Pathogenic mechanisms and etiologic aspects of Mycobacterium avium subspecies paratuberculosis as an infectious cause of cutaneous melanoma.

Infectious etiologies have previously been proposed as causes of both melanoma and non-melanoma skin cancer. This exploratory overview explains and presents the evidence for the hypothesis that a microorganism excreted in infected ruminant animal feces, Mycobacterium avium subspecies paratuberculosis (MAP), is the cause of some cases of cutaneous melanoma (CM). Occupational, residential, and recreational contact with MAP-contaminated feces, soil, sand, and natural bodies of water may confer a higher rate of CM. Included in our hypothesis are possible reasons for the differing rates and locations of CM in persons with white versus nonwhite skin, why CM develops underneath nails and in vulvar skin, why canine melanoma is an excellent model for human melanoma, and why the Bacille Calmette-Guérin (BCG) vaccine has demonstrated efficacy in the prevention and treatment of CM. The pathogenic mechanisms and etiologic aspects of MAP, as a transmittable agent underlying CM risk, are carefully deliberated in this paper. Imbalances in gut and skin bacteria, genetic risk factors, and vaccine prevention/therapy are also discussed, while acknowledging that the evidence for a causal association between MAP exposure and CM remains circumstantial.

The evidence for Mycobacterium avium subspecies paratuberculosis (MAP) as a cause of nonsolar uveal melanoma: a narrative review.

Background and Objective: Animal microorganisms have been proposed as a cause of human cancers associated with farming, agricultural occupation or residence, and related downstream exposures. Several studies have described uveal melanoma (UvM) as a farming-associated cancer. A possible suspect is the animal microorganism Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of paratuberculosis in dairy cows. This microbe is transmitted to humans through various means, including contact with animal faeces, contaminated dust and soil, organic fertilizers, and as workers in slaughterhouses/animal processing facilities. The objective of the current manuscript was to examine the putative association between Mycobacterium avium sub-species paratuberculosis and non-solar UvM. Methods: Online data sources (PubMed, Scopus, Cochrane Library, and Google) published in English between 1980 to present were searched for key words pertaining to MAP exposure, farming-related occupations and activities, and locations with or in the vicinity of dairy cattle. Key Content and Findings: While higher than expected rates of eye cancer have been suggested among dairy farmers, with MAP being ubiquitous in their environment, the involvement of MAP in the aetiology of non-solar UvMs (which account for ~97% of UvM cases) remains uncertain. Conclusions: Alternative explanations exist and future cause-and-effect research is needed to answer this hypothesis. A precautionary approach to exposure continues to be a prudent strategy.

Dermatological Autoimmune Considerations of Immune Checkpoint Therapy.

The most common immune-related adverse events (irAEs) involve the skin, and several serve as predictors of response to immune checkpoint inhibitor (ICI) therapy, especially in melanoma. Patients with pre-existing skin autoimmune diseases (ADs) have been excluded from ICI studies for safety concerns, yet recent research has shown that dermatological ADs can be managed without discontinuing ICI therapy. Patients with ADs respond as well or better to ICIs and can be included as candidates in clinical trials. Frequently taken during ICI therapy, steroids impair immunotherapy efficacy in certain anatomical sites of tumors but not others, including the brain. ICI efficacy can be enhanced by radiotherapy without increasing adverse events, as neoadjuvant radiotherapy is thought to sensitize tumors to ICIs. This perspective highlights clinical autoimmune considerations of ICI therapy in melanoma and discusses important areas for future exploration.

On the Frontiers of Breast Cancer Diagnosis and Treatment: Current and Future Directions in a Rapidly Changing Field.

Breast cancer (BCa) represents a medically heterogeneous group of malignancies, with differing biological and genetic makeups [...].

Breast Cancer Disparities in Asian Women: The Need for Disaggregated Research.

Asian (AZN) women are a heterogeneous group, comprising a wide array of cultural beliefs, languages, and healthcare needs. Yet, studies of breast cancer (BCa) risks and outcomes predominately consider AZNs in aggregate, assuming that the distinct ethnicities have similar disease profiles and homogeneous responses to treatment. This stereotypical portrayal of AZNs as a homogenous group tends to mask disparities. For example, healthcare-seeking behaviors and attitudes of medical providers toward AZN BCa patients frequently differ within this group and from other races. Misconceptions may arise that significantly influence the prevention, detection, treatment, and post-therapeutic care of AZN women. In addition to low BCa screening rates among AZN women, disparities also exist in various stages of BCa treatment-omission of radiation after breast-conserving surgery, less access to hypofractionation, underutilization of hormonal therapy, and higher-cost treatment owing to high HER2+ incidence. In this perspective, we highlight the need for disaggregated research of BCa among AZN women and advocate for comprehensive, culturally sensitive strategies to address health disparities in this priority population. Improving BCa literacy and awareness, access to care, and equitable recruitment into clinical trials are a few amelioratory goals to consider in the future.

