Analysis of chromosomal microarray and FISH data revealed that deletions of SH2B3, encoding a negative regulator of multiple tyrosine kinase and cytokine signaling pathways, are enriched among leukemias harboring iAMP21. Enrichment of SH2B3 aberrations in the iAMP21 subtype may indicate that loss of SH2B3 contributes to disease progression and raises the possibility that these leukemias may be sensitive to tyrosine kinase inhibitors.



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Molecular Profiling of Pancreatic Cancer Patients: Initial Results from the Know Your Tumor Initiative

Purpose: To broaden access to and implementation of precision medicine in the care of pancreatic cancer patients, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multi-omic profiling to determine molecularly rationalized clinical trials and off-label therapies. Experimental Design: Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. CAP/CLIA-accredited laboratories were used for genomic, proteomic and phosphoprotein-based molecular profiling. Results: Tumor samples were adequate for next-generation sequencing in 96% and immunohistochemistry in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes (BRCA1/2 or ATM mutations, 8.4%) and cell cycle genes (CCND1/2/3 or CDK4/6 alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy (n=17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy (n=18; PFS = 4.1 vs. 1.9 months; HR: 0.47; 95% CI: 0.24-0.94; adjusted P-value = 0.03). Conclusions: A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer.

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STAG2 Is a Biomarker for Prediction of Recurrence and Progression in Papillary Non-Muscle-Invasive Bladder Cancer

Purpose: Most bladder cancers are early-stage tumors known as papillary non–muscle-invasive bladder cancer (NMIBC). After resection, up to 70% of NMIBCs recur locally, and up to 20% of these recurrences progress to muscle invasion. There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. We previously identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence in a pilot cohort that STAG2-mutant tumors recurred less frequently than STAG2 wild-type tumors. Here, we report a STAG2 biomarker validation study using two independent cohorts of clinically annotated papillary NMIBC tumors from the United States and Europe.

Experimental Design: The value of STAG2 immunostaining for prediction of recurrence was initially evaluated in a cohort of 82 patients with papillary NMIBC ("Georgetown cohort"). Next, the value of STAG2 immunostaining for prediction of progression to muscle invasion was evaluated in a progressor-enriched cohort of 253 patients with papillary NMIBC ("Aarhus cohort").

Results: In the Georgetown cohort, 52% of NMIBC tumors with intact STAG2 expression recurred, whereas 25% of STAG2-deficient tumors recurred (P = 0.02). Multivariable analysis identified intact STAG2 expression as an independent predictor of recurrence (HR = 2.4; P = 0.05). In the progressor-enriched Aarhus cohort, 38% of tumors with intact STAG2 expression progressed within 5 years, versus 16% of STAG2-deficient tumors (P < 0.01). Multivariable analysis identified intact STAG2 expression as an independent predictor of progression (HR = 1.86; P = 0.05).

Conclusions: STAG2 IHC is a simple, binary, new assay for risk stratification in papillary NMIBC. Clin Cancer Res; 1–9. ©2018 AACR.

https://ift.tt/2IBzE1s

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012, Published online: 29 June 2018; doi:10.1038/s41416-018-0131-9

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012

https://ift.tt/2KhJgEB

Integrative analysis of oncogenic fusion genes and their functional impact in colorectal cancer

Integrative analysis of oncogenic fusion genes and their functional impact in colorectal cancer

Integrative analysis of oncogenic fusion genes and their functional impact in colorectal cancer, Published online: 29 June 2018; doi:10.1038/s41416-018-0153-3

Integrative analysis of oncogenic fusion genes and their functional impact in colorectal cancer

https://ift.tt/2Mvy0Rr

A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin

A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin

A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin, Published online: 29 June 2018; doi:10.1038/s41416-018-0138-2

A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin

https://ift.tt/2KrVjOF

Characterisation of tumour microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact (an OCTIPS Consortium study).

Characterisation of tumour microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact (an OCTIPS Consortium study).

Characterisation of tumour microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact (an OCTIPS Consortium study)., Published online: 29 June 2018; doi:10.1038/s41416-018-0157-z

Characterisation of tumour microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact (an OCTIPS Consortium study).

https://ift.tt/2Mx2BhL

Corrigendum to “Systematic Identification of Druggable Epithelial–Stromal Crosstalk Signaling Networks in Ovarian Cancer”

Corrigendum to "Systematic Identification of Druggable Epithelial–Stromal Crosstalk Signaling Networks in Ovarian Cancer" by Tsz-Lun Yeung et al. JNCI. J Natl Cancer Inst 2018; doi: 10.1093/jnci/djy097.

https://ift.tt/2N5o7uR

Transcriptome Characterization of Matched Primary Breast and Brain Metastatic Tumors to Detect Novel Actionable Targets

Abstract

Background

Breast cancer brain metastases (BrMs) are defined by complex adaptations to both adjuvant treatment regimens and the brain microenvironment. Consequences of these alterations remain poorly understood, as does their potential for clinical targeting. We utilized genome-wide molecular profiling to identify therapeutic targets acquired in metastatic disease.

Methods

Gene expression profiling of 21 patient-matched primary breast tumors and their associated brain metastases was performed by TrueSeq RNA-sequencing to determine clinically actionable BrM target genes. Identified targets were functionally validated using small molecule inhibitors in a cohort of resected BrM ex vivo explants (n = 4) and in a patient-derived xenograft (PDX) model of BrM. All statistical tests were two-sided.

Results

Considerable shifts in breast cancer cell-specific gene expression profiles were observed (1314 genes upregulated in BrM; 1702 genes downregulated in BrM; DESeq; fold change > 1.5, P_adj < .05). Subsequent bioinformatic analysis for readily druggable targets revealed recurrent gains in RET expression and human epidermal growth factor receptor 2 (HER2) signaling. Small molecule inhibition of RET and HER2 in ex vivo patient BrM models (n = 4) resulted in statistically significantly reduced proliferation (P < .001 in four of four models). Furthermore, RET and HER2 inhibition in a PDX model of BrM led to a statistically significant antitumor response vs control (n = 4, % tumor growth inhibition [mean difference; SD], anti-RET = 86.3% [1176; 258.3], P < .001; anti-HER2 = 91.2% [1114; 257.9], P < .01).

Conclusions

RNA-seq profiling of longitudinally collected specimens uncovered recurrent gene expression acquisitions in metastatic tumors, distinct from matched primary tumors. Critically, we identify aberrations in key oncogenic pathways and provide functional evidence for their suitability as therapeutic targets. Altogether, this study establishes recurrent, acquired vulnerabilities in BrM that warrant immediate clinical investigation and suggests paired specimen expression profiling as a compelling and underutilized strategy to identify targetable dependencies in advanced cancers.

https://ift.tt/2Kyf0RF

Acquired Factor X Deficiency in Light-chain (AL) Amyloidosis is Rare and Associated with Advanced Disease

Publication date: Available online 28 June 2018
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Gina Patel, Parameswaran Hari, Aniko Szabo, Lisa Rein, Lisa Baumann Kreuziger, Saurabh Chhabra, Binod Dhakal, Anita D'Souza
Systemic light-chain (AL) amyloidosis can lead to an acquired coagulopathy secondary to acquired factor X (aFX) deficiency. However, it is not very clear who develops aFX deficiency in AL amyloidosis. We, therefore, undertook this single-center study to better characterize AL amyloidosis-associated aFX deficiency. Out of 121 AL patients who had FX testing at the time of their first evaluation at our institution, including 17 patients on warfarin at the time of testing, 10 out of 104 patients (9.6%) with systemic AL amyloidosis were found to have FX levels below 50%. aFX deficiency was associated with advanced stage of AL amyloidosis and elevated cardiac biomarkers. Lower FX activity, advanced stage, and cardiac involvement by disease were associated with higher hazard of death on univariate analysis. On multivariate analysis, stage of AL amyloidosis was the only significant predictor of survival. Median survival time of patients with FX deficiency was 9.3 months compared with 118.4 months in those without the deficiency. We conclude that while aFX deficiency is rare in systemic AL amyloidosis, it is a marker of advanced disease.



https://ift.tt/2yUjRvg

A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin

https://ift.tt/2tIXova

Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012

https://ift.tt/2lEHVIY

Integrative analysis of oncogenic fusion genes and their functional impact in colorectal cancer

https://ift.tt/2tOSBIV

Characterisation of tumour microvessel density during progression of high-grade serous ovarian cancer: clinico-pathological impact (an OCTIPS Consortium study).

https://ift.tt/2lG6WUc

Rare variability in adrenoleukodystrophy: a case report

X-linked adrenoleukodystrophy is a genetic disorder with diverse clinical phenotypes. Of these phenotypes, the cerebral form usually manifests during early childhood with rapid cognitive and neurological deter...

