Pharmacological management of cachexia in adult cancer patients: a systematic review of clinical trials.

BACKGROUND: Cachexia is a multisystem syndrome characterized by weight loss, anorexia, loss of muscle mass, systemic inflammation, insulin resistance, and functional decline. Management of cachexia involves addressing multiple underlying biological mechanisms. Previous review on pharmacological management of cancer cachexia identified progestins and corticosteroids as effective agents for treatment of cachexia. However, to date no consensus exists on a single effective or standard treatment for management of cachexia. The aim of this systematic review is to determine the effectiveness of pharmacological treatments used to manage cachexia among adult cancer patients. METHODS: We performed literature searches of PubMed (NLM), Embase (Ovid), and Medline(Ovid) to identify clinical trials focused on pharmacological management of cancer cachexia among adult cancer patients from 2004 to 2018. Three reviewers screened a random selection of abstracts to measure for interrater reliability. After this step, each screener screened two-thirds of all abstracts and 177 studies were identified for full text review. The primary outcome was impact of pharmacological management on change in either weight or lean body mass in cancer patients. RESULTS: We identified 19 articles (representing 20 RCTs) that focused on pharmacological management of cancer cachexia. Agents showing promising results included Anamorelin and Enobosarm. Anamorelin at 50 or 100 mg per day for 12 weeks showed a consistent benefit across all studies and resulted in significant improvement in weight as compared to baseline among cancer patients. Enobosarm at 1 and 3 mg per day was also effective in improving lean body mass and QOL symptoms among advancer stage cancer patients. Finally, use of combination agents provide evidence for targeting multiple pathways underlying cachexia mechanism to achieve maximum benefit. No agents showed functional improvement in cancer patients. CONCLUSION: Anamorelin as a single agent shows promising results in improving cachexia related weight loss among cancer patients. Further research on combination therapies may be helpful to address critical gaps in cachexia management.

Outcomes in patients with aortic stenosis and severely reduced ejection fraction following surgical aortic valve replacement and transcatheter aortic valve replacement.

BACKGROUND: Patients with severe aortic stenosis (AS) and left ventricular (LV) dysfunction demonstrate improvement in left ventricular injection fraction (LVEF) after aortic valve replacement (AVR). The timing and magnitude of recovery in patients with very low LVEF (≤ 25%) in surgical or transcatheter AVR is not well studied. OBJECTIVE: Determine clinical outcomes following transcatheter aortic valve replacement (TAVR) and surgical aortic valve repair (SAVR) in the subset of patients with severely reduced EF ≤ 25%. METHODS: Single-center, retrospective study with primary endpoint of LVEF 1-week following either procedure. Secondary outcomes included 30-day mortality and delayed postprocedural LVEF. T-test was used to compare variables and linear regression was used to adjust differences among baseline variables. RESULTS: 83 patients were enrolled (TAVR = 56 and SAVR = 27). TAVR patients were older at the time of procedure (TAVR 77.29 ± 8.69 vs. SAVR 65.41 ± 10.05, p < 0.001). One week post procedure, all patients had improved LVEF after both procedures (p < 0.001). There was no significant difference in LVEF between either group (TAVR 33.5 ± 11.77 vs. SAVR 35.3 ± 13.57, p = 0.60). Average LVEF continued to rise and increased by 101% at final follow-up (41.26 ± 13.70). 30-day mortality rates in SAVR and TAVR were similar (7.4% vs. 7.1%, p = 0.91). CONCLUSION: Patients with severe AS and LVEF ≤ 25% have a significant recovery in post-procedural EF following AVR regardless of method. LVEF doubled at two years post-procedure. There was no significant difference in 30-day mortality or mean EF recovery between TAVR and SAVR. TRIAL REGISTRATION: Indiana University institutional review board granted approval for above study numbered 15,322.

Advance lung cancer inflammation index (ALI) at diagnosis is a prognostic marker in patients with metastatic non-small cell lung cancer (NSCLC): a retrospective review.

BACKGROUND: Systemic inflammation has been linked with cancer development, cancer cachexia and poor outcome. Advanced lung cancer inflammation index (ALI) was developed to assess degree of systemic inflammation at the time of diagnosis in metastatic non-small cell lung (NSCLC) cancer patients. METHODS: In a single institution retrospective review 173 patients with metastatic NSCLC diagnosed between Jan 1 2000 and June 30 2011 were included. ALI was calculated as (BMI x Alb / NLR) where BMI = body mass index, Alb = serum albumin, NLR (neutrophil lymphocyte ratio, a marker of systemic inflammation). Patients were divided into low inflammation (ALI ≥ 18) and high inflammation (ALI < 18) groups. Kaplan-Meier method was used to estimate progression free survival and overall survival. Log-rank test were used to compare the survivals among various factors. Multivariate Cox regression was used to perform survival analysis in order to estimate the hazards ratio for various factors. RESULTS: Among 173 patients median age was 57 years, 67% were male, 52% had adenocarcinoma. Patients with an ALI score of < 18 suggesting high systemic inflammation were significantly more likely to have more than 2 sites of metastatic disease, have poor performance status and less likely to receive any chemotherapy. Their median progression free survival and overall survival was 2.4 months and 3.4 months as opposed to 5.1 months and 8.3 months in patients with ALI >18 (P < 0.001). On multi-variate analysis ALI score of <18 (1.42, 95% CI 1.003-2.01) remained significantly associated with worse outcome. CONCLUSION: ALI (<18) at diagnosis is an independent marker of poor outcome in patients with advanced NSCLC.

