'All the progressive forms of life are built up on the attraction of sex': Development and the social function of the sexual instinct in late 19th- and early 20th-century Western European sexology.

This article explores the relationship between sexual science and evolutionary models of human development and progress. It examines the ways in which late 19th- and early 20th-century Western European sexual scientists constructed the sexual instinct as an evolutionary force that not only served a reproductive purpose, but was also pivotal to the social, moral, and cultural development of human societies. Sexual scientists challenged the idea that non-reproductive sexualities were necessarily perverse, pathological, or degenerative by linking sexual desire to the evolution of sociality, often focusing on forms of relationality and care that exceeded biological kinship. As a result, non-reproductive sexual expressions, including homosexual and non-reproductive heterosexual behaviours, were interpreted as manifestations of a sexual instinct operating in the service of human development. These claims were reliant on cross-cultural and historical comparisons of sexual values, behaviours, and customs that rehearsed and reinforced imperial narratives of development premised on racialized, gendered, and classed hierarchies. Sexual scientists mapped diverse sexual behaviours in terms of their perceived evolutionary benefits, contributing to colonial narratives that distinguished between different cultures according to imagined trajectories of development. These contestations around the sexual instinct and its developmental functions played a vital role in allowing sexual science to authorize itself as a field of knowledge that promised to provide expertise required to manage sexual life and secure the global development of human civilization.

Sexology and development.

The history of sexology is a well-established field of scholarly investigation animated by ongoing contestations around the disciplinary boundaries, political outlook, and transnational dimensions of the sexological field. This special issue focuses on the multivalent concept of development to address some of the most pressing questions driving current historiographical conversations in this area. The five articles examine how sexology developed in the late 19th and 20th centuries and explore how sexologists deployed various developmental categories to understand sexuality in different national, geographical, and linguistic spaces, including India, Latin America, and Western and Southern Europe. They show how central tracing the relationship between sexuality and human development became to sexologists' understanding of their project and its value. By interrogating the intersecting individual, social, cultural, and evolutionary developmental frameworks at the heart of sexological knowledge production, the articles engage with sexology as a global and transnational project deeply shaped by ideologies of race, nation, and empire and motivated by a diverse range of political concerns and intellectual questions. In so doing, the special issue as a whole demonstrates the breadth of the sexological field in terms of its interdisciplinary scope, diverse political and intellectual agendas, and global dimensions.

GMSimpute: a generalized two-step Lasso approach to impute missing values in label-free mass spectrum analysis.

MOTIVATION: Missingness in label-free mass spectrometry is inherent to the technology. A computational approach to recover missing values in metabolomics and proteomics datasets is important. Most existing methods are designed under a particular assumption, either missing at random or under the detection limit. If the missing pattern deviates from the assumption, it may lead to biased results. Hence, we investigate the missing patterns in free mass spectrometry data and develop an omnibus approach GMSimpute, to allow effective imputation accommodating different missing patterns. RESULTS: Three proteomics datasets and one metabolomics dataset indicate missing values could be a mixture of abundance-dependent and abundance-independent missingness. We assess the performance of GMSimpute using simulated data (with a wide range of 80 missing patterns) and metabolomics data from the Cancer Genome Atlas breast cancer and clear cell renal cell carcinoma studies. Using Pearson correlation and normalized root mean square errors between the true and imputed abundance, we compare its performance to K-nearest neighbors' type approaches, Random Forest, GSimp, a model-based method implemented in DanteR and minimum values. The results indicate GMSimpute provides higher accuracy in imputation and exhibits stable performance across different missing patterns. In addition, GMSimpute is able to identify the features in downstream differential expression analysis with high accuracy when applied to the Cancer Genome Atlas datasets. AVAILABILITY AND IMPLEMENTATION: GMSimpute is on CRAN: https://cran.r-project.org/web/packages/GMSimpute/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Proteolytic shedding of the prion protein via activation of metallopeptidase ADAM10 reduces cellular binding and toxicity of amyloid-ß oligomers.

The cellular prion protein (PrPC) is a key neuronal receptor for ß-amyloid oligomers (AßO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrPC is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrPC shedding would alter the cellular binding and cytotoxicity of AßO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrPC shedding and reduces the binding of AßO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrPC shedding and increased AßO binding, which was blocked by the PrPC-specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrPC shedding and decreased AßO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AßO binding to PrPC Besides blocking AßO binding and toxicity, acitretin also increased the nonamyloidogenic processing of APP. However, in the iPSC-derived neurons, Aß and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrPC in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AßO, revealing a potential therapeutic benefit of ADAM10 activation in AD.

