Oncological Safety of Oncoplastic Level II Mammoplasties After Neoadjuvant Chemotherapy for Large Breast Cancers: A Matched-Cohort Analysis.

BACKGROUND: Oncoplastic surgery (OPS) has extended the indications for breast-conserving surgery (BCS). Its role in patients with large breast cancers treated with neoadjuvant chemotherapy (NAC) is unclear. This study evaluated the oncological safety of OPS for tumors with partial response after NAC. METHODS: A consecutive series of 65 patients who underwent OPS (study group) after NAC for large breast cancer from January 2004 to July 2018 was compared with 130 matched patients treated by NAC, followed by standard BCS in 65 cases and mastectomy in 65 cases (two case-controlled groups). RESULTS: The mean initial radiological tumor size was 46 mm. Residual pathological tumor size was 22 mm in the OPS cohort, 19 mm in the standard BCS cohort, and 31 mm in the mastectomy cohort (p > 0.05). The mean follow-up was 59 months in the study cohort. Five-year local recurrence rates were 0%, 0%, and 10.5% (0-22%) for the OPS, BCS, and mastectomy cohorts, respectively, while 5-year regional recurrence rates were 4.1% (0-11.1%), 0, and 19.4% (0-35.2%, p > 0.05), respectively. Five-year overall survival was 85.3% for the OPS cohort, 94.1% for the standard BCS cohort (p = 0.194), and 79.9% for the mastectomy cohort (p = 0.165). CONCLUSIONS: OPS is safe after NAC for large breast cancers, and provides excellent local control, identical to that of tumors with a better response, treated by standard BCS. After NAC, OPS can be a valuable treatment option for tumors that did not shrink optimally and would not be suitable for standard BCS.

Long-term Results After Oncoplastic Surgery for Breast Cancer: A 10-year Follow-up.

OBJECTIVE: The aim of this study was to evaluate the long-term oncologic outcome after oncoplastic surgery (OPS). BACKGROUND: OPS combines wide tumor excision with reduction mammoplasty techniques thus extending breast conserving surgery to large tumors that might else be proposed a mastectomy. Little data are available about the oncologic results for breast conserving surgery of these larger tumors. METHODS: From January 2004 until March 2016, a total of 350 oncoplastic breast reductions were prospectively entered into a database. Patients were included if their breast reshaping included a reduction mammoplasty with skin excision (Level 2 oncoplastic techniques). RESULTS: Histologic subtypes were: invasive ductal carcinoma in 219 cases (62.6%), ductal carcinoma in situ (DCIS) in 88 cases (25.1%), and invasive lobular carcinoma in 43 (12.3%) cases. Seventy-three of the invasive cancers (27.9%) received neoadjuvant chemotherapy. The mean resection weight was 177 grams. The mean pathological tumor size was 26 mm (range 0-180 mm) and varied from 23 mm (4-180 mm) for invasive cancers to 32 mm (0-100 mm) for DCIS. Specimen margins were involved in 12.6% of the cases; 10.5% of invasive ductal, 14.7% of DCIS, and 20.9% of invasive lobular. The overall breast conservation rate was 92% and varied from 87.4% for DCIS to 93.5% for the invasive cancers. Thirty-one patients (8.9%) developed one or more postoperative complications, inducing a delay in postoperative treatments in 4.6% of patients. The median follow up was 55 months. The cumulative 5-year incidences for local, regional, and distant recurrences were 2.2%, 1.1%, and 12.4%, respectively. CONCLUSIONS: Oncoplastic breast reductions allow wide resections with free margins and can be used for large cancers as an alternative to mastectomy.

Landscape genomic analysis of candidate genes for climate adaptation in a California endemic oak, Quercus lobata.

PREMISE OF THE STUDY: The ability of California tree populations to survive anthropogenic climate change will be shaped by the geographic structure of adaptive genetic variation. Our goal is to test whether climate-associated candidate genes show evidence of spatially divergent selection in natural populations of valley oak, Quercus lobata, as preliminary indication of local adaptation. METHODS: Using DNA from 45 individuals from 13 localities across the species' range, we sequenced portions of 40 candidate genes related to budburst/flowering, growth, osmotic stress, and temperature stress. Using 195 single nucleotide polymorphisms (SNPs), we estimated genetic differentiation across populations and correlated allele frequencies with climate gradients using single-locus and multivariate models. RESULTS: The top 5% of FST estimates ranged from 0.25 to 0.68, yielding loci potentially under spatially divergent selection. Environmental analyses of SNP frequencies with climate gradients revealed three significantly correlated SNPs within budburst/flowering genes and two SNPs within temperature stress genes with mean annual precipitation, after controlling for multiple testing. A redundancy model showed a significant association between SNPs and climate variables and revealed a similar set of SNPs with high loadings on the first axis. In the RDA, climate accounted for 67% of the explained variation, when holding climate constant, in contrast to a putatively neutral SSR data set where climate accounted for only 33%. CONCLUSIONS: Population differentiation and geographic gradients of allele frequencies in climate-associated functional genes in Q. lobata provide initial evidence of adaptive genetic variation and background for predicting population response to climate change.

