Molecular Simulations of Hydrogen Sorption in Semicrystalline High-Density Polyethylene: The Impact of the Surface Fraction of Tie-Chains.

The modeling of the barrier properties of semicrystalline polymers has gained interest following the possible application of such materials as protective liners for the safe supply of pressurized hydrogen. The mass transport in such systems is intimately related to the complex intercalation between the crystal and amorphous phases, which was approached in this work through an all-atom representation of high-density polyethylene structures with a tailored fraction of amorphous-crystalline connections (tie-chains). Simulations of the polymer pressure-volume-temperature data and hydrogen sorption were performed by means of molecular dynamics and the Widom test particle insertion method. The discretization of the simulation domains of the semicrystalline structures allowed us to obtain profiles of density, degree of order, and gas solubility. The results indicated that the gas sorption in the crystalline regions is negligible and that the confinement of the amorphous phase between crystals induces a significant increase in density and a drop in the sorption capacity, even in the absence of tie-chains. Adding ties between the crystal and the amorphous phase results in further densification, an increase of the lamella tilt angle, and a decrease in the degree of crystallinity and hydrogen sorption coefficient, in agreement with several literature references.

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care.

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Erythrocyte PIG-A mutant frequencies in cancer patients receiving cisplatin.

BACKGROUND: Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the current study, we have used the erythrocyte PIG-A assay to evaluate mutagenesis in non-tumor hematopoietic tissue of cancer patients receiving cisplatin chemotherapy. METHODS: Twenty-one head and neck cancer patients undergoing treatment with cisplatin were monitored for the presence of PIG-A mutant total erythrocytes and the young erythrocytes, reticulocytes (RETs), in peripheral blood for up to five and a half months from the initiation of the anti-neoplastic chemotherapy. RESULTS: PIG-A mutant frequency (MF) in RETs increased at least two-fold in 15 patients at some point of the monitoring, while the frequency of total mutant RBCs increased at least two-fold in 6 patients. A general trend for an increase in the frequency of mutant RETs and total mutant RBCs was observed in 19 and 18 patients, respectively. Only in one patient did both RET and total RBC PIG-A MFs did not increase at any time-point over the monitoring period. CONCLUSION: Cisplatin chemotherapy induces moderate increases in the frequency of PIG-A mutant erythrocytes in head and neck cancer patients. Mutagenicity measured with the flow cytometric PIG-A assay may serve as a tool for predicting adverse outcomes of genotoxic antineoplastic therapy.

Supporting the Health and Well-Being of Indigenous Communities: A Position Paper From the American College of Physicians.

Indigenous peoples in the United States experience many health disparities and barriers to accessing health care services. In addition, Indigenous communities experience poor social drivers of health, including disproportionately high rates of food insecurity, violence, and poverty, among others. These challenges are unsurprising, given historical societal discrimination toward Indigenous peoples and government policies of violence, forced relocation with loss of ancestral home, and erasure of cultures and traditions. Indigenous peoples have displayed resilience that has sustained their communities through these hardships. Through treaties between the federal government and Indigenous nations, the federal government has assumed a trust responsibility to provide for the health and well-being of Indigenous populations through the direct provision of health care services and financial support of tribally operated health systems. However, despite serving a population that has endured substantial historical trauma and subsequent health issues, federal programs serving Indigenous peoples receive inadequate federal funding and substantially fewer resources compared with other federal health care programs. Access to care is further challenged by geographic isolation and health care workforce vacancies. Given the history of Indigenous peoples in the United States and their treatment by the federal government and society, the American College of Physicians (ACP) asserts the federal government must faithfully execute its trust responsibility through increased funding and resources directed toward Indigenous communities and the undertaking of concerted policy efforts to support the health and well-being of Indigenous people. ACP believes that these efforts must be community-driven, Indigenous-led, and culturally appropriate and accepted, and center values of respect and self-determination.

Stem Cell Theory of Cancer: Implications for Translational Research from Bedside to Bench.

A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.

Long-Term Services and Supports for Older Adults: A Position Paper From the American College of Physicians.