Extracellular Vesicles Isolated from Human Induced Pluripotent Stem Cell-Derived Neurons Contain a Transcriptional Network.

Healthy brain function is mediated by several complementary signalling pathways, many of which are driven by extracellular vesicles (EVs). EVs are heterogeneous in both size and cargo and are constitutively released from cells into the extracellular milieu. They are subsequently trafficked to recipient cells, whereupon their entry can modify the cellular phenotype. Here, in order to further analyse the mRNA and protein cargo of neuronal EVs, we isolated EVs by size exclusion chromatography from human induced pluripotent stem cell (iPSC)-derived neurons. Electron microscopy and dynamic light scattering revealed that the isolated EVs had a diameter of 30-100 nm. Transcriptomic and proteomics analyses of the EVs and neurons identified key molecules enriched in the EVs involved in cell surface interaction (integrins and collagens), internalisation pathways (clathrin- and caveolin-dependent), downstream signalling pathways (phospholipases, integrin-linked kinase and MAPKs), and long-term impacts on cellular development and maintenance. Overall, we show that key signalling networks and mechanisms are enriched in EVs isolated from human iPSC-derived neurons.

Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms.

The generation of the amyloid-ß (Aß) peptides from the amyloid precursor protein (APP) through sequential proteolysis by ß- and γ-secretases is a key pathological event in the initiation and propagation of Alzheimer's disease. Aß and the transcriptionally active APP intracellular domain are generated preferentially from the APP695 isoform compared to the longer APP751 isoform. As the Aß and amyloid precursor protein intracellular domain produced from cleavage of APP695 and APP751 are identical we hypothesised that the two isoforms have differences within their interactomes which mediate the differential processing of the two isoforms. To investigate this, we applied a proteomics-based approach to identify differences in the interactomes of the APP695 and APP751 isoforms. Using stable isotope labelling of amino acids in cell culture and quantitative proteomics, we compared the interactomes of APP695 and APP751 expressed in human SH-SY5Y cells. Through this approach, we identified enrichment of proteins involved in mitochondrial function, the nuclear pore and nuclear transport specifically in the APP695 interactome. Further interrogation of the APP interactome and subsequent experimental validation (co-immunoprecipitation and siRNA knockdown) revealed GAP43 as a specific modulator of APP751 proteolysis, altering Aß generation. Our data indicate that interrogation of the APP interactome can be exploited to identify proteins which influence APP proteolysis and Aß production in an isoform dependent-manner. Cover Image for this issue: doi: 10.1111/jnc.14504.

Is a Wider Margin (2 cm vs. 1 cm) for a 1.01-2.0 mm Melanoma Necessary?

BACKGROUND: The current NCCN recommendation for resection margins in patients with melanomas between 1.01 and 2 mm deep is a 1-2 cm radial margin. We sought to determine whether margin width had an impact on local recurrence (LR), disease-specific survival (DSS), and type of wound closure. METHODS: Melanomas measuring 1.01-2.0 mm were evaluated at a single institution between 2008 and 2013. All patients had a 1 or 2 cm margin. RESULTS: We identified 965 patients who had a 1 cm (n = 302, 31.3 %) or 2 cm margin (n = 663, 68.7 %). Median age was 64 years, and 592 (61.3 %) were male; 32.5 and 48.7 % of head and neck and extremity patients had a 1 cm margin versus 18.9 % of trunk patients (p < 0.001). LR was 2.0 and  2.1 % for a 1 and 2 cm margin, respectively (p = not significant). Five-year DSS was 87 % for a 1 cm margin and 85 % for a 2 cm margin (p = not significant). Breslow thickness, melanoma on the head and neck, lymphovascular invasion, and sentinel lymph node biopsy (SLNB) status significantly predicted LR on univariate analysis; however, only location and SLNB status were associated with LR on multivariate analysis. Margin width was not significant for LR or DSS. Wider margins were associated with more frequent graft or flap use only on the head and neck (p = 0.025). CONCLUSIONS: Our data show that selectively using a narrower margin of 1 cm did not increase the risk of LR or decrease DSS. Avoiding a 2 cm margin may decrease the need for graft/flap use on the head and neck.