MAGI: a Node.js web service for fast microRNA-Seq analysis in a GPU infrastructure.

SUMMARY: MAGI is a web service for fast MicroRNA-Seq data analysis in a graphics processing unit (GPU) infrastructure. Using just a browser, users have access to results as web reports in just a few hours->600% end-to-end performance improvement over state of the art. MAGI's salient features are (i) transfer of large input files in native FASTA with Qualities (FASTQ) format through drag-and-drop operations, (ii) rapid prediction of microRNA target genes leveraging parallel computing with GPU devices, (iii) all-in-one analytics with novel feature extraction, statistical test for differential expression and diagnostic plot generation for quality control and (iv) interactive visualization and exploration of results in web reports that are readily available for publication. AVAILABILITY AND IMPLEMENTATION: MAGI relies on the Node.js JavaScript framework, along with NVIDIA CUDA C, PHP: Hypertext Preprocessor (PHP), Perl and R. It is freely available at http://magi.ucsd.edu.

Influence of ABCB1 polymorphisms and docetaxel pharmacokinetics on pathological response to neoadjuvant chemotherapy in breast cancer patients.

We have previously reported an association between ABCB1 C3435T polymorphism and docetaxel pharmacokinetics in breast cancer patients. We therefore investigated whether these parameters could account for variations in pathological response. Five ABCB1 polymorphisms including C3435T polymorphism were analyzed in breast cancer patients receiving neoadjuvant chemotherapy with doxorubicin and docetaxel (n = 101). Pathological response was assessed using the Sataloff classification. Pharmacokinetic analysis was performed for the first course of docetaxel (n = 84). No significant association was found between ABCB1 polymorphisms or docetaxel pharmacokinetics and pathological complete response. C3435T genotype was an independent predictive factor of good response in breast (response >50 %, i.e., Sataloff T-A and T-B): OR: 4.6 (95 % CI: 1.3-16.1), p = 0.015, for TT patients versus CT and CC patients. Area under the plasma concentration-time curve (AUC) of docetaxel was the only independent predictive factor of the total absence of response in breast (Sataloff T-D): OR: 14.3, (95 % CI: 1.7-118), p = 0.015, for AUC of docetaxel <3,500 µg h/L versus ≥3,500 µg h/L. These results suggest that C3435T polymorphism and docetaxel exposure are involved in the response to neoadjuvant chemotherapy in breast cancer patients and may be useful to optimize individualized therapy.

A machine learning algorithm with subclonal sensitivity reveals widespread pan-cancer human leukocyte antigen loss of heterozygosity.

Human leukocyte antigen loss of heterozygosity (HLA LOH) allows cancer cells to escape immune recognition by deleting HLA alleles, causing the suppressed presentation of tumor neoantigens. Despite its importance in immunotherapy response, few methods exist to detect HLA LOH, and their accuracy is not well understood. Here, we develop DASH (Deletion of Allele-Specific HLAs), a machine learning-based algorithm to detect HLA LOH from paired tumor-normal sequencing data. With cell line mixtures, we demonstrate increased sensitivity compared to previously published tools. Moreover, our patient-specific digital PCR validation approach provides a sensitive, robust orthogonal approach that could be used for clinical validation. Using DASH on 610 patients across 15 tumor types, we find that 18% of patients have HLA LOH. Moreover, we show inflated HLA LOH rates compared to genome-wide LOH and correlations between CD274 (encodes PD-L1) expression and microsatellite instability status, suggesting the HLA LOH is a key immune resistance strategy.

Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms.

PURPOSE: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). EXPERIMENTAL DESIGN: Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. RESULTS: Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002). CONCLUSIONS: NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.

What is the real impact of bone pain on survival in patients with metastatic hormone-refractory prostate cancer treated with docetaxel?