https://ift.tt/2z1X5Sr

The clinical significance of KIT mutations in melanoma: a meta-analysis

This study aimed to evaluate the association of KIT mutations with clinicopathologic features of melanomas using a meta-analysis and to identify differences between Asian and White populations using subgroup analyses. We selected 32 studies from the literature including 5224 patients. The pooled data were combined, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity and publication bias were also determined. KIT mutations were reported in 497 (9.5%) of 5224 patients with melanomas, and were associated significantly with age, clinical melanoma subtype, anatomic location, and chronic sun-damage (CSD), but not with sex, histological type, Breslow thickness, ulceration, mitotic rate, or tumor stage. The incidence of KIT mutation was significantly higher in older individuals (OR=1.296, 95% CI: 1.025–1.641; P=0.031), and showed a positive association with mucosal melanoma (OR=1.363, 95% CI: 1.094–1.697; P=0.006), acral melanoma (OR=1.374, 95% CI: 1.123–1.682; P=0.02), and CSD (OR=1.880, 95% CI: 1.127–3.136; P=0.016), but a negative relationship with melanomas arising in non-CSD skin (OR=0.562, 95% CI: 0.392–0.805; P=0.002). The frequency of KIT mutations was associated negatively with melanomas located on the extremities. KIT mutations, which are critical in the genetic pathogenesis of melanomas, define a unique subtype of melanoma associated closely with older age, and acral, mucosal, or CSD sites, but not associated with any histological features or tumor stage. Although the KIT mutation rate is higher in White than Asian populations, no significant difference in clinical association with KIT mutations was detected between the two groups.

https://ift.tt/2yQZfnt

Fatty acid receptor GPR120: a novel marker for human melanoma

The correlation between ultraviolet radiation of the skin and melanoma incidence in humans is well established. Interestingly, epidemiologic data suggest also a correlation to an increased BMI pointing to metabolic trigger factors in melanoma pathogenesis. To substantiate this connection, we studied the expression of G-protein-coupled receptor 120 (GPR120), a receptor sensitive to unsaturated long-chain free fatty acids in melanoma tissues. One-hundred fourteen tissue sections histologically confirmed as nevi (n=32), primary melanoma (n=39), and melanoma metastasis (n=43) were immunohistochemically stained against GPR120. The staining was evaluated by three trained dermatopathologists and independently scored. Compared with nevi, primary melanoma and melanoma metastasis showed significantly higher levels of GPR120 staining. Only three out of 32 nevi showed strong GPR120 expression [median immunoreactivity-scoring system (IRS) score: 1, range: 0–10], whereas in primary melanomas 14 out of 39 were highly GPR120-positive (median IRS score: 7, range: 0–12) and in melanoma metastasis 27 out of 43 were highly GPR120-positive (median IRS score: 9, range: 0–12). GPR120 expression and tumor thickness (mm) show a statistically significant correlation in primary melanoma (P=0.011). Moreover, GPR120-positive staining was found throughout the epidermis and in sebaceous and sweat glands, which is yet not described. This study identified GPR120 as a novel marker for melanoma, indicating that melanoma cells are sensitive to free fatty acids. It is tempting to speculate that pharmacologically interfering with GPR120 signaling might improve melanoma therapy.

https://ift.tt/2lEzzRC

Epidemiological trends in the diagnosis of melanoma in a Southern European population: analysis of a large database from a tertiary referral center

The aim of this study was to present the epidemiological, clinicopathological, and treatment characteristics of patients diagnosed and treated in a tertiary referral center and to analyze independent factors associated with these characteristics. In this cohort study, epidemiological, clinicopathological, and treatment characteristics of 1461 consecutive melanoma patients diagnosed and treated in a tertiary referral center in 1987–2015 were prospectively collected in a registry. All patients underwent resection of their melanoma lesion. Multiple logistic regression analysis was used to examine independent correlations between characteristics. Internal validation of these correlations was performed by the bootstrap method. The median age of the patients was 53 years. Female sex had a slight predominance, whereas the majority were of Southern European origin. Superficial spreading melanoma was associated with younger age (P

https://ift.tt/2yNiP46

Sensitization of recombinant human tumor necrosis factor-related apoptosis-inducing ligand-resistant malignant melanomas by quercetin

Malignant melanoma is the most commonly diagnosed skin cancer associated with a high rate of metastasis. Low-stage melanoma is easily treated, but metastatic malignant melanoma is an extremely treatment-resistant malignancy with low survival rates. The application of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) for the treatment of metastatic malignant melanoma holds considerable promise because of its selective proapoptotic activity towards cancer cells and not nontransformed cells. Unfortunately, the clinical utilization of rhTRAIL has been terminated due to the resistance of many cancer cells to undergo apoptosis in response to rhTRAIL. However, rhTRAIL-resistance can be abrogated through the cotreatment with compounds derived from 'Mother Nature' such as quercetin that can modulate cellular components responsible for rhTRAIL-resistance. Here, we show that rhTRAIL-resistant malignant melanomas are sensitized by quercetin. Quercetin action is manifested by the upregulation of rhTRAIL-binding receptors DR4 and DR5 on the surface of cancer cells and by increased rate of the proteasome-mediated degradation of the antiapoptotic protein FLIP. Our data provide for a new efficient and nontoxic treatment of malignant melanoma.

https://ift.tt/2lGhjYj

The impact of patient characteristics and disease-specific factors on first-line treatment decisions for BRAF-mutated melanoma: results from a European expert panel study

Treatment decisions for advanced melanoma are increasingly complex and guidelines provide limited advice on how to choose between immunotherapy and targeted therapy for first-line treatment. A Delphi study was carried out to understand which patient characteristics and disease-related factors inform clinicians' choices of first-line treatment for BRAF-mutated melanoma. Twelve European melanoma specialists experienced in using immunotherapies and targeted agents participated in a double-blind two-phase Delphi study. In phase 1, participants completed a questionnaire developed after reviewing patient characteristics and disease-related factors reported in trials, clinical guidelines, and health technology assessments. Phase 2 was an expert panel meeting to explore outstanding issues from phase 1 and seek consensus, defined as 80% agreement. Twenty patient-related and disease-related characteristics were considered. There was consensus that tumor burden (83% of clinicians) and disease tempo (83%) are very or extremely important factors when selecting first-line treatment. Several components were deemed important when assessing tumor burden: brain metastases (82% of clinicians) and location of metastases (89%). There was consensus that disease tempo can be quantified in clinical practice, but not on a formal classification applicable to all patients. Lactate dehydrogenase level is a component of both tumor burden and disease tempo; all clinicians considered lactate dehydrogenase important when choosing first-line treatment. The majority (92%) did not routinely test programmed death ligand-1 status in patients with melanoma. Clinicians agreed that choosing a first-line treatment for advanced melanoma is a complex, multifactorial process and that clinical judgment remains the most important element of decision-making until research can provide clinicians with better scientific parameters and tools for first-line decision-making.

https://ift.tt/2ySziUO

Pregnancy and the apoptotic pathway in experimental melanoma

Pregnancy-associated melanoma is defined as melanoma diagnosed during pregnancy or within 1 year of delivery. The association of pregnancy with melanoma is well known, but its underlying molecular mechanisms of association are poorly understood. The aim was to assess the expression of apoptosis-related genes in melanoma tumors during pregnancy in an attempt to elucidate the molecular mechanisms underlying apoptosis-driven activation of melanoma cells in this period. Mice were allocated across two experimental groups (nonpregnant and pregnant) and implanted with the melanoma cell line BF16-F10. Tumor tissue was collected for RNA extraction and purification, and gene expression was quantified using the mouse apoptosis RT2ProfilerTM PCR array. Different intracellular apoptotic pathways were activated (positively or negatively) by pregnancy in tumor cells: intrinsic (21.5%), extrinsic (32%), caspase (14%), apoptosis (21.5%), and caspase-activated DNase (11%). The proportion of upregulated genes for each of these pathways was 100, 30, 50, 17, and 0%, respectively. MetaCore software was then used to analyze gene ontology processes and pathways by building networks. Among the gene ontology processes, the majority of differentiated genes were related to the apoptotic process. The main pathway activated by pregnancy was the intrinsic one (genes Api-5, Bcl2-L1, Birc-2, Birc-3, Bok, and Trp53bp2). Pregnancy activates the intrinsic apoptosis pathway to stimulate caspases 7 and 9, but the final balance is inhibition of apoptosis mechanisms. In mice, pregnancy cannot promote or worsen melanoma.

https://ift.tt/2lI5GQI

Malignant melanoma clinically mimicking pyogenic granuloma: comparison of clinical evaluation and histopathology

Amelanotic melanomas (AMMs) account for a small proportion of all melanomas. They pose a risk of delayed diagnosis and, consequently, poor prognosis. AMMs may atypically present as a pyogenic granuloma-like lesion. This study sought to investigate the prevalence and clinical and histological features of AMM masquerading as pyogenic granuloma. The database of a tertiary medical center was screened for all patients pathologically diagnosed with melanoma in 2005–2016. Those with a suspected primary (i.e. pre-excision) clinical diagnosis of pyogenic granuloma were identified, and their demographic, clinical, histologic, and outcome data were collected from the medical files. Of 2038 patients diagnosed with melanoma, 10 (∼0.5%) had a pyogenic granuloma-like AMM. The mean±SD age at lesion presentation was 56±18.9 years and the mean time from lesion appearance to diagnosis was 91.5±117.1 months. Nine tumors were located on the skin surface, and one on the oral mucosa. The mean lesion size was 19.6±14.1 mm2 and the mean Breslow's depth was 6.47±3.1 mm; all tumors presented in the vertical growth phase. Seven (70%) patients had lymph node involvement or metastasis at diagnosis. Two patients died of the disease within 1 year of diagnosis. Given the potential lethality of AMM and the benign nature of pyogenic granuloma, clinician recognition of pyogenic granuloma-like AMMs is crucial. In the presence of a pyogenic granuloma-like lesion, findings of older patient age and large tumor size should raise the index of suspicion and prompt a biopsy study, thereby ensuring early and accurate treatment.