Hypothalamic volume loss is associated with reduced melatonin output in Parkinson's disease.

BACKGROUND: Recent studies have suggested that melatonin-a hormone produced by the pineal gland under circadian control-contributes to PD-related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. METHODS: A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24-hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme-linked immunosorbent assays. RESULTS: PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. CONCLUSION: Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Construction and Validation of a Multi-Institutional Tissue Microarray of Invasive Ductal Carcinoma From Racially and Ethnically Diverse Populations.

BACKGROUND: The scarcity of tissues from racial and ethnic minorities at biobanks poses a scientific constraint to research addressing health disparities in minority populations. METHODS: To address this gap, the Minority Biospecimen/Biobanking Geographic Management Program for region 3 (BMaP-3) established a working infrastructure for a "biobanking" hub in the southeastern United States and Puerto Rico. Herein we describe the steps taken to build this infrastructure, evaluate the feasibility of collecting formalin-fixed, paraffin-embedded tissue blocks and associated data from a single cancer type (breast), and create a web-based database and tissue microarrays (TMAs). RESULTS: Cancer registry data from 6 partner institutions were collected, representing 12,408 entries from 8,279 unique patients with breast cancer (years 2001-2011). Data were harmonized and merged, and deidentified information was made available online. A TMA was constructed from formalin-fixed, paraffin-embedded samples of invasive ductal carcinoma (IDC) representing 427 patients with breast cancer (147 African Americans, 168 Hispanics, and 112 non-Hispanic whites) and was annotated according to biomarker status and race/ethnicity. Biomarker analysis of the TMA was consistent with the literature. CONCLUSIONS: Contributions from participating institutions have facilitated a robust research tool. TMAs of IDC have now been released for 5 projects at 5 different institutions.

SERS as a tool for in vitro toxicology.

Measuring markers of stress such as pH and redox potential are important when studying toxicology in in vitro models because they are markers of oxidative stress, apoptosis and viability. While surface enhanced Raman spectroscopy is ideally suited to the measurement of redox potential and pH in live cells, the time-intensive nature and perceived difficulty in signal analysis and interpretation can be a barrier to its broad uptake by the biological community. In this paper we detail the development of signal processing and analysis algorithms that allow SERS spectra to be automatically processed so that the output of the processing is a pH or redox potential value. By automating signal processing we were able to carry out a comparative evaluation of the toxicology of silver and zinc oxide nanoparticles and correlate our findings with qPCR analysis. The combination of these two analytical techniques sheds light on the differences in toxicology between these two materials from the perspective of oxidative stress.

Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.

BACKGROUND: Several new polyomaviruses have been discovered in the last decade, including Merkel cell polyomavirus (MCPyV). Little is known about the natural history of the more recently discovered polyomaviruses. We estimated the incidence, prevalence, and persistence of 9 polyomaviruses (MCPyV, BK polyomavirus, KI polyomavirus, JC polyomavirus, WU polyomavirus, Human polyomavirus 6 [HPyV6], HPyV7, HPyV9, and Trichodysplasia spinulosa-associated polyomavirus) and examined factors associated with MCPyV infection in a prospective cohort of 209 men initially enrolled in the HPV Infection in Men (HIM) study. METHODS: Participants enrolled at the US site of the HIM study were recruited into a substudy of cutaneous viral infections and followed for a median of 12.6 months. Eyebrow hair and normal skin swab specimens were obtained at each study visit, and the viral DNA load was measured using multiplex polymerase chain reaction. RESULTS: MCPyV infection showed the highest prevalence (65.1% of normal skin swab specimens and 30.6% of eyebrow hair specimens), incidence (81.7 cases per 1000 person-months among normal skin swab specimens, and 24.1 cases per 1000 person-months among eyebrow hair specimens), and persistence (85.8% of normal skin swab specimens and 58.9% of eyebrow hair specimens) among all polyomaviruses examined. Age of >44 years (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.03-4.33) and Hispanic race (OR, 2.64; 95% CI, 1.01-6.88) were associated with an increased prevalence of MCPyV infection in eyebrow hair and normal skin swab specimens, respectively. CONCLUSION: MCPyV infection is highly prevalent in adults, with age and race being predisposing factors.

