Metformin and blood cancers

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies

Myosteatosis in a systemic inflammation-dependent manner predicts favorable survival outcomes in locally advanced esophageal cancer

Increased adiposity and its attendant metabolic features as well as systemic inflammation have been associated with prognosis in locally advanced esophageal cancer (LAEC). However, whether myosteatosis and its combination with systemic inflammatory markers are associated with prognosis of esophageal cancer is unknown. Our study aimed to investigate the influence of myosteatosis and its association with systemic inflammation on progression-free survival (PFS) and overall survival (OS) in LAEC patients treated with definitive chemoradiotherapy (dCRT). We retrospectively gathered information on 123 patients with LAEC submitted to dCRT at the University of Campinas Hospital. Computed tomography (CT) images at the level of L3 were analyzed to assess muscularity and adiposity. Systemic inflammation was mainly measured by calculating the neutrophil-to-lymphocyte ratio (NLR). Median PFS for patients with myosteatosis (n = 72) was 11.0 months vs 4.0 months for patients without myosteatosis (n = 51) (hazard ratio [HR]: 0.53; 95% confidence interval [CI], 0.34-0.83; P = .005). Myosteatosis was also independently associated with a favorable OS. Systemic inflammation (NLR > 2.8) was associated with a worse prognosis. The combination of myosteatosis with systemic inflammation revealed that the subgroup of patients with myosteatosis and without inflammation presented less than half the risk of disease progression (HR: 0.47; 95% CI: 0.26-0.85; P = .013) and death (HR: 0.39; 95% CI, 0.21-0.72; P = .003) compared with patients with inflammation. This study demonstrated that myosteatosis without systemic inflammation was independently associated with favorable PFS and OS in LAEC patients treated with dCRT81669676976FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2018/23428-

Metformin and blood cancers

Type 2 diabetes mellitus and cancer are correlated with changes in insulin signaling, a pathway that is frequently upregulated in neoplastic tissue but impaired in tissues that are classically targeted by insulin in type 2 diabetes mellitus. Many antidiabetes treatments, particularly metformin, enhance insulin signaling, but this pathway can be inhibited by specific cancer treatments. The modulation of cancer growth by metformin and of insulin sensitivity by anticancer drugs is so common that this phenomenon is being studied in hundreds of clinical trials on cancer. Many meta-analyses have consistently shown a moderate but direct effect of body mass index on the incidence of multiple myeloma and lymphoma and the elevated risk of leukemia in adults. Moreover, new epidemiological and preclinical studies indicate metformin as a therapeutic agent in patients with leukemia, lymphomas, and multiple myeloma. In this article, we review current findings on the anticancer activities of metformin and the underlying mechanisms from preclinical and ongoing studies in hematologic malignancies

TRATAMENTO BEM-SUCEDIDO DE PACIENTE COM DIAGNÓSTICO DE VIPOMA METASTÁTICO COM TRATAMENTO TERANÓSTICO OCTREOTATO-DOTA-177 LUTÉCIO