OBJECTIVES: To determine the benefit of starting early chemotherapy with docetaxel (the recommended first-line treatment) for patients with asymptomatic metastatic hormone-refractory prostate cancer (HRPC). PATIENTS AND METHODS: Data were analysed from 145 patients with HRPC treated with chemotherapy between February 2000 and June 2002 in one French centre. Eligible patients were categorized into three groups according to the bone pain at baseline, i.e. minimal/no pain, mild, and moderate/severe pain. The primary endpoint was the effect of bone pain on overall survival (OS). RESULTS: Docetaxel was administered to 67% of patients. The risk of death was 1.56 and 2.11 times higher for patients with mild or moderate/severe pain than for those with minimal/no pain (P = 0.027). The median (95% confidence interval (CI)) OS was 23.1 (18.5-27.6) and 14.1 (8.9-19.2) months (P = 0.001, log-rank-test) for patients with minimal pain or no pain treated with docetaxel-based chemotherapy compared with mitoxantrone, respectively. The prostate-specific antigen doubling time (PSA-DT) had a significant effect on OS in patients with minimal/no pain, with a median of 32.4 and 16.5 months for a PSA-DT of >or=45 and <45 days, respectively (P < 0.001). CONCLUSIONS: Our results suggest that patients with HRPC and minimal or no bone pain could have better survival than those with mild pain or moderate to severe pain, independent of the treatment administered. In addition, patients with HRPC and minimal or no bone pain treated with docetaxel-based chemotherapy have a significantly better OS than those treated with mitoxantrone. The PSA-DT can be useful to identify asymptomatic patients who are candidates for early treatment.

Penile Preservation With Subcutaneous Transposition During Fournier's Gangrene.

A 50-year-old male with past medical history of diabetes mellitus presented with extensive Fournier's Gangrene. He had a wide-spread area of involvement and the wound vacuum placement involved the entirety of the phallus. We describe a surgical technique where the penis can be diverted from the site of the wound to allow for more secure wound vacuum placement and future reconstructive options.

Whole genome sequencing of an African American family highlights toll like receptor 6 variants in Kawasaki disease susceptibility.

Kawasaki disease (KD) is the most common acquired pediatric heart disease. We analyzed Whole Genome Sequences (WGS) from a 6-member African American family in which KD affected two of four children. We sought rare, potentially causative genotypes by sequentially applying the following WGS filters: sequence quality scores, inheritance model (recessive homozygous and compound heterozygous), predicted deleteriousness, allele frequency, genes in KD-associated pathways or with significant associations in published KD genome-wide association studies (GWAS), and with differential expression in KD blood transcriptomes. Biologically plausible genotypes were identified in twelve variants in six genes in the two affected children. The affected siblings were compound heterozygous for the rare variants p.Leu194Pro and p.Arg247Lys in Toll-like receptor 6 (TLR6), which affect TLR6 signaling. The affected children were also homozygous for three common, linked (r2 = 1) intronic single nucleotide variants (SNVs) in TLR6 (rs56245262, rs56083757 and rs7669329), that have previously shown association with KD in cohorts of European descent. Using transcriptome data from pre-treatment whole blood of KD subjects (n = 146), expression quantitative trait loci (eQTL) analyses were performed. Subjects homozygous for the intronic risk allele (A allele of TLR6 rs56245262) had differential expression of Interleukin-6 (IL-6) as a function of genotype (p = 0.0007) and a higher erythrocyte sedimentation rate at diagnosis. TLR6 plays an important role in pathogen-associated molecular pattern recognition, and sequence variations may affect binding affinities that in turn influence KD susceptibility. This integrative genomic approach illustrates how the analysis of WGS in multiplex families with a complex genetic disease allows examination of both the common disease-common variant and common disease-rare variant hypotheses.

Incidence and Effect of Thromboembolic Events in Radical Cystectomy Patients Undergoing Preoperative Chemotherapy for Muscle-invasive Bladder Cancer.

BACKGROUND: We evaluated the incidence and effect of thromboembolic events (TEEs) in patients with muscle-invasive bladder cancer treated with preoperative chemotherapy (POC) and radical cystectomy (RC) with pelvic lymph node dissection (PLND). PATIENTS AND METHODS: We performed a retrospective review of all patients who had undergone POC followed by RC plus PLND for muscle-invasive bladder cancer from June 2000 to January 2013 (n = 357). The chemotherapy type (neoadjuvant vs. induction), incidence and timing of TEE diagnosis (preoperatively vs. ≤ 90 days postoperatively), and effect of TEEs on clinical outcomes were recorded. RESULTS: Overall, 79 patients (22%; 95% confidence interval [CI], 18%-27%) experienced a TEE: 57 (16%) occurred during POC and 22 (6.2%) were diagnosed postoperatively. Forty patients (11%; 95% CI, 8.1%-15%) required an inferior vena cava filter. We found no significant differences in neoadjuvant versus induction chemotherapy and the risk of TEEs (difference, 3.3%; 95% CI, -5% to 12%; P = .5). No significant difference were found in the rates of POC completion according to the presence of a TEE (difference, 1.0%; 95% CI, -11% to 13%; P = .9). The occurrence of TEE did not significantly affect other perioperative outcomes. The risk of recurrence and overall survival were not associated with TEE on multivariable analysis. CONCLUSION: We found a high incidence of TEEs (22%) in patients undergoing POC before RC plus PLND, with a 16% incidence in the preoperative period. TEEs in the POC setting leads to invasive procedures; however, we did not find a significant effect on POC completion or postoperative complication risk. Further research is required to determine whether preventative TEE measures during POC can improve clinical outcomes.

