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Andropause is defined as late-onset hypogonadism that increases with advancing age and is diagnosed based on symptoms of hypogonadism like loss of libido, loss of morning penile tumescence, and laboratory confirmation of low testosterone. Unlike menopause, it is a slow and progressive condition with varying symptoms and presentations. There is very little awareness and insufficient utilization of screening methods, and the majority of the cases remain undiagnosed. This study was done to get deeper insight into this topic and elicit correlations among different variables. Objectives The primary objective is to assess the prevalence of andropause in diabetic and non-diabetic males aged 40-60 years in the Maharashtra state of western India. Material and methods After ethics committee clearance, exclusion criteria were applied, and 120 participants were enrolled over a period of 21 months. All enrolled subjects were thoroughly evaluated for andropause symptoms. An early morning venous blood sample was taken and sent for routine blood tests, including HbA1c, serum total testosterone, and serum luteinizing hormone. Total testosterone values were compared in patients with symptoms of hypogonadism, loss of libido, and erectile dysfunction. The effects of HbA1c levels, duration of diabetes, body mass index (BMI), smoking, alcoholism, and hypertension on hypogonadism and low testosterone were assessed. Luteinizing hormone levels were compared among the case and control groups in subjects with low total testosterone. Results Total testosterone levels were low for age, loss of libido and erectile dysfunction were more common, and symptoms of hypogonadism appeared at an earlier age in diabetics compared to non-diabetics. The duration of diabetes and HbA1c had a negative impact on serum testosterone levels and andropause symptoms. Diabetic patients with low testosterone levels had significantly lower LH levels. Conclusions Andropause is a syndrome of hypogonadism that occurs due to low serum testosterone levels. This study puts emphasis on secondary hypogonadism playing an important role in diabetic patients, causing the early occurrence of andropause in them. Glycemic control and BMI have a significant effect on both andropause symptoms and total testosterone levels, necessitating strict glycemic control and lifestyle modifications to delay or prevent the occurrence of andropause.
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Hemochromatosis is a condition marked by excessive iron accumulation, causing dysfunction in various organs. A 50-year-old woman, previously in good health, reported abdominal pain and yellowing of the skin and eyes for one month. Upon examination, she exhibited widespread jaundice, leg swelling, and abdominal distention. Her total bilirubin level was 24.52 mg/dL at admission, indicating hyperbilirubinemia. Imaging studies, including USG and CT scans, revealed mild to moderate ascites and altered liver texture. Elevated serum ferritin (1443 ng/mL) and transferrin saturation (84%) suggested iron overload. A liver biopsy confirmed the presence of iron deposits in hepatocytes, leading to a diagnosis of hemochromatosis. Genetic testing was negative for the C282Y and H63D mutations, resulting in a diagnosis of non-homeostatic iron regulator (non-HFE) related hereditary hemochromatosis. The patient began weekly phlebotomy and was monitored regularly, with a liver transplant being considered as a potential treatment.
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Pheochromocytoma is a rare endocrine tumor originating from chromaffin cells of the adrenal medulla, which leads to the overproduction of catecholamines. Most symptoms, ranging from simple headaches to life-threatening cardiac arrests, are due to excess catecholamines. Usually, patients present with persistent or paroxysmal hypertension, headaches, sweating, and palpitations. Here, we describe a case that initially presented as an acute coronary syndrome and was treated accordingly. However, she had a history of nocturnal awakenings and panic attacks, which she had ignored for a month. On further evaluation, it turned out to be pheochromocytoma. This case report will surely help physicians better diagnose and treat such cases.
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Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is even rarer in the adult population. It requires a high degree of suspicion from the treating physician, and if diagnosed early, patients might have a survival benefit from this highly fatal condition. HLH is a disorder of immune regulation where the hyperactivity of cytokines attacks different cells, which leads to multiple organ dysfunctions. Varying presentations and similarities with other diseases make diagnosis difficult. Familial HLH is commonly seen in the pediatric population, while acquired or secondary HLH is seen in adults. Secondary HLH is commonly triggered by neoplasms, infections, rheumatological diseases, and other autoimmune diseases. Here is a case of HLH that presented as chronic undiagnosed fever. In this case report, we have discussed in detail this disease, its presentation, investigations, treatment, and other important information that will help practicing doctors better diagnose and treat HLH patients.
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Selinexor is a first in class selective inhibitor of nuclear export (SINE), blocks exportin 1 (XPO1), a protein transporter, that among other actions, shuttles cargo proteins such as tumor suppressor proteins (TSPs), the glucocorticoid receptor (GR), and oncoprotein messenger RNAs (mRNAs) across the nuclear membrane to cytoplasm. By blocking XPO1, selinexor facilitates nuclear preservation and activation of TSPs, and prevents mRNA translation of the oncoproteins leading to induction of apoptosis. The therapeutic value of selinexor in combination with dexamethasone has been successfully demonstrated in treating relapsed and/or refractory myeloma (RRMM), leading to the Food and Drug Administration (FDA) approval of selinexor in combination with dexamethasone in 2019 for the treatment of adult patients with RRMM who received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (mAb) - a pentarefractory myeloma. More recently, selinexor in combination with bortezomib and dexamethasone was approved by the FDA in December 2020, based on the BOSTON study among RRMM patients who had received at least one prior line of therapy. With more available safety and efficacy data supporting the increased interval between dosing of selinexor (and lesser cumulative weekly dosing) and schedule, contrary to the originally approved dose of 160 mg per week, the supportive care guidelines needed to be revisited. The current manuscript summarizes the supportive care solutions with weekly dosing of selinexor and identifies the ideal potential patient for selinexor treatment.