Lifestyle modification in colorectal cancer patients: an integrative oncology approach.

Colorectal cancer (CRC) is predominantly a disease of economically developed countries, with many lifestyle-related risk factors proposed that contribute to a higher incidence. These risk factors include obesity, especially visceral fat, lack of physical activity, high consumption of red and processed meat, alcohol and a low intake of dietary fiber. Many population-based studies suggest that a combination of these lifestyle-related risk factors not only increases the incidence of CRC, but also contributes to an increased risk of CRC recurrence after the initial diagnosis. In this article we have reviewed various scientific studies that link lifestyle risk factors with CRC and we propose lifestyle modification as an adjunct intervention to surgery and chemotherapy in patients with early stage and locally advanced CRC.

Metastatic seminoma presenting as neck and axillary lymphadenopathy in an elderly man.

A man in his 60s presented with a gradual progressive right-sided neck mass. Initial core biopsy was inconclusive and he was treated with a short course of oral prednisone for presumed sarcoidosis. Two months later, the patient developed worsening dysphagia, hoarseness of voice, dyspnea, and weight loss. Physical examination revealed bilateral cervical and right axillary lymphadenopathy. A right axillary lymph node excisional biopsy was performed and immunohistochemistry was diffusely positive for OCT4, SALL4, CD117, PLAP, confirming the diagnosis of metastatic seminoma. He received three cycles of bleomycin, etoposide, and cisplatin; bleomycin was omitted for the fourth cycle due to concern for toxicity. Restaging scans after four cycles of chemotherapy showed a favorable response to therapy. Unfortunately, the patient died from bleomycin pulmonary toxicity. This case illustrates a rare and atypical presentation of metastatic seminoma in an elderly patient.

Mapping the Heartbeat of America with ChatGPT-4: Unpacking the Interplay of Social Vulnerability, Digital Literacy, and Cardiovascular Mortality in County Residency Choices.

Cardiovascular disease remains a leading cause of morbidity and mortality in the United States (US). Although high-quality data are accessible in the US for cardiovascular research, digital literacy (DL) has not been explored as a potential factor influencing cardiovascular mortality, although the Social Vulnerability Index (SVI) has been used previously as a variable in predictive modeling. Utilizing a large language model, ChatGPT4, we investigated the variability in CVD-specific mortality that could be explained by DL and SVI using regression modeling. We fitted two models to calculate the crude and adjusted CVD mortality rates. Mortality data using ICD-10 codes were retrieved from CDC WONDER, and the geographic level data was retrieved from the US Department of Agriculture. Both datasets were merged using the Federal Information Processing Standards code. The initial exploration involved data from 1999 through 2020 (n = 65,791; 99.98% complete for all US Counties) for crude cardiovascular mortality (CCM). Age-adjusted cardiovascular mortality (ACM) had data for 2020 (n = 3118 rows; 99% complete for all US Counties), with the inclusion of SVI and DL in the model (a composite of literacy and internet access). By leveraging on the advanced capabilities of ChatGPT4 and linear regression, we successfully highlighted the importance of incorporating the SVI and DL in predicting adjusted cardiovascular mortality. Our findings imply that just incorporating internet availability in the regression model may not be sufficient without incorporating significant variables, such as DL and SVI, to predict ACM. Further, our approach could enable future researchers to consider DL and SVI as key variables to study other health outcomes of public-health importance, which could inform future clinical practices and policies.

Glutamic acid decarboxylase (GAD) antibody-positive paraneoplastic stiff person syndrome associated with mediastinal liposarcoma.

Stiff person syndrome (SPS) is a rare, debilitating neurological illness characterised by rigidity and spasms of the axial muscles, causing severe restrictions to mobility. SPS can be classic, partial or paraneoplastic. We report a case of a young woman who presented with seizures and painful spasms of the thoracolumbar muscles who was subsequently diagnosed with SPS. Serological work revealed glutamic acid decarboxylase (GAD) antibodies and imaging showed a large mediastinal mass. The patient underwent surgical resection of the mediastinal mass and final pathology revealed well-differentiated mediastinal liposarcoma. She received five sessions of plasma exchange and her neurological symptoms gradually improved after surgery. This case highlights a rare case of GAD antibody-positive paraneoplastic SPS associated with mediastinal liposarcoma.