Multicenter study of a frozen glove to prevent docetaxel-induced onycholysis and cutaneous toxicity of the hand.

PURPOSE: Onycholysis and skin toxicity occur in approximately 30% of patients treated with docetaxel. We investigated the efficacy and safety of an Elasto-Gel (84400 APT Cedex, Akromed, France) frozen glove (FG) for the prevention of docetaxel-induced onycholysis and skin toxicity. PATIENTS AND METHODS: Patients receiving docetaxel 75 mg/m2 alone or in combination chemotherapy were eligible for this case-control study. Each patient wore an FG for a total of 90 minutes on the right hand. The left hand was not protected and acted as the control. Onycholysis and skin toxicity were assessed at each cycle by National Cancer Institute Common Toxicity Criteria and documented by photography. Wilcoxon matched-pairs rank test was used. RESULTS: Between August 2002 and September 2003, 45 patients were evaluated. Onycholysis and skin toxicity were significantly lower in the FG-protected hand compared with the control hand (P = .0001). Onycholysis was grade (G) 0 in 89% v 49% and G1 to 2 in 11% v 51% for the FG-protected hand and the control hand, respectively. Skin toxicity was G0 in 73% v 41% and G1 to 2 in 27% v 59% for the FG-protected and the control hand, respectively. Median time to nail and skin toxicity occurrence was not significantly different between the FG-protected and the control hand, respectively (106 v 58 days for nail toxicity; 57 v 58 days for skin toxicity). Five patients (11%) experienced discomfort due to cold intolerance. CONCLUSION: FG significantly reduces the nail and skin toxicity associated with docetaxel and provides a new tool in supportive care management to improve a patient's quality of life.

Pharmacokinetics of daptomycin in a critically ill adolescent with vancomycin-resistant enterococcal endocarditis.

Daptomycin is a lipopeptide antibiotic active against multidrug-resistant gram-positive organisms. Our search of the literature found no published pediatric pharmacokinetic data. We report the use of pharmacokinetic analysis of daptomycin in a 13-year-old boy with vancomycin-resistant Enterococcus faecium endocarditis. Pharamcokinetic parameters were found to be significantly different from published adult parameters, such as a faster elimination rate, shorter half-life, and increased clearance. These age-related differences in the pharmacokinetic profile of daptomycin have significant dosing implications. As the use of this drug for off-label indications and in pediatric populations increases, it is important for clinicians to better understand the drug's pharmacokinetic profile in these patient populations.

[Nausea and vomiting in cancer patients]. / Nausées et vomissements chez les patients atteints de cancer.

Despite an increasing number of antiemetic drugs available, nausea and vomiting (NV) remain a central problem during chemotherapy. Acute and delayed NV benefit most often from the combination of classical antiemetic (such as metoclopramide or metopimazin), corticosteroids and 5HT3 inhibitors (setrons). Since 2006, a new class of antiemetics are available, the NK1 inhibitors (aprepitant), which improve the control of NV in combination with setrons and corticosteroids. Anticipatory NV must be treated with benzodiazepines. Other causes of NV must be discussed in those patients, such as gastro intestinal or metabolic disorders, cancer evolution such as occlusion, brain metastases. A global approach is necessary to improve the quality of life all along the courses of chemotherapy, including somatic and psychologic aspects.

I don't want the money, I just want your time: How moral identity overcomes the aversion to giving time to prosocial causes.

Four studies show that moral identity reduces people's aversion to giving time-particularly as the psychological costs of doing so increase. In Study 1, we demonstrate that even when the cost of time and money are held equivalent, a moral cue enhances the expected self-expressivity of giving time-especially when it is given to a moral cause. We found that a moral cue reduces time aversion even when giving time was perceived to be unpleasant (Study 2), or when the time to be given was otherwise seen to be scarce (Study 3). Study 4 builds on these studies by examining actual giving while accounting for the real costs of time. In this study, we found that the chronic salience of moral identity serves as a buffer to time aversion, specifically as giving time becomes increasingly costly. These findings are discussed in terms of the time-versus-money literature and the identity literature. We also discuss policy implications for prosocial cause initiatives. (PsycINFO Database Record

Immune DNA signature of T-cell infiltration in breast tumor exomes.