Sentinel lymph node biopsy is indicated for patients with thick clinically lymph node-negative melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is indicated for the staging of clinically lymph node-negative melanoma of intermediate thickness, but its use is controversial in patients with thick melanoma. METHODS: From 2002 to 2012, patients with melanoma measuring ≥4 mm in thickness were evaluated at a single institution. Associations between survival and clinicopathologic characteristics were explored. RESULTS: Of 571 patients with melanomas measuring ≥4 mm in thickness and no distant metastases, the median age was 66 years and 401 patients (70.2%) were male. The median Breslow thickness was 6.2 mm; the predominant subtype was nodular (45.4%). SLNB was performed in 412 patients (72%) whereas 46 patients (8.1%) presented with clinically lymph node-positive disease and 113 patients (20%) did not undergo SLNB. A positive SLN was found in 161 of 412 patients (39.1%). For SLNB performed at the study institution, 14 patients with a negative SLNB developed disease recurrence in the mapped lymph node basin (false-negative rate, 12.3%). The median disease-specific survival (DSS), overall survival (OS), and recurrence-free survival (RFS) for the entire cohort were 62.1 months, 42.5 months, and 21.2 months, respectively. The DSS and OS for patients with a negative SLNB were 82.4 months and 53.4 months, respectively; 41.2 months and 34.7 months, respectively, for patients with positive SLNB; and 26.8 months and 22 months, respectively, for patients with clinically lymph node-positive disease (P<.0001). The median RFS was 32.4 months for patients who were SLNB negative, 14.3 months for patients who were SLNB positive, and 6.8 months for patients with clinically lymph node-positive disease (P<.0001). CONCLUSIONS: With an acceptably low false-negative rate, patients with thick melanoma and a negative SLNB appear to have significantly prolonged RFS, DSS, and OS compared with those with a positive SLNB. Therefore, SLNB should be considered as indicated for patients with thick, clinically lymph node-negative melanoma.

Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation.

Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin ß-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin ß-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients' magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype-phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable.

Ratiometric biological nanosensors.

The measurement of intracellular analytes has been key in understanding cellular processes and function, and the use of biological nanosensors has revealed the spatial and temporal variation in their concentrations. In particular, ratiometric nanosensors allow quantitative measurements of analyte concentrations. The present review focuses on the recent advances in ratiometric intracellular biological nanosensors, with an emphasis on their utility in measuring analytes that are important in cell function.

Resection of residual disease after isolated limb infusion (ILI) is equivalent to a complete response after ILI-alone in advanced extremity melanoma.

BACKGROUND: Isolated limb infusion (ILI) is a limb-preserving treatment for in-transit extremity melanoma. The benefit of resecting residual disease after ILI is unclear. METHODS: A multi-institutional experience was analyzed comparing patients who underwent ILI plus resection of residual disease (ILI + RES) versus ILI-alone. RESULTS: A total of 176 patients were included, 154 with ILI-alone and 22 with ILI + RES. There were no differences between the groups with respect to gender, age, extremity affected, or time from diagnosis to ILI. All surgical resections were performed as an outpatient procedure, separate from the ILI. Within the ILI + RES group, 15 (68%) had a partial response (PR), 2 (9%) stable disease (SD), and 5 (23%) progressive disease (PD). The ILI-alone group had 52 (34%) CR, 30 (19%) PR, 15 (10%) SD, and 46 (30%) PD. Eleven (7%) ILI-alone patients did not have 3-month response available for review. Evaluating overall survival (OS) from date of ILI, the ILI-alone group had a median OS of 30.9 months, whereas the ILI + RES group had not reached median OS, p = 0.304. Although the ILI + RES group had a slightly longer disease-free survival (DFS) compared to those with a CR after ILI-alone (12.4 vs. 9.6), this was not statistically significant, p = 0.978. Within the ILI + RES group, those with an initial PR after ILI had improved DFS versus those with SD or PD after ILI, p < 0.0001. CONCLUSIONS: Resection of residual disease after ILI offers a DFS and OS similar to those who have a CR after ILI-alone. It may offer a treatment strategy that benefits patients undergoing ILI.

Serum albumin retains independent prognostic significance in diffuse large B-cell lymphoma in the post-rituximab era.