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Mieloma Múltiplo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Consenso , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Humanos , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Mieloma Múltiplo/patologia , TriazóisRESUMO
BACKGROUND: Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19. CASE PRESENTATION: The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria. CONCLUSION: Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).
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Antígeno de Maturação de Linfócitos B/imunologia , COVID-19/fisiopatologia , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/imunologia , Anticorpos Antivirais/imunologia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/imunologia , Teste de Ácido Nucleico para COVID-19 , Teste Sorológico para COVID-19 , Tosse , Ciclofosfamida/uso terapêutico , Progressão da Doença , Febre , Hospitalização , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , SARS-CoV-2 , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
The spiro[chromane-2,4'-piperidine]-4(3H)-one is an important pharmacophore. It is a structural component in many drugs, drug candidates (or lead compounds) and various biochemical reagents. This review demonstrated an impressive progress in syntheses of spiro[chromane-2,4'-piperidine]-4(3H)-one-derived compoundsin the recent years and focuses on features of their biological relevance's. The prospects for the development of new biologically active substances containing a spiro[chromane-2,4'-piperidine]-4(3H)-one pharmacophore are analyzed and briefly discussed in terms of its structure, reaction, mechanism, scope and potential utility.
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Química Farmacêutica , Cromanos/química , Piperidinas/química , Compostos de Espiro/química , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Antioxidantes/química , Anidrases Carbônicas/química , Anidrases Carbônicas/metabolismo , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Compostos de Espiro/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel Mg3N2-assisted one-pot annulation strategy has been developed via cyclo-condensation reaction of 2-pyridyl ketones with alkyl glyoxylates or aldehydes, allowing the formation of imidazo[1,5-a]pyridines exclusively with an exellent yield.
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Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of coexpressed genes correlate with disease stage, tumor clonality and early progression. We validated CDC42BPA and CLEC11A as novel regulators and candidate therapeutic targets of MMSET-related myeloma. We then used MMNet to discover novel genes associated with high-risk myeloma and identified a novel four-gene prognostic signature. We identified new patient classes defined by network features and enriched for clinically relevant genetic events, pathways and deregulated genes. Finally, we demonstrated the ability of deep sequencing techniques to detect relevant structural rearrangements, providing evidence that encourages wider use of such technologies in clinical practice. An integrative network analysis of CoMMpass data identified new insights into multiple myeloma disease biology and provided improved molecular features for diagnosing and stratifying patients, as well as additional molecular targets for therapeutic alternatives.
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Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Medula Óssea/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/fisiologia , Genoma/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , PrognósticoRESUMO
Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated.
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Adjuvantes Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Prognóstico , Recidiva , Análise de SobrevidaRESUMO
Change in tumor size estimated using longitudinal tumor growth inhibition (TGI) modeling is an early predictive biomarker of clinical outcomes for multiple cancer types. We present the application of TGI modeling for subjects with multiple myeloma (MM). Longitudinal time course changes in M-protein data from relapsed and/or refractory MM subjects who received single-agent carfilzomib in phase II studies (n = 456) were fit to a TGI model. The tumor growth rate estimate was similar to that of other anti-myeloma agents, indicating that the model is robust and treatment-independent. An overall survival model was subsequently developed, which showed that early change in tumor size (ECTS) at week 4, Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin, sex, percent bone marrow cell involvement, and number of prior regimens were significant independent predictors for overall survival (P < 0.001). ECTS based on M-protein modeling could be an early biomarker for survival in MM following exposure to single-agent carfilzomib.
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Several cytogenetic abnormalities are associated with poor outcomes in multiple myeloma (MM). We prospectively analyzed the impact of cytogenetic abnormalities on outcomes during the phase 2 PX-171-003-A1 study of single-agent carfilzomib for relapsed and refractory MM. In the response-evaluable population (257/266), fluorescence in situ hybridization (FISH)/conventional cytogenetic profiles were available for 229 patients; 62 (27.1%) had high-risk cytogenetics--del 17p13, t(4;14) or t(14;16) by interphase FISH or deletion 13 or hypodiploidy by metaphase cytogenetics--and 167 (72.9%) had standard-risk profiles. Generally, baseline characteristics were similar between the subgroups, but International Staging System stage III disease was more common in high- vs standard-risk patients (41.9% vs 27.5%) as was Eastern Cooperative Oncology Group performance status 1/2 (85.5% vs 68.3%). Overall response was comparable between the subgroups (25.8% vs 24.6%, respectively; P=0.85), while time-to-event end points showed a trend of shorter duration in high-risk patients, including median duration of response (5.6 months (95% confidence interval (CI) 3.7-7.8) vs 8.3 months (95% CI 5.6-12.3)) and overall survival (9.3 (95% CI 6.5-13.0) vs 19.0 months (95% CI 15.4-NE); P=0.0003). Taken together, these findings demonstrate that single-agent carfilzomib is efficacious and has the potential to at least partially overcome the impact of high-risk cytogenetics in heavily pre-treated patients with MM.