Pretreatment neutrophil-to-lymphocyte ratio as an important prognostic marker in stage III locally advanced non-small cell lung cancer: confirmatory results from the PROCLAIM phase III clinical trial.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is an important pretreatment marker of systemic inflammation and tumor aggressiveness. Increased levels of this ratio have been associated with reduced survival in several observational studies of lung cancer. However, supporting analyses from large clinical trial data are lacking. METHODS: To validate the prognostic role of NLR, the current study evaluated data from a randomized phase III study (PROCLAIM; clinicaltrial.gov ID: NCT00686959) of patients with stage IIIA/B, unresectable, non-squamous, non-small cell lung cancer (NSCLC), originally comparing combination pemetrexed-cisplatin chemoradiotherapy with etoposide-cisplatin chemoradiotherapy. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for survival were estimated using a Cox proportional hazards model. Models were adjusted for age, race, sex, stage, treatment, and body mass index (BMI). Patients were followed for a median of 24 months. RESULTS: Increased NLR levels at baseline were associated with reduced overall (PTrend <0.0001) and progression-free survival (PTrend <0.005). A similar but decreasing linear trend was not observed for lymphocytes count alone. CONCLUSIONS: These findings provide substantiating evidence that NLR, which is routinely available from standard blood testing of patients diagnosed with NSCLC, is an important inflammation-based prognostic marker for survival among patients with locally advanced disease undergoing chemoradiation. Future research will benefit by assessing the prognostic potential of NLR in the context of genetic mutations and molecular markers.

Role of radiation in extensive stage small cell lung cancer: a National Cancer Database registry analysis.

The role of prophylactic cranial irradiation (PCI) and thoracic radiation therapy (TRT) in extensive-stage small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with extensive-stage small cell lung cancer with no brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive polychemotherapy, had other palliative radiation or had missing information. A propensity score-matched analysis was also performed. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received PCI and 21% received TRT. The addition of PCI and TRT improved median survival and survival at 1 and 2 years (p ≤ 0.05). The propensity score-matched analysis confirmed the same overall survival benefit with both PCI and TRT. This registry-based analysis of >1500 accredited cancer programs shows that PCI and TRT are not commonly utilized for extensive-stage small cell lung cancer patients who are treated with multiagent chemotherapy. The addition of PCI and TRT significantly improves overall survival in this otherwise poor prognostic group. Further research is needed to confirm the role of PCI and TRT, especially in the era of improved systemic therapy.

Lay abstract The role of radiation therapy in patients with metastatic small cell lung cancer remains controversial. The authors examined the National Cancer Database and identified patients with metastatic small cell lung cancer without brain metastasis. Patients were excluded if they died 30 days from diagnosis, did not receive multiagent chemotherapy, had other palliative radiation or had missing information regarding treatment. A total of 21,019 patients were identified. The majority of patients did not receive radiation (69%), whereas 10% received radiation to the brain and 21% received radiation to their lungs. The addition of brain and lung radiation therapy improved median survival and survival at 1 and 2 years. The addition of prophylactic cranial irradiation and thoracic radiation therapy improves survival in extensive-stage small cell lung cancer. Future research is needed to evaluate the role of radiation in the era of chemoimmunotherapy.

A Pilot Study Examining the Prognostic Utility of Tumor Shrinkage on Cone-Beam Computed Tomography (CBCT) for Stage III Locally Advanced Non-Small Cell Lung Cancer Patients Treated with Definitive Chemoradiation.