Introdução/Justificativa: Os Vipomas são tumores neuroendócrinos raros do pâncreas, caracterizados pela produção excessiva de peptídeo intestinal vasoativo (VIP), levando a diarreia aquosa, desequilíbrios eletrolíticos, desidratação e consequentes graves complicações potenciais. O tratamento convencional envolve a terapia com análogos de somatostatina e cirurgias. No entanto, a disponibilidade irregular de medicamentos pode comprometer o controle da doença. Relato: Um homem de 56 anos apresentou-se com diarreia intensa, perda de peso significativa e desidratação. Exames revelaram hipocalemia grave, elevação de enzimas pancreáticas e escórias nitrogenadas renais. O tratamento de urgência envolveu terapia renal substitutiva, reposição eletrolítica, com recuperação completa do quadro clínico. A tomografia computadorizada (TC) de abdome total evidenciou um tumor neuroendócrino em cauda pancreática medindo 4 centímetros com metástases hepáticas, linfonodais e peritoneais. Iniciou-se tratamento empírico com Octreotida de liberação rápida, resultando em melhora sintomática significativa. A investigação complementar revelou dosagem de VIP 79,5 pmol/l (valor de referência até 30 pmol/l), ressonância de sela túrcica e dosagem de paratormônio normais. A cirurgia de debulking foi realizada para diagnóstico e citoredução tumoral, confirmando o diagnóstico de tumor neuroendócrino grau 2 com extensão para órgãos adjacentes. Após irregularidade do fornecimento do análogo de somatostatina de longa duração, o paciente retornou a apresentar sintomatologia com risco elevado de complicações agudas. Optou-se pela terapia teranóstica com Octreotato-Dota-177Lutécio (Lu) devido a sua eficácia comprovada para terapia de tumores neuroendócrinos gastroenteropancreáticos bem diferenciados com expressão comprovada para receptores de somatostatina. O paciente permaneceu em uso regular mensal de análogo de somatostatina durante cinco anos. Desde então continua assintomático, últimas tomografias realizadas sem evidência de recidiva ou de doença mensurável. Conclusão: O tratamento com Octreotato-Dota-177Lu em um paciente com vipoma metastático demonstrou eficácia na ausência de acesso regular a análogos de somatostatina de longa duração. Este caso destaca a importância de alternativas terapêuticas em contextos em que a disponibilidade de medicamentos é limitada, resultando em controle da doença e melhora significativa na qualidade de vida do paciente. A terapia com Octreotato-Dota-177Lu mostrou-se uma opção viável e eficaz em casos semelhantes, merecendo consideração em pacientes com dificuldades de acesso a tratamentos convencionais

Independent Radiologic Review in Metastatic Colorectal Cancer: Systematic Review and Meta-Analysis

Purpose: To perform a meta-analysis addressing evaluation bias in local radiologic assessment (LRA) of lesions when compared with independent radiologic review (IRR) in randomized controlled trials (RCTs) testing chemotherapy for metastatic colorectal cancer (CRC). Materials and Methods: MEDLINE, EMBASE, ClinicalTrials.gov, the Cochrane Library, and Web sites for major medical meetings were searched for RCTs of chemotherapy for metastatic CRC that reported response evaluation by both LRA and IRR. The risk ratios (RRs) of response in the experimental (RRexp) and control (RRcont) arms were calculated (response rate in LRA divided by response rate in IRR) for each selected study. The ratio of RR of response was calculated (RR of response of LRA divided by RR of response of IRR). The random-effects model was applied. Meta-regression was used to examine the effect of study characteristics on outcomes. Results: LRA and IRR results were concordant (13 studies; 7742 patients; ratio of RR of response = 0.97; 95% confidence interval [95% CI]: 0.90, 1.04; P = .35). However, LRA overestimated tumor response independently of therapy allocation (interaction test, P = .81) both in control (RRcont, 1.163; 95% CI: 1.086, 1.246; P < .001) and experimental (RRexp, 1.156; 95% CI: 1.093, 1.222; P < .001) therapies. Meta-regression did not show any effect of trial characteristics on effects. Conclusion: LRA yields higher response rates in RCTs testing chemotherapy for metastatic CRC, although there was no sign of bias toward experimental therapy. The need for IRR to control evaluation bias must be reappraised. (C) RSNA, 20122631869