The number of Americans aged 65 years or older is expected to increase in the coming decades. Because the risk for disability increases with age, more persons will need long-term services and supports (LTSS) to help with bathing, eating, dressing, and other everyday tasks. Long-term services and supports are delivered in nursing homes, assisted living facilities, the person's home, and other settings. However, the LTSS sector faces several challenges, including keeping patients and staff safe during the COVID-19 pandemic, workforce shortages, quality problems, and fragmented coverage options. In this position paper, the American College of Physicians offers policy recommendations on LTSS coverage, financing, workforce, safety and quality, and emergency preparedness and calls on policymakers and other stakeholders to reform and improve the LTSS sector so that care is high quality, accessible, equitable, and affordable.

Strengthening Food and Nutrition Security to Promote Public Health in the United States: A Position Paper From the American College of Physicians.

Food insecurity functions as a social driver of health, directly negatively impacting health status and outcomes, which can further negatively impact employment and income and increase medical expenditures-all of which exacerbates food insecurity. Progress in meaningfully reducing the food-insecurity rate has stalled in recent years. Although rates have decreased since their peak during the Great Recession, these gains have been reversed by the economic implications of the COVID-19 pandemic. As the federal government is the largest provider of food assistance, there is much potential in better leveraging nutrition assistance programs like the Supplemental Nutrition Assistance Program (SNAP) and the Child Nutrition Programs to increase access to healthful foods and improve public health. However, these programs face many funding challenges and internal shortcomings that create uncertainties and prevent maximal effect. Physicians and other medical professionals also have a role in improving nutritional health by screening for food insecurity and serving as connectors between patients, community organizations, and government services. Governments and payers must support these efforts by providing sufficient resources to practices to fulfill this role. In this position paper, the American College of Physicians (ACP) offers several policy recommendations to strengthen the federal food-insecurity response and empower physicians and other medical professionals to better address those social drivers of health occurring beyond the office doors.

An advanced molecular medicine case report of a rare human tumor using genomics, pathomics, and radiomics.

Background: Pulmonary Sclerosing Pneumocytoma (PSP) is a rare tumor of the lung with a low malignant potential that primarily affects females. Initial studies of PSP focused primarily on analyzing features uncovered using conventional X-ray or CT imaging. In recent years, because of the widespread use of next-generation sequencing (NGS), the study of PSP at the molecular-level has emerged. Methods: Analytical approaches involving genomics, radiomics, and pathomics were performed. Genomics studies involved both DNA and RNA analyses. DNA analyses included the patient's tumor and germline tissues and involved targeted panel sequencing and copy number analyses. RNA analyses included tumor and adjacent normal tissues and involved studies covering expressed mutations, differential gene expression, gene fusions and molecular pathways. Radiomics approaches were utilized on clinical imaging studies and pathomics techniques were applied to tumor whole slide images. Results: A comprehensive molecular profiling endeavor involving over 50 genomic analyses corresponding to 16 sequencing datasets of this rare neoplasm of the lung were generated along with detailed radiomic and pathomic analyses to reveal insights into the etiology and molecular behavior of the patient's tumor. Driving mutations (AKT1) and compromised tumor suppression pathways (TP53) were revealed. To ensure the accuracy and reproducibility of this study, a software infrastructure and methodology known as NPARS, which encapsulates NGS and associated data, open-source software libraries and tools including versions, and reporting features for large and complex genomic studies was used. Conclusion: Moving beyond descriptive analyses towards more functional understandings of tumor etiology, behavior, and improved therapeutic predictability requires a spectrum of quantitative molecular medicine approaches and integrations. To-date this is the most comprehensive study of a patient with PSP, which is a rare tumor of the lung. Detailed radiomic, pathomic and genomic molecular profiling approaches were performed to reveal insights regarding the etiology and molecular behavior. In the event of recurrence, a rational therapy plan is proposed based on the uncovered molecular findings.

Health Care for Our Nation's Veterans: A Policy Paper From the American College of Physicians.