There has been growing interest in utilizing information from cone-beam computed tomography (CBCT) to help guide both treatment delivery and prognosis. In this assessment of locally advanced unresectable stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation, we aimed to determine the survival advantage associated with using CBCT to measure tumor regression. Patient, tumor, and treatment characteristics were collected. The serial tumor shrinkage for each patient was determined from tumor volume contours on weekly CBCTs. Survival analysis was performed using the Kaplan-Meier technique and a Cox proportional hazards model. At least two-thirds of patients had a tumor volume reduction of at least 5% after each week of chemoradiation. A weekly reduction in tumor volume of 5% or greater seen on the CBCT images during radiation therapy was significantly associated with improved overall survival, which remained significant when adjusted for age, histology, grade, and T- and N-stages (p = 0.0036). Additionally, the presence of N3 disease was associated with a five-fold increased risk of recurrence (p = 0.0006) and a nearly three-fold increased risk of death (p = 0.053) compared with N0-N2 disease. Tumor volume shrinkage observed in the CBCT images during definitive chemoradiation holds promise as a prognostic indicator of stage III NSCLC, especially given its affordability, availability, and applicability. Further evaluation in a prospective fashion is warranted to validate the tumor volume shrinkage and its clinical utility.

Slow Burns: A Qualitative Study of Burn Pit and Toxic Exposures Among Military Veterans Serving in Afghanistan, Iraq and Throughout the Middle East.

During deployment to the Persian Gulf War and Southwest Asia theatre of operations, Veterans often experienced various hazards, foremost being open-air burn pits and oil well fires. While over 23 presumptive conditions (ranging from brain cancer, interstitial lung disease, and lymphomas to sleep/mood disorders, depression, and cognitive impairment) have been studied in connection with their military-related exposures, there is a paucity of qualitative research on this topic. This is especially true in the context of explanatory models and health belief systems, vis-à-vis underlying social and cultural factors. The current paper provides a balanced conceptual framework (summarizing causal virtues and shortcomings) about the challenges that Veterans encounter when seeking medical care, screening assessments and subsequent treatments.

Pathologic Complete Response (pCR) and Survival of Women with Inflammatory Breast Cancer (IBC): An Analysis Based on Biologic Subtypes and Demographic Characteristics.

In this US-based study of the National Cancer Database (NCDB), we examined 8550 patients diagnosed with non-metastatic, invasive inflammatory breast cancer (IBC) who received surgery from 2004⁻2013. Patients were grouped into four biologic subtypes (HR⁺/HER2-, HR⁺/HER2⁺, HR-/HER2⁺, HR-/HER2-). On average, women were 56 years of age at diagnosis and were followed for a median of 3.7 years. The majority were white (80%), had private health insurance (50%), and presented with poorly differentiated tumors (57%). Approximately 46% of the cancers were >5 cm. Most patients underwent mastectomy (94%) and received radiotherapy (71%). Differences by biologic subtypes were observed for grade, lymph node invasion, race, and tumor size (p < 0.0001). Patients experiencing pathologic complete response (pCR, 12%) vs. non-pCR had superior 5-year overall survival (OS) (77% vs. 54%) (p < 0.0001). Survival was poor for triple-negative (TN) tumors (37%) vs. other biologic subtypes (60%) (p < 0.0001). On multivariable analysis, TN-IBC, positive margins, and not receiving either chemotherapy, hormonal therapy or radiotherapy were independently associated with poor 5-year survival (p < 0.0001). In this analysis of IBC, categorized by biologic subtypes, we observed significant differential tumor, patient and treatment characteristics, and OS.

A simple matrix to predict treatment success and long-term survival among patients undergoing pancreatectomy.

BACKGROUND: A more accurate measure of long-term survival among patients who have undergone a successful resection for pancreatic adenocarcinoma may be computed by accounting for time already survived during the initial treatment window. METHODS: Patients diagnosed with pancreatic adenocarcinoma, from 2004 through 2013, were identified from the American College of Surgeons National Cancer Database (NCDB). A risk-stratification matrix was constructed including age, histopathologic factors and the use of adjuvant therapy, given successful treatment and survival at 3-month following diagnosis. RESULTS: A total of 25,897 patients (50% male, 53% >65 years of age) presented with stage I-III pancreatic cancer. The majority of patients had tumors >2 cm size (82%), grade I/II (65%), lymphatic invasion (LI) (66%), and negative margins (76%). A survival advantage for adjuvant therapy was observed among all patients, independent of their risk-profile. For example, a patient ≤65 years of age, with early stage cancer (size ≤2 cm, grade I/II, -ve LI, -ve margins) who received adjuvant therapy had a 62% probability of being alive beyond three years (95%CI = 59%-66%). In contrast, the survival probability decreased to 53% (95%CI = 59%-66%) without adjuvant therapy. CONCLUSIONS: These results provide surgeons and patients with more accurate information regarding long-term survival, as well as the benefit of opting for adjuvant therapy after successful pancreatic surgery.

