Motivation to Join and Adhere to SilverSneakers Among Older Adults.

The purpose of this exploratory study was to determine the reasons why older adults begin attending SilverSneakers exercise program and why they continue to participate. Participants completed a survey (104 complete surveys). Initial attendance was mainly due to SilverSneakers being a health insurance benefit or hearing from a friend, with a lower percentage hearing from a health care provider. Factors that encouraged ongoing attendance included the level of programming, liking the instructor, and working out with peers. Statistically significant relationships were found between long-term adherence and a desire to promote fitness (p = .024) and social aspects of SilverSneakers (p < .01). These insights can be of value when planning outreach to older adults, as well as to promote retention, with physical activity programming.

Early-Stage Non-Small Cell Lung Cancer Stereotactic Body Radiation Therapy (SBRT) Outcomes in an Equal Access Military Setting.

Introduction Lung stereotactic body radiation therapy (SBRT) is a first-line treatment for early-stage lung cancer in non-surgical candidates or those who refuse surgery. We compared our institutional outcomes from a unique patient population with decreased barriers to care with a recently published prospective series. Materials and methods  We retrospectively reviewed all patients who received definitive lung SBRT at the Walter Reed National Military Medical Center from 2015 to 2020. All patients underwent a positron emission tomography-computed tomography (PET-CT) and all were presented at a multidisciplinary tumor board. Patients were treated on a Trubeam linear accelerator (LINAC)-based system with daily cone-beam CT. The results were qualitatively compared to outcomes from prospective studies including RTOG 0236 and RTOG 0618. Results A total of 105 patients with 114 lesions were included. Median age was 77 years and 54.7% had ≥ 40-pack year smoking history. 36.8% did not have pathologic confirmation. With a median follow-up of 24 months, three-year local control (LC), disease-free survival (DFS) and overall survival (OS) rates were 92.4%, 81.0%, and 80.0%, respectively. Rates of Grade 1 and 2 toxicity were 21.9% and 6.7% and no patients experienced Grade ≥ 3 toxicity. Conclusions In our military setting with universal coverage and routine multidisciplinary care, lung SBRT provides outcomes comparable to prospective studies conducted at high-volume academic centers. More than one-third of patients were treated empirically without pathologic confirmation of disease, demonstrating a difference between clinical trials and community practice. Further investigation is warranted to integrate multidisciplinary management and achieve equal access to care to bridge existing health disparities in the community setting.

Aneurysmal Fibrous Histiocytoma: A Large Soft Tissue Tumor with Metastases Treated with Palliative Radiation Therapy and Targeted Therapy.

Aneurysmal fibrous histiocytoma (AFH) is a rare variant of cutaneous fibrous histiocytoma, with low malignant potential and infrequent metastatic progression. We present the case of a 19-year-old female with a large AFH of the neck metastatic to soft tissue and treated with radiation therapy and molecularly targeted therapy. To our knowledge, this is the first report describing either radiation therapy and palliation or the use of targeted therapy in this uncommon malignancy and can provide insight into future therapeutic strategies.

Exploring the rationale for combining ionizing radiation and immune checkpoint blockade in head and neck cancer.

BACKGROUND: The ability of radiation to enhance antitumor immunity under specific experimental conditions is well established. Here, we explore preclinical data and the rationale for combining different radiation doses and fractions with immune checkpoint blockade immunotherapy. METHODS: We conducted a review of the literature. RESULTS: The ability of high-dose or hypofractionated radiation to enhance antitumor immunity resulting in additive or synergistic tumor control when combined with checkpoint blockade is well studied. Whether low-dose daily fractionated radiation does the same is less well studied and available data suggests it may be immunosuppressive. CONCLUSION: Although daily fractionated radiation is well established as the standard of care for the treatment of patients with head and neck cancer, how this radiation schema alters antitumor immunity needs further study. If the radiation doses and fractions alter antitumor immunity differently can have profound implications in the rational design of clinical trials investigating whether radiation can enhance response rates to immune checkpoint blockade.

PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation.

Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8+ T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8+ T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.