https://ift.tt/2yQZdfl

Serum exosomal microRNAs as potent circulating biomarkers for melanoma

Exosomes are small homogenous membrane vesicles that derive from the exocytosis process of cells and can contain DNA, microRNAs (miRNAs), and/or proteins. Characterization of the content profile of exosomes may reflect the state of the cells that release them, and this could be predictive of disease. In this study, to explore the potential biomarkers for melanoma, we isolated serous exosomes from 30 patients with melanoma and 30 healthy individuals using the ultracentrifugation method. Five miRNAs were subsequently detected in each sample by quantitative reverse transcription-PCR: miRNA-532-5p, miRNA-106b, miRNA-200c, miRNA-199a-5p, and miRNA-210. Only the levels of exo-miRNA-532-5p and exo-miRNA-106b differed between the two groups (Z=−4.17 and −4.57, respectively, P

https://ift.tt/2lGhanJ

Vemurafenib in BRAF-mutant metastatic melanoma patients in real-world clinical practice: prognostic factors associated with clinical outcomes

The aim of this population-based study was to identify the factors associated with clinical outcomes in vemurafenib-treated patients and to evaluate outcomes across subgroups of patients with different risk profiles. Data were retrieved from the Dutch Melanoma Treatment Registry. Time to next treatment (TTNT) and overall survival (OS) of all metastatic melanoma patients who received vemurafenib between 2012 and 2015 were assessed using Kaplan–Meier estimates. A risk score was developed on the basis of all prognostic factors associated with TTNT and OS derived from multivariable Cox regression analyses. Patients were stratified according to the presence of prognostic risk factors by counting the number of factors, ranging from 0 to 6. A total of 626 patients received vemurafenib with a median follow-up of 35.8 months. The median TTNT and OS were 4.7 months [95% confidence intervals (CI): 4.4–5.1] and 7.3 months (95% CI: 6.6–8.0). The strongest prognostic factors were serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance score, number of organ sites involved and brain metastases. Patients with a favourable risk profile (no risk factors) had a median TTNT and OS of 7.1 (95% CI: 5.8–8.5) and 15.4 months (95% CI: 10.0–20.9). The median OS more than halved for patients with greater than or equal to 2 risk factors compared with patients with no risk factors. The clinical outcomes of vemurafenib in metastatic melanoma patients with a favourable risk profile are comparable with the results of the trials. Combining prognostic factors into a risk score could be valuable to stratify patients into favourable and poor-prognosis groups.

https://ift.tt/2tMl9mk

Correlation with lymphocyte infiltration, but lack of prognostic significance of MECA-79-positive high endothelial venules in primary malignant melanoma

High endothelial venules (HEVs) are specialized vessels in lymphoid organs, supporting lymphocyte trafficking from the blood. As the presence of these vessels was described recently in tumors, it was proposed that they could facilitate the development of antitumor immune response, resulting in improved prognosis. The aim of our study was to analyze the correlation of the density of HEVs with that of the different immune cell types as well as with the clinicopathologic parameters and the disease outcomes in patients with cutaneous melanoma. Primary melanoma samples of 118 patients were analyzed retrospectively by immunohistochemical labeling and quantitation of vessels stained with the MECA-79 antibody, as well as a panel of eight different immune cell types (CD8+ and CD45RO+ T cells, lymphocytes expressing the CD25, CD134, or CD137 activation markers, FOXP3+ regulatory T cells, CD20+ B cells, and DC-LAMP+ mature dendritic cells). Correlations of MECA-79+ vessel density with that of the immune cells, as well as with clinicopathologic parameters and disease outcomes were evaluated. We showed that the number of MECA-79+ vessels correlates strongly with the peritumoral density of B and T lymphocytes. Moreover, higher HEV numbers were detected in tumors hosting tertiary lymphoid structures as well as in those of axial location compared with the ones in the extremity and in men compared with women, whereas no association was found with patient age, tumor thickness, histologic type or ulceration, or with the survival of melanoma patients. The density of MECA-79+ HEVs in primary melanomas shows a correlation with B and T-lymphocyte density and differences according to the presence of tertiary lymphoid structures, tumor site, and the sex of the patient. However, it has no prognostic value.

https://ift.tt/2lE0PzP

Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a tertiary care center

Denosumab is a monoclonal antibody against RANK ligand with a role in the prevention of skeletal-related events and is also known to possess antitumor properties. In this retrospective review, we aim to evaluate the synergist effect of a combination therapy with immune checkpoint inhibitors and denosumab in malignant melanoma patients. Patients of 18 years of age or older with a diagnosis of malignant melanoma who have received immune checkpoint inhibitors and denosumab between June 2015 and May 2017 were divided into two cohorts: cohort A (immune checkpoint inhibitors only) and cohort B (immune checkpoint inhibitors and denosumab). Overall survival, progression-free survival, objective response rate, and safety analysis were performed. Stratified analysis based on metastatic (M) status was performed as well. Eleven (29.72%) out of 37 patients received immune checkpoint inhibitors and denosumab combination. Median overall survival in cohort B was 57 months compared with 22.8 months in cohort A and 22 months in M1c patients from cohort A. Median progression-free survival was 4.15 months in cohort B compared with 11.6 months in cohort A and 5.12 months in M1c patients from cohort A. The mean number of distant sites involved in metastasis were significantly higher in cohort B (3.54 vs. 2.23, P=0.0015). Cohort B also had more patients with more than two distant metastatic sites (90.9 vs. 30.8%, P=0.001). A combination therapy with denosumab and immune checkpoint inhibitors may have a beneficial effect on survival and progression as in our study; the patients receiving combination therapy did not behave poorly despite having poor prognostic features.

https://ift.tt/2ySl867

Predictive value of excision repair cross-complementing group 2 gene Lys751Gln and Asp312Asn polymorphisms in melanoma risk

Epidemiological studies have assessed the association between excision repair cross-complementing group 2 (ERCC2) Lys751Gln and Asp312Asn polymorphisms and melanoma risk with conflicting results. Relevant articles were searched from PubMed, Embase, and Web of Science with a time limit of 3 September 2016. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. We performed this meta-analysis with 12 studies including 6157 cases and 8873 controls for Lys751Gln and nine studies including 5037 cases and 7542 controls for Asp312Asn polymorphism. Overall, no significant associations were found under all the models for Lys751Gln polymorphism, and significant associations were found for Asp312Asn polymorphism for AA versus GG (OR=1.12, 95% CI=1.00–1.26) and for the recessive model (OR=1.11, 95% CI=1.00–1.24). In the stratification analyses by source of control: for Lys751Gln polymorphism, significant associations were found for CC versus AA (OR=1.19, 95% CI=1.04–1.36) and the recessive model (OR=1.15, 95% CI=1.02–1.30); for Asp312Asn polymorphism, significant associations were found for AA versus GG (OR=1.31, 95% CI=1.11–1.53) and the recessive model (OR=1.29, 95% CI=1.11–1.50). This meta-analysis suggested that both the Lys751Gln and Asp312Asn polymorphisms were risk factors for melanoma risk in population-based subgroup.

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Immune privilege: failure of immunotherapy in controlling metastatic cutaneous melanoma to the eye

This report concerns a 49-year-old female with cutaneous malignant melanoma and systemic metastases. These resolved following combination immunotherapy with ipilimumab and nivolumab. She subsequently experienced unilateral floaters, an increase in iris pigmentation and pigmentary glaucoma. The eye progressively lost vision and became painful due to iris neovascularization. The clinical diagnosis was of cutaneous melanoma metastatic to the vitreous, ciliary body and iris. Enucleation was performed for symptom control, with histopathology confirming the clinical diagnosis. The immune privilege of the eye may preclude ocular metastasis control with immunotherapy. Ocular symptoms in such patients merit referral to an ophthalmologist.

https://ift.tt/2tNrRbv

Targeted ultrasound and fine-needle aspiration cytology for sentinel node diagnostics in early-stage melanoma: a validation study

Ultrasound-guided fine-needle aspiration cytology (US-FNAC) is used to evaluate the involvement of lymph nodes in various malignant diseases. Its value in detecting sentinel lymph node (SN) metastasis preoperatively in melanoma patients is controversial and is the subject of this study. In this prospective validation study, 91 consecutive patients with melanoma clinical stage I (n=64) and II (n=27) were examined with US-FNAC before SN biopsy from 2012 to 2014 at a tertiary center. All patients underwent lymphoscintigraphy before the US-FNAC. Lymph nodes that showed any of the Berlin morphologic criteria on ultrasonography were examined using FNAC. The median Breslow thickness of the melanomas was 1.22 mm (range: 0.47–11.5 mm). Twenty-two percent of the patients had metastases in their SNs, 90% of which were smaller than 2 mm in largest diameter. The percentages of metastases with a size more than 1 mm were 50 and 29%, respectively, in the true-positive and false-negative US groups. The sensitivity, specificity, positive predictive value, and negative predictive value for overall US examination were 30, 81, 24, and 83%, respectively. None of the FNACs contained conclusive malignant cells. The specificity of the FNAC was 76%. Our results show that US-FNAC was not a useful diagnostic tool in our setting as it did not add significantly to the staging and management of patients with mainly thin cutaneous melanomas, perhaps because of the often small size of the SN metastases. It may be useful in the early diagnosis of lymph node metastases in a subgroup of melanoma patients with larger metastases.

https://ift.tt/2lL6wMB

Painful acute thyroiditis following a first cure of Ipilimumab plus Nivolumab for metastatic melanoma

No abstract available

https://ift.tt/2tJLZLO

Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer

Abstract

Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.

