Invasive Nodal Staging via Endobronchial Ultrasound and Outcome in Patients Treated with Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer - Results from a Single Institution Study.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an effective treatment for medically inoperable early-stage non-small cell lung cancer (NSCLC). The prognostic value of invasive nodal staging (INS) for patients undergoing SRBT has not been studied extensively. Herein, we report the impact of INS in addition to 18F-FDG-PET on treatment outcome for patients with NSCLC undergoing SBRT. MATERIALS AND METHODS: Patients with stage I/ II NSCLC who underwent SBRT were included with IRB approval. Clinical, dosimetric, and radiological data were obtained. Overall survival (OS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), and distant recurrence free survival (DRFS) were analyzed using Kaplan Meyer method. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to assess the relationship between the variables and the outcomes. RESULTS: A total of 376 patients were included in the analysis. Median follow up was 43 months (IQ 32.6-45.8). Median OS, LRFS, RRFS, DRFS were 40, 32, 32, 33 months, respectively. The 5-year local, regional, and distant failure rates were 13.4%, 23.5% and 25.3%, respectively. The 1-year, 3-year and 5-year OS were 83.8%, 55.6%, and 36.3%, respectively. On MVA, INS was not a predictor of either improved overall or any recurrence free survival endpoints while larger tumor size, age, and adjusted Charleston co-morbidity index (aCCI) were significant for inferior LRFS, RRFS, and DRFS. CONCLUSION: Invasive nodal staging did not improve overall or recurrence free survival among patients with early-stage NSCLC treated with SBRT whereas older age, aCCI, and larger tumor size were significant predictors of LRFS, RRFS, and DRFS.

Characteristics of Patients With Second Primary Lung Cancer Following Breast Cancer: A Retrospective Descriptive Study.

BACKGROUND: Breast cancer (BC) is the most common noncutaneous malignancy in women and survivors are at an increased risk for secondary malignancy with lung cancer (LC) being the most common. There are few studies that have explored the clinicopathological specifics of LC in BC survivors. METHODS: In this single-institution, retrospective study, we identified BC survivors who subsequently developed LC, examined their breast and LC clinical and pathological characteristics and compared them to the general BC and LC population as published in the literature. RESULTS: In our study, we found the following associations that could be meaningful: an association between receiving radiation (RT) and LC (including a statistically significant P = .03 chance of ipsilateral LC after BC treatment with RT), a higher incidence and amount of smoking and LC, high BRCA positivity (78.9%) in the few patients who had germline testing, and a higher incidence of EGFR mutations in NSCLC after BC (60.9%) as well as an earlier stage of NSCLC disease. CONCLUSION: Treatments such as RT, genetic factors such as BRCA mutations, and tobacco use may increase the risk of developing LC amongst BC survivors. Exploring this further can potentially lead to better risk stratification through modified low-dose CT chest screening protocols to catch LCs earlier and ultimately improve outcomes. Past studies have shown that BC survivors who are subsequently diagnosed with NSCLC may have improved OS compared with primary NSCLC and our study showed a high incidence of EGFR mutated NSCLC, which also suggest both improved prognosis and a different molecular profile of NSCLC, which warrants further investigation. Lastly, BC survivors who subsequently are diagnosed with NSCLC had earlier stage disease in our study, perhaps a result of surveillance, highlighting the importance of close monitoring of BC survivors.

Phase I trial of dose-escalated stereotactic radiosurgery (SRS) boost for unfavorable locally advanced oropharyngeal cancer.