The Veterans Health Administration (VHA) is the United States' largest integrated health care delivery system, serving over 9 million enrollees at nearly 1300 health care facilities. In addition to providing health care to the nation's military veterans, the VHA has a research and development program, trains thousands of medical residents and other health care professionals, and conducts emergency preparedness and response activities. The VHA has been celebrated for delivering high-quality care to veterans, early adoption of electronic medical records, and high patient satisfaction. However, the system faces challenges, including implementation of an expanded community care program, modernization of its electronic medical records system, and providing care to a population with complex needs. The position paper offers policy recommendations on VHA funding, the community care program, medical and health care professions training, and research and development.

Financial Profit in Medicine: A Position Paper From the American College of Physicians.

The steady growth of corporate interest and influence in the health care sector over the past few decades has created a more business-oriented health care system in the United States, helping to spur for-profit and private equity investment. Proponents say that this trend makes the health care system more efficient, encourages innovation, and provides financial stability to ensure access and improve care. Critics counter that such moves favor profit over care and erode the patient-physician relationship. American College of Physicians (ACP) underscores that physicians are permitted to earn a reasonable income as long as they are fulfilling their fiduciary responsibility to provide high-quality, appropriate care within the guardrails of medical professionalism and ethics. In this position paper, ACP considers the effect of mergers, integration, private equity investment, nonprofit hospital requirements, and conversions from nonprofit to for-profit status on patients, physicians, and the health care system.

A Case of Metastatic Pancreatic Adenocarcinoma in Complete Remission Using Chemotherapy and Immunotherapy.

Among the various types of cancer, pancreatic cancer is considered to have a particularly grim prognosis. Treatment includes surgery, chemotherapy, or both. While the role of immunotherapy is well-studied in many types of cancer, such is not the case with pancreatic cancer. A 49-year-old female presented to the oncology clinic following a biopsy of a pancreatic mass. CT-guided needle biopsy of the mass demonstrated moderately differentiated pancreatic adenocarcinoma. Positive emission tomography-computed tomography (PET-CT) revealed metastases to the liver. She was started on chemotherapy with FOLFIRINOX (leucovorin calcium, 5-fluorouracil, irinotecan hydrochloride, oxaliplatin) and demonstrated over 60% reduction in the size of liver metastases within three months. PET-CT four months after initiation of chemotherapy revealed no focal avid fluorodeoxyglucose (FDG) uptake in the liver, and the pancreatic body mass was stable in size at 3.0 cm with stable standardized uptake value (SUV) max at 2.4, only slightly elevated from 1.9 on the previous scan. Further treatment with chemotherapy was halted after 18 cycles due to side effects. With the patient's tumor being epidermal growth factor receptor (EGFR) negative, mismatch repair (MMR) negative, 3% tumor cells PD-L1 positive with 10% tumor-associated immune cells positive, treatment with pembrolizumab was started. Follow-up PET-CTs over the next several months confirmed the patient was in complete remission from metastatic pancreatic cancer. At the time of the report, the patient had a durable response of three years. We report a rare case of complete remission of metastatic pancreatic adenocarcinoma treated with chemotherapy, followed by immunotherapy. With emerging targets for modification of tumor microenvironment, immunotherapy must be further explored in the treatment of pancreatic cancer.

Nanoparticle albumin-bound paclitaxel with cetuximab and carboplatin as first-line therapy for recurrent or metastatic head and neck cancer: A single-arm, multicenter, phase 2 trial.