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Consultation frequency in general practice before cancer diagnosis in relation to the patient’s usual consultation pattern: A population-based study

Publication date: August 2018
Source:Cancer Epidemiology, Volume 55
Author(s): Henry Jensen, Peter Vedsted, Henrik Møller
BackgroundCancer patients who usually consult the general practitioner (GP) rarely are generally diagnosed with more advanced stages of cancer. This subgroup of cancer patients may thus postpone relevant healthcare seeking.AimWe aimed to investigate the rates of daytime face-to-face consultations in general practice before a cancer diagnosis in patients with different categories of 'usual' consultation frequency.Material and methodsWe conducted a population-based comparative study using register data on all 123,934 first-time cancer patients aged 50–90 years who were diagnosed in 2009–2013 in Denmark. Usual consultation rates were based on number of consultations from 19 to 36 months before cancer diagnosis. We predicted the marginal monthly consultation rates for up to 18 months before diagnosis. These were based on the estimated (mean) rates of consultations with corresponding 95% confidence intervals (CIs), which were calculated by negative binomial regression analysis with robust variance estimation.ResultsPatients with cancer began to increase their consultation frequency four to six months before their cancer diagnosis. The average monthly consultation rates varied slightly across usual consultation groups; rates were lowest among male 'frequent' consulters (0.28 (95% CI: 0.27;0.29)) and highest among female 'frequent' consulters (0.35 (95% CI: 0.34;0.37)). The additional number of consultations was 1–2 for all combinations of usual consultation frequency, sex, and cancer type (except for female breast cancer and 'average' consulters with lung or prostate cancer).ConclusionPatients with cancer begin to increase their consultation frequency in general practice before a cancer diagnosis independently of their usual consultation frequency.



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Liver chemoembolization of hepatocellular carcinoma using TANDEM® microspheres

Future Oncology, Ahead of Print.


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Generation of Hepatic Stellate Cells from Human Pluripotent Stem Cells Enables In Vitro Modeling of Liver Fibrosis

Publication date: Available online 28 June 2018
Source:Cell Stem Cell
Author(s): Mar Coll, Luis Perea, Ruben Boon, Sofia B. Leite, Julia Vallverdú, Inge Mannaerts, Ayla Smout, Adil El Taghdouini, Delia Blaya, Daniel Rodrigo-Torres, Isabel Graupera, Beatriz Aguilar-Bravo, Christophe Chesne, Mustapha Najimi, Etienne Sokal, Juan José Lozano, Leo A. van Grunsven, Catherine M. Verfaillie, Pau Sancho-Bru
The development of complex in vitro hepatic systems and artificial liver devices has been hampered by the lack of reliable sources for relevant cell types, such as hepatic stellate cells (HSCs). Here we report efficient differentiation of human pluripotent stem cells into HSC-like cells (iPSC-HSCs). iPSC-HSCs closely resemble primary human HSCs at the transcriptional, cellular, and functional levels and possess a gene expression profile intermediate between that of quiescent and activated HSCs. Functional analyses revealed that iPSC-HSCs accumulate retinyl esters in lipid droplets and are activated in response to mediators of wound healing, similar to their in vivo counterparts. When maintained as 3D spheroids with HepaRG hepatocytes, iPSC-HSCs exhibit a quiescent phenotype but mount a fibrogenic response and secrete pro-collagen in response to known stimuli and hepatocyte toxicity. Thus, this protocol provides a robust in vitro system for studying HSC development, modeling liver fibrosis, and drug toxicity screening.

Graphical abstract

Teaser

Coll et al. describe efficient differentiation of human pluripotent stem cells into hepatic stellate cell-like cells (iPSC-HSCs). iPSC-HSCs share phenotypic and functional features with primary HSCs and are useful for studying HSC development and for the generation of 3D in vitro liver systems for toxicity assessment and fibrosis modeling.


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Id1 Ablation Protects Hematopoietic Stem Cells from Stress-Induced Exhaustion and Aging

Publication date: Available online 28 June 2018
Source:Cell Stem Cell
Author(s): Satyendra K. Singh, Shweta Singh, Stephen Gadomski, Lei Sun, Alexander Pfannenstein, Valentin Magidson, Xiongfong Chen, Serguei Kozlov, Lino Tessarollo, Kimberly D. Klarmann, Jonathan R. Keller
Defining mechanisms that maintain tissue stem cells during homeostasis, stress, and aging is important for improving tissue regeneration and repair and enhancing cancer therapies. Here, we show that Id1 is induced in hematopoietic stem cells (HSCs) by cytokines that promote HSC proliferation and differentiation, suggesting that it functions in stress hematopoiesis. Genetic ablation of Id1 increases HSC self-renewal in serial bone marrow transplantation (BMT) assays, correlating with decreases in HSC proliferation, mitochondrial biogenesis, and reactive oxygen species (ROS) production. Id1^−/− HSCs have a quiescent molecular signature and harbor less DNA damage than control HSCs. Cytokines produced in the hematopoietic microenvironment after γ-irradiation induce Id1 expression. Id1^−/− HSCs display a blunted proliferative response to such cytokines and other inducers of chronic proliferation including genotoxic and inflammatory stress and aging, protecting them from chronic stress and exhaustion. Thus, targeting Id1 may be therapeutically useful for improving HSC survival and function during BMT, chronic stress, and aging.

Graphical abstract

Teaser

Singh et al. show that Id1 is an important mediator of stress hematopoiesis. They found that Id1 deletion protects HSCs from exhaustion in multiple paradigms of chronic and physiologically relevant stress and promotes their quiescence, suggesting that targeting Id1 may improve HSC survival and function during chronic stress and aging.


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Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity

Publication date: Available online 28 June 2018
Source:Cell Stem Cell
Author(s): Ye Li, David L. Hermanson, Branden S. Moriarity, Dan S. Kaufman
Chimeric antigen receptors (CARs) significantly enhance the anti-tumor activity of immune effector cells. Although most studies have evaluated CAR expression in T cells, here we evaluate different CAR constructs that improve natural killer (NK) cell-mediated killing. We identified a CAR containing the transmembrane domain of NKG2D, the 2B4 co-stimulatory domain, and the CD3ζ signaling domain to mediate strong antigen-specific NK cell signaling. NK cells derived from human iPSCs that express this CAR (NK-CAR-iPSC-NK cells) have a typical NK cell phenotype and demonstrate improved anti-tumor activity compared with T-CAR-expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR-expressing cells. In an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared with PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells. Additionally, NK-CAR-iPSC-NK cells demonstrate in vivo activity similar to that of T-CAR-expressing T cells, although with less toxicity. These NK-CAR-iPSC-NK cells now provide standardized, targeted "off-the-shelf" lymphocytes for anti-cancer immunotherapy.

Graphical abstract

Teaser

Natural killer (NK) cells are a key part of the immune system's ability to mediate anti-cancer activity. Li et al. utilize human iPSCs to produce NK cells with novel chimeric antigen receptors that specifically target cancer cells in an antigen-specific manner to improve survival in an ovarian cancer xenograft model.


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Altering Chemotherapy Improves Outcomes in Early-Stage Pancreatic Cancer

Results from two clinical trials are expected to improve the outlook for some people with early-stage pancreatic cancer. Altering the chemotherapy drugs used and the timing of treatment substantially improved survival.

https://ift.tt/2KvX1yH

Abdominal pain leading to incidental finding of polyarteritis nodosa

Description 

A 51-year-old man with new-onset hypertension presented with mild epigastric pain that started 3 days ago. The pain was associated with emesis, subjective fevers and diaphoresis. He denied haematemesis, haematochezia, melena, fatigue, night sweats, abnormal bowel movements, weight change, skin changes or neuropathy.

His vitals were significant for heart rate of 120 bpm. He appeared pale with peripheral cyanosis. Abdomen was diffusely tender with normal bowel sounds. There was no rebound tenderness. Complete blood count, comprehensive metabolic panel, amylase and lipase levels were normal. CT of the abdomen demonstrated an abdominal haematoma centred ventral to the third portion of the duodenum and bilateral renal wedge-shaped infarcts (figures 1–3). Abdominal angiogram showed irregular pancreaticoduodenal arcade with microaneurysms originating from a branch of the proximal superior mesenteric artery (figure 4). The rupture of one of the microaneurysms was presumed to be the...

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Tip of the iceberg: congenital cataract with pre-existing posterior capsule defect (PPCD): how vital is the role of ultrasound biomicroscopy?