BACKGROUND AND PURPOSE: Patients with locally advanced oropharynx squamous cell carcinoma have suboptimal outcomes with standard chemoradiation. Here, we evaluated toxicity and oncologic outcomes of dose escalation using radiosurgical boost for patients with unfavorable oropharynx squamous cell carcinoma. MATERIALS AND METHODS: Between 2010-2017, Thirty four patients with intermediate- or high-risk oropharynx squamous cell carcinoma were enrolled onto this prospective phase I trial. Each patient received concurrent cisplatin and fractionated radiotherapy totaling 60 Gy or 66 Gy followed by radiosurgery boost to areas of residual gross tumor: single fraction of 8 Gy or 10 Gy, or two fractions of 5 Gy each. Primary endpoint was treatment toxicity. Secondary endpoints were local, regional, and distant disease control. RESULTS: Eleven, sixteen and seven patients received radiosurgery boost with 8 Gy in 1 fraction, 10 Gy in 1 fraction, and 10 Gy in 2 fractions respectively. Acute toxicities include 4 patients with tumor necrosis causing grade 3 dysphagia, of which 3 developed grade 4 pharyngeal hemorrhage requiring surgical intervention. At 24 months after treatment, 7%, 9%, and 15% had grade 2 dysgeusia, xerostomia, and dysphagia, respectively, and two patients remained feeding tube dependent. No grade 5 toxicities occurred secondary to treatment. Local, regional, and distant control at a median follow up of 4.2 years were 85.3%, 85.3% and 88.2%, respectively. Five patients died resulting in overall survival of 85.3%. CONCLUSIONS: This study is the first to report the use of radiosurgery boost dose escalation in patients with unfavorable oropharynx squamous cell carcinoma. Longer follow-up, larger cohorts, and further refinement of boost methodology are needed prior to implementation in routine clinical practice. TRIAL REGISTRATION: Northwell Health Protocol #09-309A (NCT02703493) ( https://clinicaltrials.gov/ct2/show/NCT02703493 ).

Stereotactic body radiotherapy as primary treatment for elderly and medically inoperable patients with head and neck cancer.

BACKGROUND: Patients with head and neck cancer (HNC) who are not candidates for definitive treatment represent an increasing challenge, with limited data to guide management. Conventional local therapies such as surgery and chemoradiation can significantly impact quality of life (QoL). There has been limited data published using stereotactic body radiotherapy (SBRT) as primary treatment in previously unirradiated patients. We hypothesize that SBRT provides high rates of control while limiting toxicity. METHODS: A total of 66 medically unfit previously unirradiated patients with HNC were treated with SBRT, consisting of 35-40 Gy to gross tumor volume and 30 Gy to clinical target volume in five fractions. RESULTS: Median age was 80 years. Local control (LC) and overall survival (OS) at 1 year were 73% and 64%. Two patients experienced grade 3 toxicity. CONCLUSION: SBRT shows acceptable outcomes with relatively low toxicity in previously unirradiated patients with HNC who are medically unfit for conventional treatment. SBRT may provide an aggressive local therapy with high rates of LC and OS while maintaining QoL.

Morbidity and Mortality of Meningioma Resection Increases in Octogenarians.

BACKGROUND: The incidence of meningioma has increased drastically recently, particularly in older adults. Surgical intervention has the potential to reduce neurologic symptoms and achieve favorable, long-term outcomes. There is considerable variability in the literature examining the relationship between age and outcomes after meningioma surgery. The objective of this study was to identify the relationship between age and postoperative complications after craniotomy for resection of meningioma. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify patients undergoing craniotomy for meningioma resection between 2005 and 2012. Multivariate analysis was used to identify associations between age and postoperative complications. RESULTS: Age >80 years is an independent risk factor for any complication (odds ratio [OR], 2.374; 95% confidence interval [CI], 1.3-4.4; P = 0.015), death within 30 days of surgery (OR, 15.7; 95% CI, 3.0-81.0; P < 0.001), and length of stay >5 days (OR, 3.2; 95% CI, 1.8-5.6; P < 0.001). CONCLUSIONS: Advanced age, particularly >80 years, is an independent predictor of morbidity and mortality in patients undergoing craniotomy for resection of meningioma. As such, it should be considered in preoperative optimization and risk stratification.

Palliation of Ulcerative Breast Lesions with Radiation.

