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.

Interaction of Vitamin D and Corticosteroid Use in Hospitalized COVID-19 Patients: A Potential Explanation for Inconsistent Findings in the Literature.

Vitamin D is an important immune-modulator with anti-inflammatory properties. While this prohormone has been studied extensively in the prevention and treatment of COVID-19, findings have been inconsistent regarding its overall benefit in patients hospitalized with COVID-19. Most studies to date have been observational in nature, not accounting for the use of corticosteroids. Furthermore, the few randomized clinical trials designed to examine the effect of vitamin D supplementation on COVID-19 outcomes have been relatively small and thus insufficiently powered to assure a balance of corticosteroid use between study arms. The current perspective addresses the interaction of vitamin D and corticosteroids as a potential explanation for the divergent results reported in the literature. Future research on vitamin D and COVID-19 will benefit by considering this interaction, especially among hospitalized patients requiring oxygen and mechanical ventilation.

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.

The Interaction of Vitamin D and Corticosteroids: A Mortality Analysis of 26,508 Veterans Who Tested Positive for SARS-CoV-2.

This data-based cohort consisted of 26,508 (7%) United States veterans out of the 399,290 who tested positive for SARS-CoV-2 from 1 March to 10 September 2020. We aimed to assess the interaction of post-index vitamin D (Vit D) and corticosteroid (CRT) use on 30-day mortality among hospitalized and non-hospitalized patients with coronavirus disease 2019 (COVID-19). Combination Vit D and CRT drug use was assessed according to four multinomial pairs (-|+, -|-, +|+, +|-). Respective categorical effects were computed on a log-binomial scale as adjusted relative risk (aRR). Approximately 6% of veterans who tested positive for SARS-CoV-2 died within 30 days of their index date. Among hospitalized patients, a significantly decreased aRR was observed for the use of Vit D in the absence of CRTs relative to patients who received CRTs but not Vit D (aRR = 0.30; multiplicity corrected, p = 0.0004). Among patients receiving systemically administered CRTs (e.g., dexamethasone), the use of Vit D was associated with fewer deaths in hospitalized patients (aRR = 0.51) compared with non-hospitalized patients (aRR = 2.5) (P-for-Interaction = 0.0071). Evaluating the effect of modification of these compounds in the context of hospitalization may aid in the management of COVID-19 and provide a better understanding of the pathophysiological mechanisms underlying this and future infectious disease outbreaks.

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.

The Prevention and Management of COVID-19: Seeking a Practical and Timely Solution.

We read with interest several manuscripts recently published in the International Journal of Environmental Research and Public Health (IJERPH) on the ongoing coronavirus pandemic. While these articles provide a well-rounded overview on the risk and current status of this virus, we herein add some relevant information on its etiology, prevention and management, especially for resource-limited healthcare systems. The use of protective actions is both complex and expensive. Affordable options are essential to respond to this and future viral outbreaks.

A Pilot Study of Airborne Hazards and Other Toxic Exposures in Iraq War Veterans.

During their deployment to Iraq in support of Operation Iraqi Freedom (OIF), many Veterans were exposed to a wide array of toxic substances and psychologic stressors, most notably airborne/environmental pollutants from open burn pits. Service members do not deploy whilst unhealthy, but often they return with a multitude of acute and chronic symptoms, some of which only begin to manifest years after their deployment. Our findings, while preliminary in nature, suggest that Iraq War Veterans who participated in our survey reported a decrease in overall physical fitness and increased respiratory clinical symptoms compared with pre-deployment periods. The objective of this report is to provide information that will benefit how combat Veterans are cared for post-deployment. Strategies for a wider and more comprehensive assessment and medical screening process post-deployment are recommended.

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.