Description

A 14-month-old female child presented to the outpatient clinic with abnormal white reflex of the left eye (LE) noticed by parents for the last 6 months. The right eye (RE) had similar history and was operated for a white cataract at an outside hospital 3 months before. Intraoperatively, pre-existing posterior capsule defect (PPCD) was noted in the RE with inadvertent lens matter drop, which occurred after hydrodissection and was removed subsequently. The PPCD was quite large and the RE had to be left aphakic. Anterior segment examination of the LE with fully dilated pupil showed total cataractous lens with invisible posterior capsular details (figure 1A). Ultrasound biomicroscopy (UBM) of the LE showed a large posterior capsular defect with subluxation of the lens into the vitreous cavity1 beyond the capsule (figure 1B). Care was taken to avoid lens drop during irrigation–aspiration. Viscoat can be used to coat the area of the PPCD to temporarily seal the defect....

https://ift.tt/2Mqa3uI

Rare case of Gordon Holmes syndrome

Young-onset cerebellar syndromes are quite interesting and challenging for treating clinicians. While dealing with such cases, a clinician should be aware of rare possible causes too. We report a rare case of Gordon Holmes syndrome—an autosomal recessive cerebellar ataxia with endocrinal abnormalities.

https://ift.tt/2KuclvD

Cavum vergae and psychiatric illness: substantive or serendipity?

Description

A 38-year-old woman presented with 1-month history of restlessness, decreased sleep, religious song auditory hallucination and delusion of persecution and reference. She had no insight into her illness. She was not on any long-term medications. There was no history of head trauma or exposure to toxins. She suffered from postpartum psychosis during both her pregnancies (8 and 11 years ago) which warranted inpatient treatment with antipsychotics and mood stabilisers. She defaulted treatment both times once she got better and did not experience any recurrence of symptoms until current episode. She had no other comorbidities or significant family history. Her general medical and neurological examination findings were within normal limits. Routine laboratory tests did not reveal any abnormality. A brain MRI diffusion weighted imaging sequence demonstrated cavum vergae (CV, figure 1A) and MRI brain apparent diffusion coefficient sequence showing CV and thinned out cavum septum pellucidum (CSP, figure 1B). She was initially...

https://ift.tt/2KxglYU

'A snake and a crescent moon in a coronary angiogram

Description 

A  coronary artery fistula   (CA F) is a direct connection between a coronary artery and any one of the cardiac chambers, the coronary sinus or superior vena cava, or a pulmonary artery or pulmonary vein close to the heart. CAF accounts for 48.7% of all congenital coronary anomalies.1 The most common drainage sites in a decreasing frequency are the right ventricle (41%), right atrium (26%), pulmonary artery (17%), coronary sinus (7%), left atrium (5%), left ventricle (3%) and superior vena cava (1%).2 Further occurrence of this CAF along with the presence of aortic sinus to pulmonary artery fistula is very rare.

We present a case of a 53-year-old, hypertensive man who had presented with a first episode of chest pain of 8 hours' duration. At presentation in the emergency department, his heart rate was 90/min and blood pressure measured 158/85 mm Hg. His cardiac and chest examinations were...

https://ift.tt/2KqSzRD

Acute subclavian artery occlusion with associated clavicle fracture managed with bypass graft alone

Subclavian artery injury is a rare consequence of clavicle fracture. It most often results from penetrating trauma but can result from blunt trauma with adjacent bone fragments causing rupture, pseudoaneurysm, dissection or thrombosis of the artery. If flow through the subclavian artery is compromised there is a risk of ipsilateral upper limb ischaemia. Life-threatening haemorrhage may result in cases of laceration, and cerebral infarction may result from dissection. Vascular injury in association with clavicle fracture is typically regarded as an indication for internal fixation of the fracture. We present a case of subclavian artery thrombosis in association with a comminuted midshaft clavicle fracture causing limb ischaemia managed by carotid to brachial artery bypass without internal fracture fixation. The fracture united at 4 weeks and there was no sustained vascular or neurological impairment at follow-up. We advocate urgent vascular intervention in subclavian artery injury. There is little discussion in the literature regarding non-operative management of clavicle fractures with subclavian artery injury. We suggest that select clavicle fractures with subclavian artery injury can be safely managed non-operatively.

https://ift.tt/2KuYUbu

A case of oligodendroglioma and multiple sclerosis: Occams razor or Hickams dictum?

Tumefactive appearing lesions on brain imaging can cause a diagnostic dilemma. We report a middle-aged man who presented with right-sided optic neuritis. A brain MRI showed enhancement of the right optic nerve, and non-enhancing white matter lesions including a 3 cm right frontal lesion with adjacent gyral expansion. Cerebrospinal fluid analysis showed five oligoclonal bands not present in serum. Glatiramer acetate was started for suspected tumefactive multiple sclerosis (MS). A follow-up brain MRI 6 months later showed persistence of the frontal gyral expansion. A brain biopsy led to the diagnosis of an oligodendroglioma, isocitrate dehydrogenase-mutant and 1 p/19q co-deleted (WHO grade II), managed with surgical resection and radiotherapy. Postoperative brain MRI showed a new enhancing periventricular lesion, making the choice of optimal disease-modifying therapy for MS challenging. This case highlights the possibility of coexistence of MS and oligodendroglioma, and emphasises the importance of a tissue diagnosis when atypical MS imaging features are present.

https://ift.tt/2KeWZM5

Early onset necrotising enterocolitis in association with congenital diaphragmatic hernia in a term baby

We report a case of a male, term newborn with known left congenital diaphragmatic hernia (CDH) who presented with circulatory compromise requiring maximal inotropic support in the first 24 hours of life. Repeat X-ray at 24 hours showed pneumatosis intestinalis. Emergency laparotomy was performed for suspected necrotising enterocolitis. The terminal ileum to the sigmoid colon were frankly necrotic with multiple perforations. Subtotal colectomy was performed. Although the recovery was protracted, the baby had a favourable outcome with progressive weight gain on follow-up at 3, 6 and 9 months of age.

This case of CDH had a postnatal systemic instability that was more severe than predicted, and as well as assessing for persistent pulmonary hypertension of newborn should trigger immediate suspicion for other organ involvement.

https://ift.tt/2Mx9gbo

Orbital blowout fracture from nose blowing

Orbital blowout fractures are nearly always caused by acute trauma. Non-traumatic cases of orbital blowout fractures have only been rarely described. In this case study, we discuss an orbital blowout fracture directly caused by nose blowing. The patient developed unilateral eye swelling and orbital emphysema. It is important for the clinician to investigate all suspected orbital blowout fractures with imaging and full ophthalmological examination regardless of a trauma history. Most cases of orbital emphysema resolve spontaneously, however one must always exclude compression of the central retinal artery. This may present as acute loss of vision and/or ophthalmoplegia.

https://ift.tt/2Ki9Opd

Post-transplant erythrocytosis refractory to ACE inhibitors and angiotensin receptor blockers

Post-transplant erythrocytosis (PTE) is a condition with elevated haematocrit (hct) in renal allograft recipients. The mainstay of treatment is ACE inhibitors (ACEi) or angiotensin II receptor blockers (ARB), but seldom phlebotomy. PTE must be recognised early to prevent major thromboembolic events. We present a case of PTE that was refractory to blockade of renin–angiotensin system (RAS) by ACEi and ARB and required phlebotomy for control of hct. Our review of medical literature about prevalence and pathophysiology of PTE suggests that approximately 22% of patients with PTE are refractory to ACEi/ARB treatment. There are four plausible pathways that appear to play a role in causing PTE: disruption of erythropoietin regulation, mitogenic effect of the RAS on erythroid lineage, insulin-like growth factor 1 and androgenic stimulation. Presently, there is no unifying hypothesis involving these factors, but refractoriness to ACEi/ARB may represent a distinct subcategory of PTE.

https://ift.tt/2KrmF4s

Acute COPD exacerbation presenting with pronounced intrabullous haemorrhage and haemoptysis

A 54-year-old man with history of chronic obstructive pulmonary disease (COPD) presented with subacute onset of chest pain, shortness of breath, productive cough with haemoptysis and night sweats. There were no fever or recent weight loss reported. The chest radiograph showed right upper lobe bullae with adjacent opacification and an emphysematous lung. Due to worsening haemoptysis and persistent chest pain, CT of the chest with contrast was performed, which revealed moderate to severe emphysema and numerous blood-filled bullae. Cardiac work-up for chest pain was negative for myocardial ischaemia and for aortic dissection. Further infectious work-ups for mycobacterial and invasive fungal infection were negative. The patient was treated for acute COPD exacerbation and responded well to the antibiotics with the resolution of haemoptysis. Follow-up CT of the chest revealed the gradual resolution of the haemorrhage, while the patient remained asymptomatic.

https://ift.tt/2Ke6jjm

Large cell neuroendocrine carcinoma and adenocarcinoma of gallbladder with concomitant hepatitis C infection

Neuroendocrinetumour (NET) of the gallbladder is an extremely rare tumour and with coexisting adenocarcinoma an even rarer occurrence. Mixed NETs have the tendency to invade the lymph nodes and the hepatic tissue from their high malignant potential, leading to poor prognosis. Survival rates of the patients with mixed NET can be improved with wide excision, adjuvant chemotherapy and radiation. We present a case of 62-year-old woman with history of hepatitis C infection, a risk factor for both hepatic and extrahepatic gastrointestinal malignancies. Patient underwent exploratory laparotomy with resection of the gallbladder and partial hepatectomy. Pathology showed high-grade larger cell neuroendocrine carcinoma 5x4x3 cm along with two separate lesions found out to be adenocarcinomas. In our patient, hepatitis C infection can be an inciting factor for the development of these carcinomas. We will discuss the presentation, treatment modalities and outcomes with this kind of coexisting tumours.