Pulmonary Microscopic Polyangiitis Presenting as Acute Respiratory Failure from Diffuse Alveolar Hemorrhage.

Microscopic polyangiitis and granulomatosis with polyangiitis are rare anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides that predominantly affect small to medium sized vessels of the lungs and kidneys. These syndromes are largely confined to older adults and often present sub-acutely following weeks to months of nonspecific prodromal symptoms. While both diseases often manifest within multiple organ systems concurrently, the disease spectrum of microscopic polyangiitis almost always includes the kidneys, while granulomatosis with polyangiitis is most commonly associated with pulmonary disease. We present two cases of rapid onset respiratory failure secondary to diffuse alveolar hemorrhage in young active duty military personnel. After serological testing and surgical lung biopsy, both patients were diagnosed with microscopic polyangiitis with isolated pulmonary involvement.

A single-institution review of 157 patients presenting with benign and malignant tumors of the ampulla of Vater: management and outcomes.

BACKGROUND: Although benign ampullary tumors are removed endoscopically, due to their potential to progress to malignant disease, the favored treatment for adenocarcinoma is pancreaticoduodenectomy. We reviewed our institution's experience in order to identify which patients were at highest risk of disease progression following surgical resection, as well as evaluate whether localized T1 tumors are best treated by pancreaticoduodenectomy. METHODS: We retrospectively reviewed 157 patients who presented with an ampullary mass, from 2001 to 2010, and identified 51 with benign adenoma and 106 with adenocarcinoma. RESULTS: Patients with malignant tumors most often presented with larger tumors and jaundice, which alone was predictive of survival (OR = 67). Forty-five percent of patients with pathologically confirmed T1 tumors had positive lymph nodes and median survival was modest at 60 months. Lymph node involvement was predictive of recurrence and decreased survival. CONCLUSION: Patients with malignant tumors often present with jaundice and larger tumors. These findings should warrant suspicion for cancer and expedited preoperative workup. Based on our finding that nearly half the patients with T1 tumors had positive lymph nodes, we recommend pancreaticoduodenectomy for any patient with biopsy proven adenocarcinoma who is a suitable candidate for surgery.

Prostate cancer risk allele specific for African descent associates with pathologic stage at prostatectomy.

PURPOSE: A region on chromosome 8q24 was recently identified as a novel prostate cancer risk locus. Inherited variation in this region is associated with prostate cancer risk in the general population (21-58%), and specific alleles show a strong association in African-American men. This study was designed to evaluate associations between 8q24 risk alleles and clinical variables, such as pathologic stage, age at diagnosis, and recurrence, in a case series of African-American men. EXPERIMENTAL DESIGN: Peripheral blood DNA samples from 114 African-American men with prostate cancer, including 106 who had undergone radical prostatectomy, were genotyped for six single-nucleotide polymorphisms on three 8q24 regions. The presence of these single-nucleotide polymorphisms was compared with clinicopathologic and follow-up data after radical prostatectomy. RESULTS: The mean age of diagnosis and follow-up time were 57.4 (+/-8.9) years and 49.1 (+/-31.6) months, respectively. Patients carrying the Broad11934905 A risk allele, which is specific for African ancestry, were more likely to have a higher pathologic stage (pT(3-4)) than individuals with the wild type (odds ratio, 4.48; 95% confidence interval, 1.42-14.14; P = 0.011). A trend toward increased frequency of and shorter time to biochemical recurrence was noted in patients with this risk allele on Kaplan-Meier unadjusted survival analysis (P = 0.076). CONCLUSIONS: The Broad11934905 polymorphism at 8q24, which is only found in people of African ancestry, is associated with an increase in non-organ-confined prostate cancer at prostatectomy. In addition, for those with this risk allele, there is a trend toward early biochemical recurrence that requires validation in larger studies.

In vitro studies of transcript initiation by Escherichia coli RNA polymerase. 1. RNA chain initiation, abortive initiation, and promoter escape at three bacteriophage promoters.