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Antineoplásicos/uso terapêutico , Aberrações Cromossômicas , Mieloma Múltiplo/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Análise de Sobrevida , Resultado do TratamentoRESUMO
Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T(0)). The median age at diagnosis was 58 years, and time from diagnosis to T(0) was 3.3 years. Following T(0), 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T(0) in 94 patients (44%) including ≥ partial response in 69 (32%). The median overall survival and event-free survival from T(0) were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.
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Antineoplásicos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Progressão da Doença , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva , Análise de SobrevidaRESUMO
Peripheral neuropathy (PN) is one of the most important complications of multiple myeloma (MM) treatment. PN can be caused by MM itself, either by the effects of the monoclonal protein or in the form of radiculopathy from direct compression, and particularly by certain therapies, including bortezomib, thalidomide, vinca alkaloids and cisplatin. Clinical evaluation has shown that up to 20% of MM patients have PN at diagnosis and as many as 75% may experience treatment-emergent PN during therapy. The incidence, symptoms, reversibility, predisposing factors and etiology of treatment-emergent PN vary among MM therapies, with PN incidence also affected by the dose, schedule and combinations of potentially neurotoxic agents. Effective management of treatment-emergent PN is critical to minimize the incidence and severity of this complication, while maintaining therapeutic efficacy. Herein, the state of knowledge regarding treatment-emergent PN in MM patients and current management practices are outlined, and recommendations regarding optimal strategies for PN management during MM treatment are provided. These strategies include early and regular monitoring with neurological evaluation, with dose modification and treatment discontinuation as indicated. Areas requiring further research include the development of MM-specific, patient-focused assessment tools, pharmacogenomic analysis of patient DNA, and trials to assess the efficacy of pharmacological interventions.
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Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ácidos Borônicos/efeitos adversos , Bortezomib , Diagnóstico Precoce , Humanos , Fatores Imunológicos/efeitos adversos , Incidência , Mieloma Múltiplo/complicações , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia , Inibidores de Proteassoma , Pirazinas/efeitos adversos , Talidomida/efeitos adversosRESUMO
The His274âTyr (H274Y) oseltamivir (Tamiflu) resistance mutation causes a substantial decrease in the total levels of surface-expressed neuraminidase protein and activity in early isolates of human seasonal H1N1 influenza, and in the swine-origin pandemic H1N1. In seasonal H1N1, H274Y only became widespread after the occurrence of secondary mutations that counteracted this decrease. H274Y is currently rare in pandemic H1N1, and it remains unclear whether secondary mutations exist that might similarly counteract the decreased neuraminidase surface expression associated with this resistance mutation in pandemic H1N1. Here we investigate the possibility of predicting such secondary mutations. We first test the ability of several computational approaches to retrospectively identify the secondary mutations that enhanced levels of surface-expressed neuraminidase protein and activity in seasonal H1N1 shortly before the emergence of oseltamivir resistance. We then use the most successful computational approach to predict a set of candidate secondary mutations to the pandemic H1N1 neuraminidase. We experimentally screen these mutations, and find that several of them do indeed partially counteract the decrease in neuraminidase surface expression caused by H274Y. Two of the secondary mutations together restore surface-expressed neuraminidase activity to wildtype levels, and also eliminate the very slight decrease in viral growth in tissue-culture caused by H274Y. Our work therefore demonstrates a combined computational-experimental approach for identifying mutations that enhance neuraminidase surface expression, and describes several specific mutations with the potential to be of relevance to the spread of oseltamivir resistance in pandemic H1N1.
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Biologia Computacional , Farmacorresistência Viral/genética , Regulação Viral da Expressão Gênica/genética , Vírus da Influenza A Subtipo H1N1/enzimologia , Mutação , Neuraminidase/genética , Oseltamivir/farmacologia , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/crescimento & desenvolvimento , Influenza Humana/epidemiologia , Influenza Humana/virologia , Modelos Moleculares , Neuraminidase/química , Pandemias , Conformação Proteica , Técnicas de Cultura de TecidosRESUMO
Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.
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Fármacos Anti-HIV/administração & dosagem , Remoção de Componentes Sanguíneos/métodos , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Mieloma Múltiplo/terapia , Benzilaminas , Ciclamos , Humanos , Mieloma Múltiplo/diagnóstico , Transplante AutólogoRESUMO
The serum immunoglobulin-free light chain (FLC) assay measures levels of free kappa and lambda immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.