https://ift.tt/2MuSVnF

Acute liver failure due to liver parenchymal infiltration with acute myelogenous leukaemia in a patient with myelodysplastic syndrome

Liver involvement by acute leukaemia is rare and has a high mortality rate despite treatment. We report a case of a 66-year-old woman undergoing treatment for myelodysplastic syndrome with Vidaza (azacitidine) who presented with abnormal liver function tests. Despite negative serologic testing and unremarkable abdominal MRI, she continued to have significant elevation in bilirubin and international normalised ratio and worsening mental status. Liver biopsy was obtained and consistent with acute myelogenous leukaemia. The patient had rapid demise due to acute liver failure and was unable to undergo treatment.

https://ift.tt/2Kg0fHe

Regressive pyridoxine-induced sensory neuronopathy in a patient with homocystinuria

Pyridoxine (vitamin B6) is an essential vitamin playing a crucial role in amino acid metabolism. Pyridoxine is used for isoniazid side-effects prevention, pyridoxine-dependent epilepsy treatment and cystathionine beta-synthase deficiency (homocystinuria) treatment. However, vitamin B6 hypervitaminosis is neurotoxic and may provoke a progressive sensory neuronopathy (sensory ganglionopathy), usually when daily uptake is above 50 mg. We describe the case of a 30-year-old patient with homocystinuria who was treated with pyridoxine 1250–1750 mg/day for 20 years and developed progressive sensory neuropathy with ataxia and impaired sensation in the extremities. Electrodiagnostic testing demonstrated non-length-dependent abnormalities of sensory nerve potentials, and sensory ganglionopathy was diagnosed. Pyridoxine dosage was reduced to 500 mg/day, resulting in the disappearance of sensory symptoms and ataxia, and the normalisation of sensory nerve potentials. Our case indicates that pyridoxine-induced sensory ganglionopathy may be reversible, even after prolonged ingestion of high doses of vitamin B6 for more than 20 years.

https://ift.tt/2Kuw0sj

Disseminated histoplasmosis mimicking relapsed chronic lymphocytic leukaemia

Histoplasma microconidia when inhaled are presented in antigenic form to T cells, limiting the extent of infection; however, defects in cellular immunity results in disseminated disease. Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder resulting in functionally impaired lymphocytes, predisposing patients to various opportunistic infections. The author reports a recently treated patient with CLL presenting with constitutional symptoms accompanied by hepatosplenomegaly and diffuse adenopathy. Considering the recent diagnosis and treatment of CLL, initial suspicion was relapsed disease. However, considering the immune deficiency associated with CLL and its treatment, infectious aetiologies were strongly considered. Further investigation revealed a case of disseminated histoplasmosis mimicking CLL in this reported patient. Considering appropriate diagnosis and timely therapy, the reported patient had good prognosis despite being diagnosed with disseminated histoplasmosis. This case highlights consideration of disseminated histoplasmosis in patients presenting with diffuse adenopathy along with hepatomegaly and/or splenomegaly in the right clinical setting.

https://ift.tt/2KvJS8G

Breast cancer metastasis to the bladder: a literature review

Given the prevalence of breast cancer and the mortality associated with metastatic disease, it is imperative for physicians to not only be aware of common sites but also of rare metastatic destinations such as the bladder. A postmenopausal woman with a medical history of stage 2 invasive ductal carcinoma, oestrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 negative, in remission for 9 years, presented to her primary care physician with concerns of increased urinary urgency, frequency and incontinence. The patient underwent cystoscopy with biopsy of an area of granulation tissue. Biopsy revealed adenocarcinoma consistent with breast primary. The common sites of metastases from breast cancer are lung, bone and liver. This case is unique where breast cancer was found to metastasise to the bladder. It is important for physicians to consider further investigation when a breast cancer survivor develops urinary symptoms even without haematuria.

https://ift.tt/2MuekNP

Untreated Congenital Hypothyroidism Mimicking Hirschsprung Disease: A Puzzling Case in a One-Year-Old Child

Congenital hypothyroidism is a clinical emergency due to its potential risk of mental retardation. Constipation might be present in hypothyroid children. However, Hirschsprung disease is rarely associated with congenital hypothyroidism. Herein, a case of congenital hypothyroidism in a one-year-old child mimicking Hirschsprung disease is described. Adequate treatment with levothyroxine sodium tablets controlled intestinal dysmotility that mimicked congenital intestinal aganglionosis due to the critical influence of thyroid hormones on bowel motility.

https://ift.tt/2tKO2iz

Preclinical models for precision oncology

Publication date: Available online 28 June 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Maider Ibarrola-Villava, Andrés Cervantes, Alberto Bardelli
Precision medicine approaches have revolutionized oncology. Personalized treatments require not only identification of the driving molecular alterations, but also development of targeted therapies and diagnostic tests to identify the appropriate patient populations for clinical trials and subsequent therapeutic implementation. Preclinical in vitro and in vivo models are widely used to predict efficacy of newly developed treatments. Here we discuss whether, and to what extent, preclinical models including cell lines, organoids and tumorgrafts recapitulate key features of human tumors. The potential of preclinical models to anticipate treatment efficacy and clinical benefit is also presented, using examples in different tumor types.



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Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

Publication date: Available online 28 June 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Linchong Sun, Caixia Suo, Shi-ting Li, Huafeng Zhang, Ping Gao
While metabolic reprogramming of cancer cells has long been considered from the standpoint of how and why cancer cells preferentially utilize glucose via aerobic glycolysis, the so-called Warburg Effect, the progress in the following areas during the past several years has substantially advanced our understanding of the rewired metabolic network in cancer cells that is intertwined with oncogenic signaling. First, in addition to the major nutrient substrates glucose and glutamine, cancer cells have been discovered to utilize a variety of unconventional nutrient sources for survival. Second, the deregulated biomass synthesis is intertwined with cell cycle progression to coordinate the accelerated progression of cancer cells. Third, the reciprocal regulation of cancer cell's metabolic alterations and the microenvironment, involving extensive host immune cells and microbiota, have come into view as critical mechanisms to regulate cancer progression. These and other advances are shaping the current and future paradigm of cancer metabolism.



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Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Publication date: Available online 28 June 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Danielle J. Sanchez, M. Celeste Simon
Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.



https://ift.tt/2N7irka

Surgical treatment of mucocele of the appendix: a systematic review and case report

Abstract

Introduction

Appendicular mucocele is a rare well-described clinico-pathological occurrence. It denotes an obstructive dilatation of the appendicular lumen by mucinous secretions.

Case report

A 60-year-old patient presented with right lower abdominal pain and nausea for 2 years. Abdominal CT scan suggested a diagnosis of a appendicular mucocele. Following informed consent, surgical exploration revealed a cystic mass arising from the body of the appendix with inflamed walls with no evidence of perforation. Simple appendectomy was performed as the caecum and the mesenteric nodes were free of pathological involvement. The final diagnosis of mucinous cystadenoma was confirmed by histopathology. Postoperative course was uneventful. The patient was in good health during a four years regular follow-up.

Discussion

Appendicular mucocele is a rare disease with vague symptoms. Abdominal imaging is an important diagnostic tool, but histopathology is the standard for definitive diagnosis. Surgery for benign appendicular mucoceles has an excellent long-term prognosis.

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Outcomes of early-stage breast cancer patients treated with sequential anthracyclines–taxanes in relationship to relative dosing intensity: a secondary analysis of a randomized controlled trial

Abstract

Purpose

To assess the impact of relative dosing intensity (RDI) on the outcomes of breast cancer patients referred for adjuvant anthracycline–taxane chemotherapy.

Methods

This is a secondary analysis of the outcomes of patients in the comparator arm of the BCIRG005 study who received adjuvant adriamycin/cyclophosphamide (AC)–docetaxel regimen. Overall survival was assessed according to RDI through Kaplan–Meier analysis. Univariate and multivariate analyses of parameters affecting overall survival were then conducted through Cox regression analysis.

Results

Kaplan–Meier analysis of overall survival according to RDI for the AC–docetaxel regimen (< 90 vs. ≥ 90%) was conducted and it showed that RDI < 90% is associated with worse overall survival (P = 0.006). In univariate Cox regression analysis, the following parameters significantly affected overall survival (P < 0.05): age, T stage, lymph node ratio, hormone receptor status, and grade of the disease and RDI for AC–docetaxel regimen. When these factors were included in multivariate analysis, the following factors were associated with worse overall survival: age less than 40 years (P < 0.0001), greater T stage (P < 0.0001), greater lymph node ratio (P < 0.0001), negative hormone receptor status (P = 0.001), high grade (P < 0.0001) and RDI ≤ 90% (P = 0.015). Formal interaction testing between RDI and hormone receptor status has a non-significant P value (P = 0.794).

Conclusion

Lower RDI for the whole anthracycline–taxane protocol is associated with worse patient survival. Every effort should be exercised to avoid unnecessary dose reductions and/or interruptions among early breast cancer patients receiving adjuvant anthracycline–taxane chemotherapy.