Tumor infiltrating lymphocytes (TILs) have been associated with favorable prognosis in multiple tumor types. The Cancer Genome Atlas (TCGA) represents the largest collection of cancer molecular data, but lacks detailed information about the immune environment. Here, we show that exome reads mapping to the complementarity-determining-region 3 (CDR3) of mature T-cell receptor beta (TCRB) can be used as an immune DNA (iDNA) signature. Specifically, we propose a method to identify CDR3 reads in a breast tumor exome and validate it using deep TCRB sequencing. In 1,078 TCGA breast cancer exomes, the fraction of CDR3 reads was associated with TILs fraction, tumor purity, adaptive immunity gene expression signatures and improved survival in Her2+ patients. Only 2/839 TCRB clonotypes were shared between patients and none associated with a specific HLA allele or somatic driver mutations. The iDNA biomarker enriches the comprehensive dataset collected through TCGA, revealing associations with other molecular features and clinical outcomes.

Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.

Cells undergoing xenobiotic or oxidative stress activate the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2), which initiates an intrinsic "stress surveillance" pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d(-/-) mice experienced a higher incidence of tumors and exacerbated viral infections compared to wild-type (WT) animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection.

FDG PET in patients with cancer of an unknown primary.

BACKGROUND: This prospective study was undertaken to address the capacity of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) to determine the primary tumour site of carcinomas with unknown primary site. PATIENTS AND METHODS: Twenty-five patients with metastases from adenocarcinoma or undifferentiated carcinoma of unknown primary site (CUP) were included prospectively. For all patients, extensive imaging was unsuccessful in localizing the primary site. Patients received 370 MBq of 18F-FDG intravenously, and whole-body images were acquired 60 min after injection. All hot spots that could not be attributed to a metastatic site were considered as the primary tumour. The evaluation of FDG PET data was based on clinical and radiological outcome or surgery if indicated. RESULTS: Twenty-four patients were eligible for analysis. All known metastases were visualized. In six patients, FDG PET showed a primary tumour site which was confirmed by follow-up or surgery. In five patients, the primary tumour site was suggested by FDG PET but not confirmed by clinical outcome. No primary tumour was found in the other patients, with a mean follow-up of 15 months. CONCLUSION: In our series, FDG PET allowed the identification of primary tumour site in one quarter of patients with CUP (6/24). We conclude that FDG PET has a place in the initial staging of these patients.

A Fluorospot assay to detect single T lymphocytes simultaneously producing multiple cytokines.

Various subpopulations of T lymphocytes-i.e. Type 1, Type 2, Tr1 T cells-play a major role in the homeostasis of the immune system and in the pathogenesis of many inflammatory and auto-immune diseases. At present, in the absence of specific surface markers, these T cells can only be reliably distinguished on the basis of their cytokine production profile. The Elispot assay detects cytokine-producing cells, but in most cases can detect only one secreted cytokine, which represents a major limitation of this technique. We have developed a Fluorospot assay to detect single cells that simultaneously produce multiple cytokines. The Fluorospot assay permits the detection of regulatory T cells with an immunosuppressive activity, identified by their coexpression of IL-10 and IFNgamma. Polarized type 1 and type 2 specific tetanus toxoid T cells are also directly detected using a dual color Fluorospot. This technique will therefore be useful for detailed analysis of T lymphocytes in various disease states in which an imbalance of T cell subpopulations is suspected, but will also provide a better characterization of polarized specific immune responses.

[Ovarian cancer: diagnosis of early stages, referral of patients and management]. / Cancer de l'ovaire: diagnostic des formes précoces, orientation des malades et prise en charge.

Early ovarian cancers account for 25 to 30% of cases. They constitute the only curable cases. There is no specific clinical symptom of early ovarian cancer. Paraneoplasic syndroms, especially phlebitis, are of major importance when they occur in young women. In most of cases, the diagnosis is performed during the management of a complex ovarian cysts. Quality of the preoperative work-up, especially sonography, and management by a specialised team are the best factors to provide an early diagnosis and a comprehensive staging. These two factors are known as predictive of good prognosis. Chemotherapy is frequently indicated post-operatively. In young women, a conservative management can be proposed to preserve their fertility.