RNA chain initiation and promoter escape is the latter stage of transcription initiation. This stage is characterized by several well-defined biochemical events: synthesis and release of short RNA products ranging 2 to 15 nucleotides in length, release of the sigma subunit from the enzyme-promoter complex, and initial translocation of the polymerase away from the promoter. In this paper, we report the use of a steady-state transcription assay with [gamma-(32)P]ATP labeling to subject the RNA chain initiation-promoter escape reaction to quantitative analysis. The specific parameters we follow to describe the chain initiation-promoter escape process include the abortive and productive rates, the abortive probability, the abortive:productive ratio, and the maximal size of the abortive product. In this study, we measure these parameters for three bacteriophage promoters transcribed by Escherichia coli RNA polymerase: T7 A1, T5 N25, and T5 N25(antiDSR). Our studies show that all three promoters form substantial amounts of abortive products under all conditions we tested. However, each of the promoters shows distinct differences from the others when the various parameters are compared. At 100 microM NTP, in a 10 min reaction, the abortive and productive yields are 87 and 13%, respectively, for T7 A1; 97 and 3%, respectively, for T5 N25; and 99.4 and 0.6%, respectively, for T5 N25(antiDSR). These values correspond to approximately 7, 32, and 165 abortive transcripts per productive transcript for the three promoters, respectively. The yield of most of the abortive products is not affected by the elevated concentration of the NTP substrate corresponding to the next template-specified nucleotide; hence, abortive products are not normally formed through a simple process of "kinetic competition". Instead, formation of abortive products appears to be determined by intrinsic DNA signals embedded in the promoter recognition region and the initial transcribed sequence region of each promoter.

In vitro studies of transcript initiation by Escherichia coli RNA polymerase. 2. Formation and characterization of two distinct classes of initial transcribing complexes.

By following the kinetics of abortive and productive synthesis in single-round transcription assays, we confirm the existence of two general classes of initial transcribing complexes (ITCs), which we term "productive ITC" and "unproductive ITC". The productive ITCs are able to escape from the promoter rapidly to produce full-length transcripts, but only after carrying out an obligate series of abortive initiation steps. The unproductive ITCs were found to synthesize mostly abortive transcripts of 2-3 nucleotides and escape from the promoter extremely slowly, if at all. Formation of the unproductive ITC is not due to the inactive RNA polymerase. Instead, RNA polymerase molecules recovered from both the productive and unproductive ITC fractions were shown to carry out abortive and productive synthesis with both the partitioning tendency and transcription kinetics similar to those of the original enzyme. Our results suggest that early transcription complexes are partitioned into the productive and unproductive ITCs most likely during the formation of open promoter complexes. The extent of partitioning varies with individual promoter sequences and is dependent on the nature and concentration of the initiating nucleotide. Thus, multiple classes of ITCs can be formed during promoter binding and transcript initiation.

In vitro studies of transcript initiation by Escherichia coli RNA polymerase. 3. Influences of individual DNA elements within the promoter recognition region on abortive initiation and promoter escape.

Abortive initiation and promoter escape are two principal biochemical reactions occurring in the latter stage of transcript initiation. We have analyzed the influences of individual DNA elements within the promoter recognition region (PRR) on these reactions by measuring the quantitative initiation parameters that describe abortive initiation and promoter escape; these parameters are the abortive rate, the productive rate, the abortive:productive ratio, the abortive probability, and the maximum size of abortive transcripts. Changes in the individual DNA elements within the PRR can have a substantial effect on each of these parameters. The discriminator region and the -10 element primarily influence the abortive probability at positions 2-5 and 6-10, respectively, while the -10 and -35 conserved hexamers and the spacer region affect the abortive probability at positions 11-15. Surprisingly, transcription of a consensus promoter invariably gives a higher abortive yield, a higher abortive probability, a longer abortive ladder, and a lower productive rate than promoter variants carrying even a single deviation in the consensus hexamers. These results suggest that strong RNA polymerase-PRR interactions stall the polymerase at the promoter, thereby reducing the rate of promoter escape and consequently enhancing the extent of abortive initiation.