BODY COMPOSITION AND INSULIN SENSITIVITY IN PATIENTS WITH RECTAL CANCER

Introduction/Justification: Glucose intolerance is a metabolic abnormality recognized in patients with cancer cachexia and has been implicated in the development of low muscularity (LM). LM is an important feature associated with the poor prognosis of cancer patients, leading to a reduction in functional capacity, poor quality of life, increased treatment intolerance, and reduced overall survival. LM have been shown to correlate with insulin sensitivity. However, clinical studies evaluating the association between body composition features and insulin resistance are scarce, and the results are contradictory. Objectives: The purpose of this study was to evaluate the association between insulin sensitivity and the body composition features of patients recently diagnosed with rectal cancer. Materials and Methods: This is a cross-sectional study involving patients diagnosed with rectal cancer. Body composition was analyzed using computed tomography (CT) images processed with the SliceOmatic software based on the difference in tissue measurements by Hounsfield Units (HU). Muscularity was categorized according to Martin's criteria. Cachexia was categorized according to Fearon's criteria. Insulin sensitivity was evaluated using euglycemic hyperinsulinemic clamp. Personal information, tumor characteristics, and biochemical exams were collected from medical records. Statistical analyses were conducted using Stata Corp LP® version 17.0 software. This study was approved by the Institutional Review Board (CAAE: 91217418.2.0000.5404). Results: A total of 33 patients were included in the analysis. Low muscularity and cachexia diagnosis were identified in 27% of the sample (n = 9). The low muscularity (LM) group consisted mostly of females aged 55–70 years. There was no difference in BMI, weight loss, tumor stage, or ECOG score between muscularity groups. The LM group had a lower skeletal muscle area (p < 0.001), lower visceral adipose tissue area (p = 0.01), and there is no difference in skeletal muscle radiodensity (p = 0.85), subcutaneous adipose tissue area (p = 0.76), and intramuscular adipose tissue area (p = 0.46) when compared to normal muscularity group. A lower handgrip strength was also observed in the LM group (p < 0.01). Regarding insulin sensitivity, the LM group had a higher M-value adjusted for Free Fat Mass (FFM) (p = 0.01) and M-value adjusted for Total Body Weight (TBW) (p = 0.0347). Additionally, a significant negative correlation was found between muscularity and M-value-FFM (rho = -0.5047, p = 0.004) and M-value-TBW (rho = -0.4742, p = 0.0076). There was no difference in M-value between cachexia and non-cachexia patients. No statistical difference was observed in inflammatory markers (C-reactive protein, Glasgow prognostic score (mGPS), and neutrophil-to-lymphocyte ratio (NLR)) according to muscularity groups. Conclusion: There is no insulin resistance associated with LM or cachexia. It is possible that the main determinant of insulin sensitivity is the amount of visceral adipose tissue and systemic inflammation. The LM group exhibits a lower area of visceral adipose tissue, with no discernible difference in inflammatory markers. This study highlights the importance of expanding investigations into the determinants of metabolic changes and body composition in cancer cachexia

SKELETAL MUSCLE RADIODENSITY AND INSULIN SENSITIVITY IN PATIENTS WITH RECTAL CANCER

Introduction/Justification: The assessment of skeletal muscle attenuation via computed tomography plays a crucial role in identifying myosteatosis among cancer patients. Myosteatosis, characterized by ectopic adipose tissue infiltration in skeletal muscles, has been linked to poor prognosis in various cancers. However, its implications specifically in rectal cancer remain uncertain. Studies have shown that myosteatosis correlates with increased insulin resistance, highlighting the need for further investigation in clinical settings. Objectives: This study aimed to investigate the relationship between insulin sensitivity and skeletal muscle radiodensity in patients recently diagnosed with rectal cancer. Materials and Methods: A cross-sectional study design was employed, inviting patients diagnosed with rectal cancer to participate. Insulin sensitivity was assessed using the M-value obtained from euglycemic hyperinsulinemic clamp tests. Skeletal muscle analysis was conducted using computed tomography (CT) images of the third lumbar vertebra processed with SliceOmatic software. Skeletal muscle was defined within the attenuation range of -29 to +150 Hounsfield Units (HU), while intermuscular adipose tissue was defined within -190 to -30 HU. The mean skeletal muscle radiodensity (SMR) was reported. Demographic and clinical data were collected from medical records. Statistical analyses were performed using Stata Corp LP® version 17.0 software. The study protocol received approval from the Institutional Review Board (CAAE: 91217418.2.0000.5404). Results: The analysis included a total of 33 patients, predominantly male (67%) with ages ranging from 55 to 70 years (58%). Patients across stages I to IV were represented, with 48% in stage III, 11% in stage I, 11% in stage II, and 30% in stage IV. Overweight and obesity were diagnosed in 37.5% and 30% of the sample, respectively. Common comorbidities included diabetes (21%), hypertension (60%), and dyslipidemia (21%). The M-value adjusted for Total Body Weight (TBW) demonstrated a significant association with Skeletal Muscle Radiodensity (rho = 0.3926, p = 0.0269), whereas no statistical difference was observed when adjusting for Free Fat Mass (FFM) (p = 0.1769). Conclusion: In conclusion, our findings suggest a moderate positive association between insulin sensitivity and skeletal muscle radiodensity in rectal cancer patients