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iTRAQ-based proteomic analysis of DMH-induced colorectal cancer in mice reveals the expressions of β-catenin, decorin, septin-7, and S100A10 expression in 53 cases of human hereditary polyposis colorectal cancer

Abstract

Purpose

The aim of this study is to explore the roles of β-catenin, decorin, septin-7, and S100A10 expression in colorectal cancer development.

Methods

Twenty-five BALB/c mice were divided into five groups; four groups were administrated N,N-dimethylhydrazine for 0, 10, 15, and 20 weeks, and one group was administrated normal saline for 20 weeks. The colons were collected for histopathological analysis. Protein samples prepared from the frozen colon tissues of mice treated with N,N-dimethylhydrazine for the different time points were evaluated using the isobaric tags for relative and absolute quantification (iTRAQ) labeling technique coupled with the 2D liquid chromatography–tandem mass spectrometry analysis. Based on the proteomic analysis results, immunohistochemical staining of β-catenin, decorin, septin-7, and S100A10 was performed in paraffin-embedded mice colorectal tissue, and 53 cases of human hereditary polyposis colorectal cancer samples.

Results

Colorectal cancer was observed in mice treated with N,N-dimethylhydrazine for 20 weeks, and adenomas were observed in mice subjected to the 10-, and 15-week treatments. Seventy-two differentially expressed proteins were involved in the development of cancer as per the iTRAQ and spectrometry analysis. In normal epithelium, adenoma, and cancer from human hereditary polyposis colorectal cancer, S100A10 expression (c2 = 100.989, P = 0.000) was highest in cancer, whereas decorin (c2 = 12.852, P = 0.002) and septin-7 (c2 = 66.519, P = 0.002) expressions were highest in the normal epithelium, which was confirmed via immunohistochemical staining.

Conclusions

The subcellular localization of β-catenin and decorin, septin-7, and S100A10 expressions are associated with the development of colorectal cancer in mice after N,N-dimethylhydrazine treatment and in human hereditary polyposis colorectal cancers.

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A randomized, double-blind, phase 2 study of ruxolitinib or placebo in combination with capecitabine in patients with advanced HER2-negative breast cancer and elevated C-reactive protein, a marker of systemic inflammation

Abstract

Purpose

The Janus-associated kinase (JAK)/signal transducer and activator of transcription pathway is a key regulator of inflammatory signaling, associated with tumorigenesis, cell survival, and progression. This randomized phase 2 trial evaluated the efficacy and safety of the addition of ruxolitinib, a JAK1/JAK2 inhibitor, to capecitabine in patients with HER2-negative advanced breast cancer and high systemic inflammation (modified Glasgow Prognostic Score [mGPS] ≥ 1).

Methods

Patients with ≤ 2 prior chemotherapy regimens for advanced or metastatic disease or hormone receptor-positive patients with disease progression on prior hormonal therapies were randomized 1:1 to 21-day cycles of ruxolitinib (n = 76) or placebo (n = 73) plus capecitabine. The primary endpoint was overall survival (OS).

Results

Baseline characteristics were well balanced between groups. For ruxolitinib plus capecitabine versus placebo plus capecitabine, median OS was 11.2 months versus 10.9 months (log-rank test P = 0.762); median progression-free survival (PFS) was 4.5 months versus 2.5 months (log-rank test P = 0.151); and overall response rate (ORR) was 28.9% versus 13.7% (Cochran–Mantel–Haenszel test P = 0.024), respectively. A more favorable change in health-related quality of life (HRQoL) was observed with ruxolitinib plus capecitabine versus placebo plus capecitabine. Both regimens were generally tolerable. A higher incidence of grade 3/4 anemia (25.4% vs 5.6%) and a lower incidence of grade 3/4 palmar–plantar erythrodysesthesia (1.4% vs 12.7%) occurred with ruxolitinib plus capecitabine versus placebo plus capecitabine.

Conclusions

The addition of ruxolitinib to capecitabine for patients with advanced breast cancer and high systemic inflammation was generally tolerable; ORR was numerically greater, a more favorable change in HRQoL was observed, but neither OS nor PFS was improved compared with placebo plus capecitabine.

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Response rates and pathologic complete response by breast cancer molecular subtype following neoadjuvant chemotherapy

Abstract

Purpose

This is the largest study to date evaluating response rates and pathologic complete response (pCR) and predictors thereof, based on molecular subtype, in women with breast cancer having undergone neoadjuvant chemotherapy (NC).

Methods

The National Cancer Database was queried for women with cT1-4N1-3M0 breast cancer having received NC. Patients were divided into four subtypes: luminal A, luminal B, Her2, or triple negative (TN). Multivariable logistic regression ascertained factors associated with developing pCR. Kaplan–Meier analysis evaluated overall survival (OS) between patients by degree of response to NC when stratifying patients by subtype.

Results

Of a total of 13,939 women, 322 (2%) were luminal A, 5941 (43%) luminal B, 2274 (16%) Her2, and 5402 (39%) TN. Overall, 19% of all patients achieved pCR, the lowest in luminal A (0.3%) and the highest in Her2 (38.7%). Molecular subtype was an independent predictor of both pCR and OS in this population. Clinical downstaging was associated with improved survival, mostly in women with luminal B, Her2, and TN subtypes. Subgroup analysis of the pCR population demonstrated 5-year OS in the luminal B, Her2, and TN cohorts of 93.0, 94.2, and 90.6%, respectively (Her2 vs. TN, p = 0.016).

Conclusions

Assessing nearly 14,000 women from a contemporary United States database, this is the largest known study examining the relationship between response to NC and molecular subtype. Women with luminal A disease are the least likely to undergo pCR, with the highest rates in Her2 disease. Degree of response is associated with OS, especially in luminal B, Her2, and TN patients. Despite the comparatively higher likelihood of achieving pCR in TN cases, this subgroup may still experience a survival detriment, which has implications for an ongoing national randomized trial.

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Physician peer group characteristics and timeliness of breast cancer surgery

Abstract

Purpose

Little is known about how the structure of interdisciplinary groups of physicians affects the timeliness of breast cancer surgery their patients receive. We used social network methods to examine variation in surgical delay across physician peer groups and the association of this delay with group characteristics.

Methods

We used linked Surveillance, Epidemiology, and End Results-Medicare data to construct physician peer groups based on shared breast cancer patients. We used hierarchical generalized linear models to examine the association of three group characteristics, patient racial composition, provider density (the ratio of potential vs. actual connections between physicians), and provider transitivity (clustering of providers within groups), with delayed surgery.

Results

The study sample included 8338 women with breast cancer in 157 physician peer groups. Surgical delay varied widely across physician peer groups (interquartile range 28.2–50.0%). For every 10% increase in the percentage of black patients in a peer group, there was a 41% increase in the odds of delayed surgery for women in that peer group regardless of a patient's own race [odds ratio (OR) 1.41, 95% confidence interval (CI) 1.15–1.73]. Women in physician peer groups with the highest provider density were less likely to receive delayed surgery than those in physician peer groups with the lowest provider density (OR 0.65, 95% CI 0.44–0.98). We did not find an association between provider transitivity and delayed surgery.

Conclusions

The likelihood of surgical delay varied substantially across physician peer groups and was associated with provider density and patient racial composition.

https://ift.tt/2tD3gXN

Association of reproductive history with breast tissue characteristics and receptor status in the normal breast

Abstract

Introduction

Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma).

Materials and methods

Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI.

Results

Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial–stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among postmenopausal women. Prior use of oral contraceptives was associated with lower epithelial–stromal ratio amongst all participants and among pre- and postmenopausal women separately.

Conclusion

Reproductive risk factors significantly influence the epithelial tissue compartment and expression of hormone receptors in later life. These changes remain after menopause. This study provides deeper insights of the biological mechanisms by which reproductive history influences epithelial area and expression of hormone receptors, and as a consequence the risk of breast cancer.

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Bilateral mastectomies: can a co-surgeon technique offer improvements over the single-surgeon method?

Abstract

Purpose

Bilateral mastectomy (BM) is traditionally performed using a single-surgeon (SS) technique (SST); a co-surgeon (CS) technique (CST), where each attending surgeon concurrently performs a unilateral mastectomy, offers an alternative approach. We sought to compare the CST and SST for BM with respect to operative times and complications.

Methods

Patients undergoing BM without reconstruction at our institution between 2005 and 2015 were identified using operative caselogs and stratified into CS- and SS-cohorts. Operative time (OT; incision to closure) was calculated. Patient age, cancer presence/stage, hormone receptor/BRCA status, breast weight, axillary procedure, and 30-day complications were extracted. Differences in OT, complications, and demographics between cohorts were assessed with t tests and Chi-square tests. A multivariate linear regression model was fit to identify factors independently associated with OT.

Results

Overall, 109 BM cases were identified (CS, n = 58 [53.2%]; SS, n = 51 [46.8%]). Average duration was significantly shorter for the CST by 33 min (21.6% reduction; CS: 120 min vs. SS: 153 min, p < 0.001), with no difference in complication rates (p = 0.65). Demographic characteristics did not differ between cohorts except for total breast weight (TBW) (CS: 1878 g vs. SS: 1452 g, p < 0.05). Adjusting for TBW, CST resulted in a 27.8% reduction in OT (44-min savings, p < 0.001) compared to SST.