NUT Carcinoma of the Submandibular Gland: A Case at This Uncommon Site with Review of the Literature.

Nuclear protein in testis (NUT) carcinoma is a rare, highly aggressive, undifferentiated carcinoma that harbors a characteristic rearrangement of the NUTM1 gene. The majority arise in adolescents and young adults especially from the midline structures of the thorax, head, and neck. Until the present, there have only been three reported cases of NUT carcinoma of the submandibular gland, two of which were reported in children and another one in an adult from Korea. Here, we report the first case of NUT carcinoma arising in the submandibular gland of an adult female in the United States, representing the fourth case worldwide. A fine needle aspiration and biopsy was performed, and the diagnosis was confirmed by NUT immunohistochemical staining and fusion of the BRD4 (19p13.12) and NUTM1 (15q14) gene loci by fluorescence in-situ hybridization on the resection specimen. Salivary gland is an unusual site for NUT carcinoma and is rarely described in submandibular gland. We reviewed the clinicopathologic features of this entity at this site along with role of NUTM1 gene rearrangements in NUT tumorigenesis.

Spindle Cell Squamous Cell Carcinoma of the Larynx with Malignant Osteoid Differentiation: A Case Report and Review of Literature.

Spindle cell squamous cell carcinoma of the larynx is a rare, aggressive variant of squamous cell carcinoma. It comprises 0.6-1.5% of all laryngeal cancers. Heterologous mesenchymal differentiation as bone, cartilage, and muscle is uncommon, especially malignant osteoid differentiation, as a handful of cases reported in the literature. We present the case of a 66-year-old male active smoker who presented with dysphonia and acute stridor. On examination, a 2.0 cm pedunculated, broad-base, glottic mass involving the left true vocal cord and ventricle was noted, with extension to the anterior commissure causing a narrowing of the airway. The patient underwent localized left vocal cordectomy. The histopathologic and immunohistochemical findings were consistent with spindle cell carcinoma with malignant osteoid differentiation. The patient is alive, status-post adjuvant five cycles of cisplatin therapy, with no recurrence at 18 months of follow-up. We discuss a literature review of this rare entity with either malignant osteoid or osteocartilaginous differentiation.

Weight Loss in Cancer Patients Correlates With p38ß MAPK Activation in Skeletal Muscle.

Unintentional weight loss, a first clinical sign of muscle wasting, is a major threat to cancer survival without a defined etiology. We previously identified in mice that p38ß MAPK mediates cancer-induced muscle wasting by stimulating protein catabolism. However, whether this mechanism is relevant to humans is unknown. In this study, we recruited men with cancer and weight loss (CWL) or weight stable (CWS), and non-cancer controls (NCC), who were consented to rectus abdominis (RA) biopsy and blood sampling (n = 20/group). In the RA of both CWS and CWL, levels of activated p38ß MAPK and its effectors in the catabolic pathways were higher than in NCC, with progressively higher active p38ß MAPK detected in CWL. Remarkably, levels of active p38ß MAPK correlated with weight loss. Plasma analysis for factors that activate p38ß MAPK revealed higher levels in some cytokines as well as Hsp70 and Hsp90 in CWS and/or CWL. Thus, p38ß MAPK appears a biomarker of weight loss in cancer patients.

Major Stressful Life Events and Risk of Developing Lung Cancer: A Case-Control Study.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality and is strongly linked with smoking. We sought to determine whether major stressful life events (e.g. divorce) are also a risk factor for developing lung cancers. METHODS: We performed a matched case-control study. Cases (CA) were lung cancer patients diagnosed within the previous 12 months. Controls (CO) were patients without a prior history of malignancy. Data on major stressful life events were collected using the modified Holmes-Rahe stress scale. The primary endpoint was the odds of having a major stressful life event between CA and CO. A sample of 360 patients (CA = 120, CO = 240) was needed to achieve 80% power to detect an odds ratio (OR) of 2.00 versus the alternative of equal odds using χ 2 = 0.05. RESULTS: Between May 2015 and December 2016, we enrolled 301 patients (CA = 102, CO = 199), matched for median age (CA = 64.4 years, CO = 63.9 years), sex (CA-Male = 48%, CO-Male = 49.2%), and smoking status (ever smoker, CA = 84%, CO = 85%). There was no difference in lifetime stressful life event rate between CA and CO (95% vs 93.9%; P = .68). However, CA were significantly more likely to have had a stressful event within the preceding 5 years than CO (CA = 77.4% vs CO = 65.8%; P = .03, OR = 1.78). ß-blocker use was significantly higher among CO (CA = 29.4%, CO = 49.7%; P = .0007, OR = 0.42), suggesting a protective effect. CONCLUSION: Patients with lung cancer are significantly more likely to have had a major stressful life event within the preceding 5 years. In addition, use of ß-blockers may be protective against lung cancer.