The Association between Age, Comorbidities and Use of Radiotherapy in Women with Breast Cancer: Implications for Survival.

Background: Radiotherapy (RT) plays an important role in the management and survival of patients with breast cancer. The aim of this study was to examine the association between age, comorbidities and use of RT in this population. Methods: Patients diagnosed with breast cancer from 2004⁻2013 were identified from the American College of Surgeons National Cancer Database (NCDB). Follow-up time was measured from the date of diagnosis (baseline) to the date of death or censoring. Adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) were used as the measure of association. Results: Independently of comorbidities and other important outcome-related factors, patients >65 years of age who received RT survived significantly longer than those who did not receive RT (aHR = 0.53, 95% CI = 0.52⁻0.54). However, as women aged, those with comorbidities were less likely to receive RT (adjusted p-trend by age < 0.0001). Conclusions: The development of decision-making tools to assist clinicians, and older women with breast cancer and comorbidities, are needed to facilitate personalized treatment plans regarding RT. This is particularly relevant as the population ages and the number of women with breast cancer is expected to increase in the near future.

Increased risk of atrial fibrillation among patients undergoing coronary artery bypass graft surgery while receiving nitrates and antiplatelet agents.

Background Postoperative atrial fibrillation (POAF) is a frequent complication of coronary artery bypass graft (CABG) surgery. This arrhythmia occurs more frequently among patients who receive perioperative inotropic therapy (PINOT). Administration of nitrates with antiplatelet agents reduces the conversion rate of cyclic guanosine monophosphate to guanosine monophosphate. This process is associated with increased concentrations of free radicals, catecholamines, and blood plasma volume. We hypothesized that patients undergoing CABG surgery who receive PINOT may be more susceptible to POAF when nitrates are administered with antiplatelet agents. Methods Clinical records were examined from a prospectively maintained cohort of 4,124 patients undergoing primary isolated CABG surgery to identify POAF-associated factors. Results POAF risk was increased among patients receiving PINOT, and the greatest effect was observed when nitrates were administered with antiplatelet therapy. Adjustment for comorbidities did not substantively change the study results. Conclusions Administration of nitrates with certain antiplatelet agents was associated with an increased POAF risk among patients undergoing CABG surgery. Additional studies are needed to determine whether preventive strategies such as administration of antioxidants will reduce this risk.

Factors Associated with Discharge to a Skilled Nursing Facility after Transcatheter Aortic Valve Replacement Surgery.

An assumption regarding transcatheter aortic valve replacement (TAVR), a minimally invasive procedure for treating aortic stenosis, is that patients remain at, or near baseline and soon return to their presurgical home to resume activities of daily living. However, this does not consistently occur. The purpose of this study was to identify preoperative factors that optimally predict discharge to a skilled nursing facility (SNF) after TAVR. Delineation of these conditions is an important step in developing a risk stratification model to assist in making informed decisions. Data was extracted from the American College of Cardiology (ACC) transcatheter valve therapy (TVT) registry and the Society of Thoracic Surgeons (STS) database on 285 patients discharged from 2012⁻2017 at a tertiary referral heart institute located in the southeastern region of the United States. An analysis of assessment, clinical and demographic variables was used to estimate relative risk (RR) of discharge to a SNF. The majority of participants were female (55%) and white (84%), with a median age of 82 years (interquartile range = 9). Approximately 27% (n = 77) were discharged to a SNF. Age > 75 years (RR = 2.3, p = 0.0026), female (RR = 1.6, p = 0.019), 5-meter walk test (5MWT) >7 s (RR = 2.0, p = 0.0002) and not using home oxygen (RR = 2.9, p = 0.0084) were identified as independent predictive factors for discharge to a SNF. We report a parsimonious risk-stratification model that estimates the probability of being discharged to a SNF following TAVR. Our findings will facilitate making informed treatment decisions regarding this older patient population.

Local therapy for triple-negative breast cancer: a comprehensive review.