BACKGROUND/AIM: Patients with advanced breast cancer may experience ulcerative breast lesions. Breast cancer with ulcerative lesions has been shown to severely affect a patient's quality of life (QoL). The role of palliative radiation therapy (RT) in the management of ulcerative breast lesions needs to be further explored. PATIENTS AND METHODS: We retrospectively reviewed the RT records for all patients who underwent palliative RT for breast cancer at our urban academic medical center. A total of 13 patients were identified, and we herein report their demographics, treatment characteristics, and clinical outcomes. RESULTS: The mean age of the patients receiving palliative RT for ulcerative breast cancer was 64 years. All patients had stage IV disease when they were evaluated for RT. The mean radiation dose received for palliative RT was 27.54 Gy in 11 fractions, with a median dose of 30 Gy in 15 fractions. Six (46%) patients had received prior RT to the same breast, with a median dose of 59.5 Gy in 31 fractions. Among these six patients, the average interval between initial RT and ulceration was 69.5 months. The median overall survival for the whole patient cohort since ulceration was 5 months and the mean survival did not differ between patients with previous history of RT and RT-naïve patients (4.50 vs. 4.57; p=0.95). Six out of the nine (69%) patients who received 30 Gy or more reported clinical improvement, whereas none of the four patients who received less than 30 Gy reported any benefit. There were no radiation-associated toxicities reported by patients. CONCLUSION: These data suggest that palliative RT (≥30 Gy) is an efficacious treatment for ulcerative breast cancer with minimal toxicity. Prior RT should not be a contraindication, as patients with previous history of RT have similar low toxicity rates compared to RT-naïve patients.

Adjuvant Therapy for Salivary Gland Carcinomas.

AIM: We compared the clinical outcomes and toxicity profile among a retrospective cohort of patients with primary major salivary gland carcinomas (SGCs) treated with surgery followed by adjuvant radiation therapy (S+RT) versus surgery and adjuvant chemoradiotherapy (S+CRT). PATIENTS AND METHODS: Twenty patients (71%) underwent S+RT and eight (29%) S+CRT at our Institution between 2006 and 2015. Microscopic positive margins were present in 54% of the patients. RESULTS: The 3-year overall survival (OS) was 100% with S+RT and 87.5% with S+CRT (p=0.141) and locoregional control (LRC) was 95% with S+RT and 87.5% with S+CRT (p=0.383). There were no significant differences in the rate of acute (p=0.801) and late (p=0.714) toxicities. CONCLUSION: While we await randomized data, adjuvant CRT may be considered as a viable therapeutic option for patients at high-risk of local or regional recurrence, especially in those with a positive microscopic margin where further surgery may result in functional cranial neuropathies.

MALT Lymphoma of the Bladder: A Case Report and Review of the Literature.

The presentation of a MALT lymphoma in the bladder is exceedingly rare. Furthermore, the optimal treatment of primary MALT confined to the bladder remains to be defined. Here, we report a case of a 65-year-old female with primary MALT lymphoma treated with definitive radiation therapy. The patient received a total dose of 30 Gy in 20 equal daily fractions to the bladder and tolerated the treatment well. In addition, we have extensively reviewed the relevant literature to better define the optimal management of this rare disease. In conclusion, primary MALT lymphoma of the bladder represents a rare malignancy with excellent prognosis if detected at an early stage. For early stage disease, definitive radiation represents an excellent treatment modality with a minimal side-effect profile.

Targeting multiple pathogenic mechanisms with polyphenols for the treatment of Alzheimer's disease-experimental approach and therapeutic implications.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and currently has no cure. Its onset and progression are influenced by multiple factors. There is growing consensus that successful treatment will rely on simultaneously targeting multiple pathological features of AD. Polyphenol compounds have many proven health benefits. In this study, we tested the hypothesis that combining three polyphenolic preparations (grape seed extract, resveratrol, and Concord grape juice extract), with different polyphenolic compositions and partially redundant bioactivities, may simultaneously and synergistically mitigate amyloid-ß (Aß) mediated neuropathology and cognitive impairments in a mouse model of AD. We found that administration of the polyphenols in combination did not alter the profile of bioactive polyphenol metabolites in the brain. We also found that combination treatment resulted in better protection against cognitive impairments compared to individual treatments, in J20 AD mice. Electrophysiological examination showed that acute treatment with select brain penetrating polyphenol metabolites, derived from these polyphenols, improved oligomeric Aß (oAß)-induced long term potentiation (LTP) deficits in hippocampal slices. Moreover, we found greatly reduced total amyloid content in the brain following combination treatment. Our studies provided experimental evidence that application of polyphenols targeting multiple disease-mechanisms may yield a greater likelihood of therapeutic efficacy.