Cisplatin, cetuximab, and radiation in locally advanced head and neck squamous cell cancer: a retrospective review.

Efficacy of cisplatin versus cetuximab with radiation in locally advanced head and neck cancer (LAHNC) was evaluated. A total of 96 patients with newly diagnosed LAHNC treated at our institution between 2006 and 2011 with concurrent radiation and cisplatin (group A, n = 45), cetuximab (group B, n = 24), or started with cisplatin but switched to cetuximab because of toxicity (group C, n = 27) were reviewed. Chi-square test, analysis of variance, and log-rank test were used for analysis. The three groups had similar baseline characteristics, except for median age, T stage, albumin levels, hemoglobin levels, performance status, and comorbidities. A complete response (CR) was seen in 77%, 17%, and 67% of patients (P < 0.001), respectively. There was no significant difference in median overall survival (OS) between groups A and C. The median OS for groups A and C was not reached (>65 months), even though it was significantly longer than median OS for group B (11.6 months; P ≤ 0.001). The 2-year OS in groups A and C is significantly higher than that in group B (70% for groups A and C, 22% for group B). There is no significant difference in progression-free survival (PFS) between groups A and C. The median PFS for these groups was not reached (>62 months), and is significantly longer than that for group B (4.3 months; P ≤ 0.001). The 2-year PFS of group A (67%) and group C (76%) was significantly longer than that of group B (20%). Cisplatin with radiation appears to be more efficacious even in suboptimal dosing than cetuximab with radiation in LAHNC but the two groups were not well matched.

Current and emerging pharmacotherapies for the treatment of relapsed small cell lung cancer.

Small cell lung cancer (SCLC) is a very aggressive cancer with poor outcome if left untreated, but it is also one of the most chemotherapy responsive cancers. Overall it has a very poor prognosis especially if it is chemotherapy resistant to first line treatment. Second line chemotherapy has not been very beneficial in SCLC as opposed to breast cancer and lymphoma. In the last few years topotecan is the only drug that has been approved by the food and drug administration (FDA) for the second line treatment of SCLC but in Japan another drug, amrubicin is approved. There are many combinations of different chemotherapies available in moderate to high intensity, in this difficult to treat patient to overcome the chemo resistance, but many of these studies are small or phase II trials. In this article we have reviewed single agent and multidrug regimens that were studied in both chemo sensitive and refractory setting, including the most recent clinical trials.

Thymoquinone and cisplatin as a therapeutic combination in lung cancer: In vitro and in vivo.

BACKGROUND: Thymoquinone (TQ) is a compound extracted from Black Caraway seeds of Nigella Sativa and is active against various cancers. Cisplatin (CDDP) is the most active chemotherapeutic agent in Lung Cancer. Here we report activity of TQ against non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines alone and in combination with Cisplatin (CDDP). METHODS: For proliferation MTT assay, cell viability trypan blue assay and for apoptosis Annexin-V FITC assay were used in NCI-H460 and NCI-H146 cell lines. Inhibition of invasion by TQ was assessed using Matrigel assay and its affect on release of various cytokines was determined using RayBio Human Cytokine detection kit. Mouse xenograft model using NCI-H460 was used to determine in vivo activity of TQ and CDDP. Inhibition of LPS induced NF-kappaB expression by TQ was determined using transgenic mice expressing a luciferase reporter. RESULTS: TQ was able to inhibit cell proliferation, reduce cell viability and induce apoptosis. TQ at 100 microM and CDDP at 5 muM inhibited cell proliferation by nearly 90% and the combination showed synergism. TQ was able to induced apoptosis in both NCI-H460 and NCI-H146 cell lines. TQ also appears to affect the extracellular environment inhibiting invasion and reducing the production of two cytokines ENA-78 and Gro-alpha which are involved in neo-angiogenesis. Using a mouse xenograft model we were able to demonstrate that combination of TQ and CDDP was well tolerated and significantly reduced tumor volume and tumor weight without additional toxicity to the mice. In the combination arms (TQ5 mg/kg/Cis 2.5 mg/kg) tumor volume was reduced by 59% and (TQ20 mg/kg/Cis 2.5 mg/kg) by 79% as compared to control which is consistent with in vitro data. TQ down regulated NF-kappaB expression which may explain its various cellular activities and this activity may prove useful in overcoming CDDP resistance from over expression of NF-kappaB. CONCLUSIONS: Thus TQ and CDDP appear to be an active therapeutic combination in lung cancer.