Serum albumin (SA) has been shown to be a prognostic marker in many hematological malignancies and in diffuse large B-cell lymphoma (DLBCL) prior to chemo-immunotherapy. SA may be a surrogate for age, comorbid status, and disease severity. Here, we aimed to assess whether SA can be an independent prognostic marker in patients with newly diagnosed DLBCL treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP). Patients who presented at the Moffitt Cancer Center from 2007 to 2010 for DLBCL diagnosis or treatment were identified using our institutional database. Clinical and treatment data were recorded, including SA levels at diagnosis. Survival time was estimated using the Kaplan-Meier method, with Cox proportional hazard model used to identify potential risk factors for time-to-event data. From 295 identified patients, 171 were excluded for not having primary treatment at our institution or not having R-CHOP treatment. In 124 included patients (mean age at diagnosis of 58 years, 91 % Caucasian), 25 % were categorized as poor by the revised International Prognostic Index. Overall and progression-free survival at 4 years were 65 % (95 % CI 57-75) and 58 % (95 % CI 0.49-0.69), respectively. Using multivariate analysis, we found that the hazard index of death of patients with SA ≥3.7 g/dL was 26 % (95 % CI 13-53) of the hazard for those patients who had SA <3.7 g/dL when controlling for the revised International Prognostic Index risk and initial lymphocyte count. Our study shows that SA ≥3.7 g/dL is an independent prognostic marker in DLBCL patients treated with R-CHOP.

Disrupted prenatal maternal cortisol, maternal obesity, and childhood wheeze. Insights into prenatal programming.

RATIONALE: Exploring prenatal factors influencing childhood wheeze may inform programming mechanisms. OBJECTIVES: We examined associations among prenatal maternal cortisol profiles, maternal obesity, and repeated wheeze up to age 2 years (n = 261). METHODS: Salivary cortisol was collected five times per day over 3 days at 29.0 ± 4.9 weeks gestation. Mothers were categorized as obese (body mass index ≥ 30 kg/m(2)) versus nonobese (body mass index < 30 kg/m(2)). Using logistic regression, we examined the influence of log-transformed cortisol metrics (level at each time point, morning rise, diurnal and afternoon slopes) and obesity on wheeze adjusting for covariates. Linear mixed models were implemented to examine associations between cortisol trajectories and wheezing. Interactions between maternal cortisol and obesity were considered. MEASUREMENTS AND MAIN RESULTS: Mothers were primarily minority (56.5% Hispanic, 24.1% African American), 61% had less than or equal to 12 years of education, 34% were obese, and 8.4% of children had repeated wheeze. An interquartile range increase in mean log cortisol at bedtime (odds ratio, 2.2; 95% confidence interval, 1.09-4.09) and maternal obesity (odds ratio, 3.43; 95% confidence interval, 1.26-9.35) were independently associated with wheeze. Linear mixed models revealed an association between a flatter afternoon slope (slower decline in log cortisol per hour) and repeated wheeze in children of obese mothers (children with [-0.017 change] and without [-0.061 change] wheeze [P = 0.009 for time × wheeze interaction]), but not in children of nonobese mothers (with [-0.050 change] and without [-0.061 change] wheeze [P = 0.51]). CONCLUSIONS: Maternal prenatal cortisol disruption and obesity were independently associated with children's wheeze. Obese women with adverse cortisol profiles were most likely to have children with repeated wheeze.

Primary care utilization and colorectal cancer incidence and mortality among Medicare beneficiaries: a population-based, case-control study.

BACKGROUND: Utilization of primary care may decrease colorectal cancer (CRC) incidence and death through greater receipt of CRC screening tests. OBJECTIVE: To examine the association of primary care utilization with CRC incidence, CRC deaths, and all-cause mortality. DESIGN: Population-based, case-control study. SETTING: Medicare program. PARTICIPANTS: Persons aged 67 to 85 years diagnosed with CRC between 1994 and 2005 in U.S. Surveillance, Epidemiology, and End Results (SEER) regions matched with control patients (n = 205,804 for CRC incidence, 54,160 for CRC mortality, and 121,070 for all-cause mortality). MEASUREMENTS: Primary care visits in the 4- to 27-month period before CRC diagnosis, CRC incidence, CRC mortality, and all-cause mortality. RESULTS: Compared with persons having 0 or 1 primary care visit, persons with 5 to 10 visits had lower CRC incidence (adjusted odds ratio [OR], 0.94 [95% CI, 0.91 to 0.96]) and mortality (adjusted OR, 0.78 [CI, 0.75 to 0.82]) and lower all-cause mortality (adjusted OR, 0.79 [CI, 0.76 to 0.82]). Associations were stronger in patients with late-stage CRC diagnosis, distal lesions, and diagnosis in more recent years when there was greater Medicare screening coverage. Ever receipt of CRC screening and polypectomy mediated the association of primary care utilization with CRC incidence. LIMITATION: This study used administrative data, which made it difficult to identify potential confounders and prevented examination of the content of primary care visits. CONCLUSION: Medicare beneficiaries with higher utilization of primary care have lower CRC incidence and mortality and lower overall mortality. Increasing and promoting access to primary care in the United States for Medicare beneficiaries may help decrease the national burden of CRC. PRIMARY FUNDING SOURCE: American Cancer Society.