Molecular topology as novel strategy for discovery of drugs with aß lowering and anti-aggregation dual activities for Alzheimer's disease.

BACKGROUND AND PURPOSE: In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer's disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy. EXPERIMENTAL APPROACH: We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of ß-amyloid (Aß) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aß lowering and anti-Aß oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features. CONCLUSION AND IMPLICATIONS: Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aß lowering and anti-aggregation dual activities for AD.

Epigenetic mechanisms linking diabetes and synaptic impairments.

Diabetes is one of the major risk factors for dementia. However, the molecular mechanism underlying the risk of diabetes for dementia is largely unknown. Recent studies revealed that epigenetic modifications may play a role in the pathogenesis of diabetes. We hypothesized that diabetes may cause epigenetic changes in the brain that may adversely affect synaptic function. We found significant elevation in the expression of histone deacetylases (HDACs) class IIa in the brains of diabetic subjects compared with control subjects, and these changes coincide with altered expression of synaptic proteins. In a mouse model of diet-induced type 2 diabetes (T2D), we found that, similar to humans, T2D mice also showed increased expression of HDAC IIa in the brain, and these alterations were associated with increased susceptibility to oligomeric Aß-induced synaptic impairments in the hippocampal formation and eventually led to synaptic dysfunction. Pharmacological inhibition of HDAC IIa restored synaptic plasticity. Our study demonstrates that diabetes may induce epigenetic modifications affecting neuropathological mechanisms in the brain leading to increased susceptibility to insults associated with neurodegenerative or vascular impairments. Our study provides, for the first time, an epigenetic explanation for the increased risk of diabetic patients developing dementia.

IVIG immunotherapy protects against synaptic dysfunction in Alzheimer's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway.

BACKGROUND: Complement component C5-derived C5a locally generated in the brain has been shown to protect against glutamate-induced neuronal apoptosis and beta-amyloid (Aß) toxicity, but the mechanism is not clear. In this study, we tested the hypothesis that C5a influences upstream signal transduction pathways associated with cAMP-response element-binding protein (CREB) activation, in which alterations of CREB levels are associated with cognitive deterioration in AD. METHODS: CREB signaling pathway, synaptic plasticity and cognitive function were studied in C5a receptor knockout mice (C5aR(-/-)), C5a over expressing mice (C5a/GFAP) and in Tg2576 mice, an AD mouse model. RESULTS: (1) Cognitive function is severely impaired in C5aR(-/-) mice, coincident with the down-regulated CREB/CEBP pathway in brain. (2) Either the application of recombinant-human-C5a (hrC5a) or exogenous expression of C5a in the brain of a mouse model (C5a/GFAP) enhances this pathway. (3) Application of hrC5a in brain slices from Tg2576 mice significantly improves deficits in long-term potentiation (LTP), while this effect is blocked by a specific AMPA receptor antagonist. (4) Searching for a pharmacological approach to locally mediate C5a responses in the brain, we found that low-dose human intravenous immunoglobulin (IVIG) treatment improves synaptic plasticity and cognitive function through C5a-mediated induction of the CREB/CEBP pathway, while the levels of Aß in the brain are not significantly affected. CONCLUSION: This study for the first time provides novel evidence suggesting that C5a may beneficially influence cognitive function in AD through an up-regulation of AMPA-CREB signaling pathway. IVIG may systematically improve cognitive function in AD brain by passing Aß toxicity.