Conclusions

The CST significantly reduces OT for BM procedures compared to the SST without increasing complication rates. While time-savings was < 50% and may not be ideal for every patient, the CST offers an alternative BM approach potentially best-suited for large TBW patients and those undergoing axillary procedures.

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Clinical and biological roles of Kelch-like family member 7 in breast cancer: a marker of poor prognosis

Abstract

Background

The functions of many proteins are tightly regulated with a complex array of cellular functions including ubiquitination. In cancer cells, aberrant ubiquitination may promote the activity of oncogenic pathways with subsequent tumour progression. Kelch-like family member 7 (KLHL7) is involved in the regulation of ubiquitination and may play a role in breast cancer (BC). Present study aims to evaluate the biological and clinical usefulness of KLHL7 in BC utilising large well-characterised cohorts with long-term follow-up.

Methods

The relationships between KLHL7 gene copy number alteration (CNA) and mRNA expression and clinicopathological variables and clinical outcomes were evaluated in 1980 patients from the METABRIC BC cohort. Prognostic significance of KLHL7 mRNA was validated using the Breast Cancer Gene-Expression Miner v4.0 datasets (n = 5206). KLHL7 protein expression was assessed using immunohistochemistry in a large annotated series of early-stage BC (n = 917) with long-term follow-up.

Results

KLHL7 CNA was significantly correlated with its mRNA expression. KLHL7 mRNA expression was higher in luminal B and basal-like molecular subtypes and in higher grade tumours. Increased KLHL7 protein expression was significantly correlated with features of aggressive phenotype including lymphovascular invasion, high histological grade, hormonal receptor negativity, high PIK3CA and p53 expression. Outcome analysis showed that high KLHL7 expression is an independent predictor of shorter survival (p = 0.0011).

Conclusions

KLHL7 appears to play an important role in BC progression. High KLHL7 protein expression identified a subgroup of BC with aggressive behaviour and provided independent prognostic information.

https://ift.tt/2Ks0yKW

Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2

Abstract

Purpose

Evaluate patient-reported outcomes (PROs) for postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer treated with first-line ribociclib plus letrozole.

Methods

In the phase III MONALEESA-2 study (NCT01958021), 668 patients were randomized 1:1 to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole. PROs were assessed using the European Organisation for Research and Treatment of Cancer core quality-of-life (EORTC QLQ-C30) and breast cancer-specific (EORTC QLQ-BR23) questionnaires. Changes from baseline and time to deterioration in health-related quality of life (HRQoL) were analyzed using linear mixed-effect and stratified Cox regression models, respectively. Exploratory analysis of area-under-the-curve for change from baseline in pain score (AUC-pain) was performed.

Results

On-treatment HRQoL scores were consistently maintained from baseline and were similar between arms. A clinically meaningful (> 5 points) reduction in pain score was observed as early as Week 8 and was maintained up to Cycle 15 in the ribociclib arm. A statistically significant increase in mean AUC-pain was also observed in the ribociclib arm. Scores for all other EORTC QLQ-C30 and EORTC QLQ-BR23 domains were maintained from baseline and were similar between arms.

Conclusions

HRQoL was consistently maintained from baseline in postmenopausal women with HR+, HER2− advanced breast cancer receiving ribociclib plus letrozole and was similar to that observed in the placebo plus letrozole arm. Together with the improved clinical efficacy and manageable safety profile, these PRO results provide additional support for the benefit of ribociclib plus letrozole in this patient population.

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MCP-1 is overexpressed in triple-negative breast cancers and drives cancer invasiveness and metastasis

Abstract

Background

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer that lacks ER/PR and HER2 receptors. Hence, there is urgency in developing new or novel therapeutic strategies for treatment of TNBC. Our study shows that the Monocyte Chemoattractant Protein-1 (MCP-1) is a marker associated with TNBC and may play a key role in TNBC disease progression.

Experimental design

ELISA method was used to measure secreted MCP-1, and mRNA levels were determined by Real-time PCR in numerous cancer cell lines, representing various breast cancer subtypes. Cellular invasiveness was determined by Boyden chamber assay.

Results

Our data show that MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in secreted protein levels compared to ER-positive luminal cell line, MCF-7. Breast cancer patients, with Basal or Claudin-low subtypes, also showed high expression of MCP-1. MCP-1 treatment induced cell invasion in various breast cancer cell types, without affecting cell proliferation. Small molecule antagonists against Chemokine Receptor 2 (CCR2), cognate receptor for MCP-1 as well as the MAP kinase pathway inhibitor U0126 negatively affected MCP-1 induced MCF-7 cell invasion. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP Kinase pathway. Knocking down MCP-1 decreased cell invasion in TNBC cell line BT-549, along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin.

Conclusion

Our study suggests that MCP-1 mediated pathways could be potential therapeutic targets for the treatment of TNBC, and could reduce cancer health disparities.

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Pre-diagnostic changes in body mass index and mortality among breast cancer patients

Abstract

Purpose

We investigated whether changes in body mass index (BMI) before a breast cancer diagnosis affected mortality and whether trajectories more accurately predict overall mortality compared to a single measure of BMI.

Methods

Our prospective cohort comprised 2012 women with breast cancer who reported their weight in each decade from 20 to 50–64 years of age. We used trajectory analysis to identify groups with similar development patterns in BMI and Cox proportional hazards models to examine the association between trajectory groups and mortality, and interactions with oestrogen receptor status and smoking. We used c-index statistics to compare the trajectory model with the single measure model of BMI.

Results

We identified three distinct trajectory groups, with a mean BMI at age 20 of 19, 22 and 24 increasing to 23 (normal-to-normal), 29 (normal-to-overweight) and 37 (normal-to-obese) at 50–64 years of age, respectively. Women in the normal-to-obese trajectory group experienced significantly higher overall mortality than those in the normal-to-normal trajectory group (HR 1.76, 95% CI 1.21‒2.56). The association declined to a non-significant level after adjustments for clinical prognostic factors. Although not significant, the same tendency was seen for breast cancer-specific mortality. The association was strongest in women with oestrogen receptor-negative tumours. Weight changes over time were not significantly different from a single BMI measure before diagnosis to predict survival.

Conclusion

Weight gain affects overall mortality after breast cancer but clinical prognostic factors largely eliminate the association. Using trajectories of weight changes did not improve the predictive value compared to a single measure of BMI.

https://ift.tt/2IyWUNH

Uptake of breast cancer preventive therapy in the UK: results from a multicentre prospective survey and qualitative interviews

Abstract

Purpose

Uptake of preventive therapy for women at increased breast cancer risk in England is unknown following the introduction of UK clinical guidelines in 2013. Preventive therapy could create socioeconomic inequalities in cancer incidence if it is more readily accepted by particular socio-demographic groups. In this multicentre study, we investigated uptake of tamoxifen and evaluated socio-demographic and clinical factors associated with initiation. We explored women's experiences of treatment decision-making using qualitative interview data.

Methods

Between September 2015 and December 2016, women (n = 732) attending an appointment at one of 20 centres in England to discuss breast cancer risk were approached to complete a survey containing socio-demographic details and nulliparity. Of the baseline survey respondents (n = 408/732, 55.7% response rate), self-reported uptake of tamoxifen at 3-month follow-up was reported in 258 (63.2%). Sixteen women participated in semi-structured interviews.

Results

One in seven (38/258 = 14.7%) women initiated tamoxifen. Women who had children were more likely to report use of tamoxifen than those without children (OR = 5.26; 95%CI: 1.13–24.49, p = 0.035). Interview data suggested that women weigh up risks and benefits of tamoxifen within the context of familial commitments, with exposure to significant other's beliefs and experiences of cancer and medication a basis for their decision.

Conclusions

Uptake of tamoxifen is low in clinical practice. There were no socio-demographic differences in uptake, suggesting that the introduction of breast cancer preventive therapy is unlikely to create socioeconomic inequalities in cancer incidence. Women's decision-making was influenced by familial priorities, particularly having children.

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Impact of port site scar on perception of patients with breast cancer: patient-reported outcomes

Abstract

Purpose

As the number of survivors continues to increase with improvements in breast cancer treatment, greater emphasis has been placed on the aesthetic outcome following breast surgery. Effort is made to minimize scarring on the breast, yet patients who require a port for treatment inevitably have a scar on the upper chest from the port itself. We hypothesized that patients with breast cancer are conscious of their port scars, and if given a choice would prefer placement of the port in the arm rather than the chest.

Methods

Female breast cancer patients treated at our Breast Center who had a port placed from 2009 to 2015 were asked to complete a 20-question, anonymous survey via SurveyMonkey® reporting demographics and treatment information, and a validated Patient Scar Assessment Questionnaire (PSAQ).

Results

Of 139 identified, 105 had email information available for contact, and 67 (64%) patients responded. Of the 67, 37 (55%) had undergone arm placement and 30 (45%), chest. Sixty (92%) patients report noticing their scars; 44 (69%) believed that their scar was noticeable to others; and 22 of the 44 (50%) made an effort to hide their scar. Thirty-seven patients were offered options for port site placement, and 24 (65%) chose placement in the arm (p = 0.057).

Conclusion

Most patients are conscious of their port scars and if offered the choice choose placement in the arm rather than the chest. Upper extremity port placement should be further explored as an alternative approach for patients with breast cancer to improve port scar consciousness.

https://ift.tt/2Ku2suT