The effects of primary care on breast cancer mortality and incidence among Medicare beneficiaries.

BACKGROUND: Primary care physician (PCP) services may have an impact on breast cancer mortality and incidence, possibly through greater use of screening mammography. METHODS: The authors conducted a retrospective, 1:1 matching case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database to examine use of PCP services and their association with breast cancer mortality and incidence. SEER cases representing the 3 outcomes of interest (breast cancer mortality, all-cause mortality among women diagnosed with breast cancer, and breast cancer incidence) were matched to unaffected controls from the 5% Medicare random sample. Conditional logistic regression was used to examine associations between physician visits and breast cancer outcomes while controlling for other covariates. RESULTS: Women who had 2 or more PCP visits during the 24-month assessment interval had lower odds of breast cancer mortality, all-cause mortality, and late-stage breast cancer diagnosis compared with women who had no PCP visits or 1 PCP visit while adjusting for other covariates, including mammography and non-PCP visits. Women who had 5 to 10 PCP visits had 0.69 times the odds of breast cancer mortality (95% confidence interval, 0.63-0.75), 0.83 times the odds of death from any cause having been diagnosed with breast cancer (95% confidence interval, 0.79-0.87), and 0.67 times the odds of a late-stage breast cancer diagnosis (95% confidence interval, 0.61-0.73) compared with those who had no PCP visits or 1 PCP visit. CONCLUSIONS: The current findings suggest that PCPs play an important role in reducing breast cancer mortality among the Medicare population. Further research is needed to better understand the impact of primary care on breast cancer and other cancers that are amendable to prevention or early detection.

Isolated limb infusion in a series of over 100 infusions: a single-center experience.

BACKGROUND: Isolated limb infusion (ILI) is a therapeutic option for patients with recurrent, unresectable extremity malignancies. METHODS: A prospectively collected single-institution database of patients undergoing ILI was analyzed for preoperative, intraoperative, and postoperative parameters and outcomes. RESULTS: From May 2007 to January 2012, a total of 76 patients successfully underwent initial ILI, and 28 after either previous hyperthermic isolated limb perfusion or ILI. Seventy-nine patients (74 %) had melanoma, 24 (22 %) sarcoma, 3 (3 %) Merkel cell, and 1 (1 %) squamous cell carcinoma. There were 55 (72 %) initial and 22 (79 %) repeat lower extremity (LE) ILIs, and 21 (78 %) initial and 6 (22 %) repeat upper extremity (UE) ILIs. Serologic toxicity, measured by serum creatine kinase (CK), peaked higher and later in LE ILIs, median 620 versus 124 IU/L, and postoperative day 4 versus 2, respectively (P < 0.05). LE ILIs had a longer hospital length of stay (LOS), median 6 versus 5 days (P < 0.0001). A median grade II Wieberdink regional toxicity was observed. Three-month follow-up was available in 94 (90 %). A response (overall response rate, ORR) was seen in 72 % of ILIs performed for melanoma and 58 % for sarcoma. No difference in response was observed between UE versus LE or between initial versus repeat ILIs. Repeat UE ILIs, however, appeared to have an improved ORR than repeat LE ILIs, 83 versus 64 %. CONCLUSIONS: ILI may be successfully performed for cutaneous and soft tissue malignancies. LE ILIs have higher CK levels and slightly longer LOS. Repeat ILIs are not associated with increased toxicity and similar ORR. UE ILIs may have better ORR.