OBJECTIVES: Macropinocytosis promotes internalization of albumin into cells to serve as a nutrient supply and is constitutively driven by signaling pathways frequently hyperactivated in head and neck squamous-cell carcinoma (HNSCC). In this way, drugs bound to albumin may selectively target HNSCC. nab-paclitaxel is a nanoparticle albumin-bound formulation of paclitaxel that improves drug delivery into tumor compared to paclitaxel. The primary aim of this single-arm, multicenter, phase 2 trial was to determine if nab-paclitaxel, cetuximab, and carboplatin (CACTUX regimen) would result in longer progression-free survival (PFS) than the historical regimen (EXTREME: 5-fluorouracil, cetuximab, and a platinum). MATERIALS AND METHODS: Patients with untreated recurrent or metastatic HNSCC received six, three-week cycles of nab-paclitaxel, cetuximab, and carboplatin, followed by maintenance nab-paclitaxel and cetuximab until progression. We hypothesized the median PFS with CACTUX would be 35% longer than with EXTREME (corresponding to 7.6 vs 5.6 months; power 0.80, α = 0.05, one-sided test, n = 70). Secondary outcomes included objective response rate (ORR) and overall survival (OS). RESULTS: Seventy-four patients enrolled into the trial; seventy were evaluable. The median PFS was 6.1 months (95% CI, 4.1-7.4). The ORR was 60%. Median follow-up was 18 months (IQR: 4.7-23). The median OS was 17.8 months (95% CI, 8.5-21.7) for all patients, and 19.8 months (95% CI, 10.9-22.0) for human papillomavirus (HPV)-related oropharynx SCC and 14.0 months (95% CI, 4.6-23.3) for HPV-unrelated HNSCC. CONCLUSION: Among patients with recurrent or metastatic HNSCC, CACTUX did not result in a longer PFS than historical EXTREME. However, CACTUX did result in a more favorable ORR and OS.

A Comprehensive Policy Framework to Understand and Address Disparities and Discrimination in Health and Health Care: A Policy Paper From the American College of Physicians.

Racial and ethnic minority populations in the United States experience disparities in their health and health care that arise from a combination of interacting factors, including racism and discrimination, social drivers of health, health care access and quality, individual behavior, and biology. To ameliorate these disparities, the American College of Physicians (ACP) proposes a comprehensive policy framework that recognizes and confronts the many elements of U.S. society, some of which are intertwined and compounding, that contribute to poorer health outcomes. In addition to this framework, which includes high-level principles and discusses how disparities are interconnected, ACP offers specific policy recommendations on disparities and discrimination in education and the workforce, those affecting specific populations, and those in criminal justice practices and policies in its 3 companion policy papers. ACP believes that a cross-cutting approach that identifies and offers solutions to the various aspects of society contributing to poor health is essential to achieving its goal of good health care for all, poor health care for none.

Pembrolizumab-Induced Cold Agglutinin Disease.

BACKGROUND The introduction of immunotherapy in the management of metastatic lung cancer appears to be changing their natural history. Most patients tolerate immunotherapy without any significant adverse events. Nevertheless, a significant number of patients still experience adverse effects. Autoimmune hemolytic anemia has been described as mostly related to warm autoantibodies. The following case report describes cold agglutinin disease with hemolysis secondary to Pembrolizumab therapy for the treatment of metastatic lung cancer. CASE REPORT A 58-year-old woman noted a left neck mass 4 months prior to her presentation. A biopsy confirmed the presence of metastatic adenocarcinoma, consistent with primary lung cancer. Further evaluation revealed the tumor to be PDL-1-positive. She was started on Pembrolizumab, Pemetrexed, and carboplatin chemotherapy regimen. Her CBC was within normal limits when she started therapy, but within 4 weeks hemoglobin dropped to 4.3 g/dL. Further evaluation showed high cryoglobulin levels and a high cold agglutinin titer. Complement C3 DAT was positive. A peripheral smear showed clumps of red cells and the serum IgM was elevated. The diagnosis of CAD was made. She was then started on Rituximab. Imaging showed a significant response, with decreased disease burden. CONCLUSIONS Our case shows a unique presentation of CAD, initially presumed to be myelosuppression secondary to chemotherapy. Instead, a peripheral smear revealed Pembrolizumab to be the cause of cold agglutinin disease. Due to the relatively unknown association between these 2 entities, patient care was delayed. Finally, after initiation of Rituximab therapy, the patient's CBC began to recover.

Racism and Health in the United States: A Policy Statement From the American College of Physicians.

Racial minorities in the United States have reported experiencing widespread racism throughout all aspects of life, from housing to education to employment. Existing research has examined the role of racism, discrimination, and violence in one's interaction with the health care system and their association with poorer mental and physical health. Systemic racism that underlies the fabric of society often manifests itself in prominent institutions, such as law enforcement agencies, regardless of individual intent. Overt and covert racist laws and policies, personal implicit biases, and other factors result in Black individuals and other people of color being the subject of law enforcement violence and criminal justice system interactions at disproportionately high rates. The demonstrated association between discriminatory law enforcement practices and violence and personal and community health necessitates treating these issues as public health issues worthy of a public policy intervention. Addressing some of the sources of institutional racism and harm through transparency and accountability measures is the first of many steps required to begin correcting historical racial injustices.