Owing to its aggressive course, triple-negative breast cancer remains an important clinical issue of current interest compared with hormone-receptor positive subtypes. Recent research has focused on determining the optimal local therapy (breast conversation therapy vs mastectomy) for this cancer subtype. In this overview, we examine outcomes based on immunohistochemistry, gene expression profiles, type of local therapy and in the era of neoadjuvant chemotherapy. Based on multiple observational reports risk for locoregional recurrence appears to be similar to reported outcomes in other subtypes. However, distant recurrence continues to be a significant concern for triple-negative breast cancer, indicating the need for better systemic therapies. To date, insufficient evidence exists to determine whether breast conserving therapy or mastectomy results in superior outcomes.

Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of 5058 patients.

BACKGROUND: Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas. METHODS: Patients with resected clinical American Joint Committee on Cancer TNM stage II or III adenocarcinomas of the stomach or GEJ from 2004 through 2013 were identified utilizing the National Cancer Data Base. Hazard ratios (HRs), 95% confidence intervals, and P values were computed using a Cox proportional hazards procedure. Multivariable models were adjusted for treatment regimen, age, race, ethnicity, tumor size, TNM stage, Charlson comorbidity index, and tumor grade. RESULTS: Patients receiving PECT had a 72% survival advantage compared with those treated with POCRT (5058 patients; HR, 0.58 [adjusted P<.0001]). The 5-year actuarial survival rate for PECT was 44% compared with 38% for POCRT. A statistically significant survival advantage for PECT also was observed when the analysis was stratified by clinical stage of disease (stage II [3192 patients]: adjusted HR, 0.79 [P = .041]; and stage III [1866 patients]: adjusted HR, 0.49 [P<.0001]). This benefit was greatest among patients with lymph node-positive disease who converted to lymph node-negative status with PECT. CONCLUSIONS: In this large series of patients with stage II/III resected gastric/GEJ adenocarcinomas from >1500 American College of Surgeons Commission on Cancer-accredited facilities, patients receiving PECT were shown to survive longer than those receiving POCRT. Cancer 2017;123:2909-17. © 2017 American Cancer Society.

Perioperative Inotrope Therapy and Atrial Fibrillation Following Coronary Artery Bypass Graft Surgery: Evidence of a Racial Disparity.

BACKGROUND AND OBJECTIVE: Following coronary artery bypass graft (CABG) surgery, mortality rates are significantly higher among black patients who experience postoperative atrial fibrillation (POAF). Perioperative inotropic therapy (PINOT) was associated with POAF in previous reports, but the extent to which race influences this association is unknown. In the present study, the relationship between PINOT, race, and POAF was examined in patients undergoing CABG surgery. METHODS AND SETTING: Clinical records were examined from a prospectively maintained cohort of 11,855 patients (median age 64 yrs; 70% male; 16% black) undergoing primary isolated CABG at a large cardiovascular institute in the southeastern region of the United States. Relative risk (RR) and 95% confidence intervals (CIs) were computed using log-binomial regression. MAIN RESULTS: The association between PINOT and POAF was significantly increased among black patients (adjusted RR 1.7, CI 1.4-2.0) compared with white patients (adjusted RR 1.3, CI 1.2-1.4) (pinteraction  = 0.013). CONCLUSIONS: These findings suggest that PINOT may be disproportionately associated with POAF among black patients undergoing CABG surgery. Additional studies are needed to examine further the potential underlying mechanisms of this association.

The survival benefit of neoadjuvant chemotherapy and pCR among patients with advanced stage triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive subtype that accounts for 15-20% of cases, with a higher incidence of relapse/death. Even with adjuvant chemotherapy, the 5 year distant metastasis-free survival rate remains low. A total of 452 tumor registry patients with TNBC and no evidence of metastatic disease were identified over the period of 1996-2011. The median age and follow-up time were 51 (range=21-88) and 3.9 (range=0.14-14) years. Approximately 75% of patients with stage III disease received neoadjuvant chemotherapy (NACT) compared with 47% for stage II. Patients with stage I disease predominantly received adjuvant chemotherapy (ACT). Among those who underwent NACT (n=202), 33% had a pathological complete response (pCR). Overall (OS) and disease-free (DFS) survival were significantly longer among patients achieving pCR (versus residual disease) following NACT (OS: all patients P<0.0001, stage II P<0.0001, stage III P=0.0062; DFS: all patients P<0.0001, stage II P=0.0011, stage III P=0.015). ACT was not associated with improved OS or DFS for stage III disease. Adjustment for age, chemotherapy, health insurance type, lymphovascular invasion, race, radiation, and surgery did not alter our results. These findings suggest that pCR following NACT is associated with improved survival among patients with TNBC, independent of diagnostic stage.