Unintended effects of cardiovascular drugs on the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is rapidly becoming one of the leading causes of disability and mortality in the elderly. As life-expectancy increases, an increasing number of people will rely on modern medicines to treat age-associated disorders. Among these medications, some might benefit, while others might exacerbate, the pathogenesis of AD. We screened 1,600 FDA approved drugs for ß-amyloid (Aß)-modifying activity and identified drugs that can potentially influence amyloid precursor protein processing. In this study, we focused on cardiovascular drugs and demonstrated that some hypertensive medication can differentially modulate Aß, both in vitro and in vivo. Our study suggests that some commonly prescribed drugs might exert unintended effects and modulate AD and provides the basis for continuing investigation of the role of individual drugs on a case-by-case basis. This line of investigation will lead to the identification of common medications that are potentially beneficial or detrimental to AD as a reference for physicians to consider when prescribing the most appropriate drugs for their patients, particularly for treating chronic disorders among the growing geriatric population.

Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated ß-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models.

Nicotinamide adenine dinucleotide (NAD)(+), a coenzyme involved in redox activities in the mitochondrial electron transport chain, has been identified as a key regulator of the lifespan-extending effects, and the activation of NAD(+) expression has been linked with a decrease in beta-amyloid (Aß) toxicity in Alzheimer's disease (AD). Nicotinamide riboside (NR) is a NAD(+) precursor, it promotes peroxisome proliferator-activated receptor-γ coactivator 1 (PGC)-1α expression in the brain. Evidence has shown that PGC-1α is a crucial regulator of Aß generation because it affects ß-secretase (BACE1) degradation. In this study we tested the hypothesis that NR treatment in an AD mouse model could attenuate Aß toxicity through the activation of PGC-1α-mediated BACE1 degradation. Using the Tg2576 AD mouse model, using in vivo behavioral analyses, biochemistry assays, small hairpin RNA (shRNA) gene silencing and electrophysiological recording, we found (1) dietary treatment of Tg2576 mice with 250 mg/kg/day of NR for 3 months significantly attenuates cognitive deterioration in Tg2576 mice and coincides with an increase in the steady-state levels of NAD(+) in the cerebral cortex; (2) application of NR to hippocampal slices (10 µM) for 4 hours abolishes the deficits in long-term potentiation recorded in the CA1 region of Tg2576 mice; (3) NR treatment promotes PGC-1α expression in the brain coinciding with enhanced degradation of BACE1 and the reduction of Aß production in Tg2576 mice. Further in vitro studies confirmed that BACE1 protein content is decreased by NR treatment in primary neuronal cultures derived from Tg2576 embryos, in which BACE1 degradation was prevented by PGC-1α-shRNA gene silencing; and (4) NR treatment and PGC-1α overexpression enhance BACE1 ubiquitination and proteasomal degradation. Our studies suggest that dietary treatment with NR might benefit AD cognitive function and synaptic plasticity, in part by promoting PGC-1α-mediated BACE1 ubiquitination and degradation, thus preventing Aß production in the brain.

Investigation of nebivolol as a novel therapeutic agent for the treatment of Alzheimer's disease.

Nebivolol is a selective ß1 adrenergic receptor antagonist with nitric oxide-mediated vasodilatory properties utilized in the treatment of hypertension. Previously, nebivolol was shown to modulate amyloid-ß protein precursor processing in vitro. In this study, we investigated the in vivo effects of nebivolol on the modulation of amyloid neuropathology in the Tg2576 mouse model of Alzheimer's disease (AD). We found that nebivolol is brain bioavailable and can be readily detected in the brain following three weeks of treatment at a dose of 1 mg/kg/day. Moreover, this treatment regime resulted in a significant reduction of amyloid-ß neuropathology in the brain, and this reduction was inversely correlated with plasma levels of amyloid-ß. Chronic nebivolol treatment of Tg2576 mice with established amyloid neuropathology and cognitive impairments significantly reduced brain amyloid content but failed to improve cognitive function. Our study demonstrates that nebivolol is highly tolerable and safe and can significantly reduce amyloid neuropathology in the brain, which could be one of the most important parameters for primary prevention of AD. Our studies support the continued investigation of nebivolol for the treatment of AD at very early stages of the disease.

Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients.

Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. RESULTS: In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. CONCLUSION: Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy.

Brain insulin controls adipose tissue lipolysis and lipogenesis.

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.