An assessment of Oxford Nanopore sequencing for human gut metagenome profiling: A pilot study of head and neck cancer patients.

Gut metagenome profiling using the Oxford Nanopore Technologies (ONT) sequencer was assessed in a pilot-sized study of 10 subjects. The taxonomic abundance of gut microbiota derived from ONT was comparable with Illumina Technology (IT) for the high-abundance species. IT better detected low-abundance species through amplification, when material was limited.

The Role of Immunotherapy and Radiation Therapy in Tumor Chemosensitivity in Advanced Head and Neck Cancer.

BACKGROUND Cancer is the second leading cause of death internationally, resulting in millions of deaths each year. While treatment in the past has heavily relied on surgery and radiotherapy, chemotherapy and immunotherapy are being increasingly utilized depending on disease presentation. CASE REPORT A 56-year-old male presented to the Emergency Department with a 3-week history of a rapidly enlarging left supraclavicular neck mass. Computed tomography scan revealed a 12×13 cm mass extending from the angle of the mandible to the supraclavicular area. A biopsy confirmed advanced stage squamous cell carcinoma of the head and neck. The patient was started on a chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TCF). The tumor progressed through chemotherapy, which was switched to cetuximab; however, this therapy was discontinued after an anaphylactic reaction. Palliative radiation treatment was begun along with pembrolizumab. Pembrolizumab was continued, and after 9 cycles, the patient's cancer was almost in complete remission. Three months later, disease progression was once again noted with pembrolizumab treatment, which was subsequently discontinued. The patient was started on paclitaxel and carboplatin chemotherapy regimen as a last resort, despite failure of prior TCF treatment, and the patient responded, this time with complete remission in 4 months. CONCLUSIONS This case demonstrates a unique outcome in which a patient who previously was resistant to chemotherapy, later responded to chemotherapy after a trial of radiation therapy and immunotherapy. Immunotherapy may have a synergistic effect with radiation therapy and play a role in tumor sensitivity to chemotherapy in head and neck cancer treatment.

Metastatic laryngeal large cell neuroendocrine carcinoma: A rare case of presentation and extreme tumor burden.

Large cell neuroendocrine carcinoma (LCNEC) of the larynx is an aggressive form of neuroendocrine carcinoma that affects smokers at an average age of 60 years. LCNEC is characterized by large cells with round to ovoid nuclei distributed in a trabecular or nested growth pattern. Previously, laryngeal LCNEC and atypical carcinoid tumors were considered identical; however, laryngeal LCNEC has been shown to have higher mitotic rates and worse prognosis, which has led to laryngeal LCNEC's being separated from atypical carcinoid and classified as a poorly differentiated neuroendocrine carcinoma in the most recent World Health Organization classification. We present a case of a 56-year-old female who presented with painful subcutaneous skin lesions that were diagnosed as metastatic carcinoma at an outside facility. Subsequent workup revealed a primary epiglottic lesion. Over the next 4 years, she continued to develop over 100 similar subcutaneous nodules. Additional workup confirmed neuroendocrine differentiation, thus clarifying the diagnosis of metastatic LCNEC. Review of literature has revealed only 1 reported case of LCNEC with skin metastasis. This is the first reported case in which skin metastasis was the initial presenting symptom; moreover, our case is unique with regard to the heavy metastatic burden to the skin.

Bortezomib with or without irinotecan in relapsed or refractory colorectal cancer: results from a randomized phase II study.

PURPOSE: To evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC). PATIENTS AND METHODS: Patients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m(2) (arm A) or bortezomib 1.3 mg/m(2) plus irinotecan 125 mg/m(2) (arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability. RESULTS: A preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade >or= 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B. CONCLUSION: Bortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.