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Frontiers in Genetics 2022This study aimed to screen potential drugs targeting a new prognostic gene signature associated with proliferation in hepatocellular carcinoma (HCC). CRISPR Library...
This study aimed to screen potential drugs targeting a new prognostic gene signature associated with proliferation in hepatocellular carcinoma (HCC). CRISPR Library and TCGA datasets were used to explore differentially expressed genes (DEGs) related to the proliferation of HCC cells. Differential gene expression analysis, univariate COX regression analysis, random forest algorithm and multiple combinatorial screening were used to construct a prognostic gene signature. Then the predictive power of the gene signature was validated in the TCGA and ICGC datasets. Furthermore, potential drugs targeting this gene signature were screened. A total of 640 DEGs related to HCC proliferation were identified. Using univariate Cox analysis and random forest algorithm, 10 hub genes were screened. Subsequently, using multiplex combinatorial screening, five hub genes (FARSB, NOP58, CCT4, DHX37 and YARS) were identified. Taking the median risk score as a cutoff value, HCC patients were divided into high- and low-risk groups. Kaplan-Meier analysis performed in the training set showed that the overall survival of the high-risk group was worse than that of the low-risk group ( < 0.001). The ROC curve showed a good predictive efficiency of the risk score (AUC > 0.699). The risk score was related to gene mutation, cancer cell stemness and immune function changes. Prediction of immunotherapy suggetsted the IC50s of immune checkpoint inhibitors including A-443654, ABT-888, AG-014699, ATRA, AUY-922, and AZ-628 in the high-risk group were lower than those in the low-risk group, while the IC50s of AMG-706, A-770041, AICAR, AKT inhibitor VIII, Axitinib, and AZD-0530 in the high-risk group were higher than those in the low-risk group. Drug sensitivity analysis indicated that FARSB was positively correlated with Hydroxyurea, Vorinostat, Nelarabine, and Lomustine, while negatively correlated with JNJ-42756493. DHX37 was positively correlated with Raltitrexed, Cytarabine, Cisplatin, Tiotepa, and Triethylene Melamine. YARS was positively correlated with Axitinib, Fluphenazine and Megestrol acetate. NOP58 was positively correlated with Vorinostat and 6-thioguanine. CCT4 was positively correlated with Nerabine. The five-gene signature associated with proliferation can be used for survival prediction and risk stratification for HCC patients. Potential drugs targeting this gene signature deserve further attention in the treatment of HCC.
PubMed: 35836576
DOI: 10.3389/fgene.2022.900380 -
British Journal of Cancer Feb 1999The use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The use of megestrol acetate in the treatment of weight loss in gastrointestinal cancer patients has been disappointing. The aim of the present study was to compare the combination of megestrol acetate and placebo with megestrol acetate and ibuprofen in the treatment of weight loss in such patients. At baseline, 4-6 weeks and 12 weeks, patients underwent measurements of anthropometry, concentrations of albumin and C-reactive protein and assessment of appetite, performance status and quality of life using EuroQol-EQ-5D and EORTC QLQ-C30. Thirty-eight and 35 patients (median weight loss 18%) were randomized to megestrol acetate/placebo or megestrol acetate/ibuprofen, respectively, for 12 weeks. Forty-six (63%) of patients failed to complete the 12-week assessment. Of those evaluable at 12 weeks, there was a decrease in weight (median 2.8 kg) in the megestrol acetate/placebo group compared with an increase (median 2.3 kg) in the megestrol acetate/ibuprofen group (P<0.001). There was also an improvement in the EuroQol-EQ-5D quality of life scores of the latter group (P<0.05). The combination of megestrol acetate/ibuprofen appeared to reverse weight loss and appeared to improve quality of life in patients with advanced gastrointestinal cancer. Further trials of this novel regimen in weight-losing patients with hormone-insensitive cancers are warranted.
Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Appetite; Appetite Stimulants; C-Reactive Protein; Combined Modality Therapy; Female; Gastrointestinal Neoplasms; Humans; Ibuprofen; Male; Megestrol Acetate; Middle Aged; Nutritional Status; Palliative Care; Prospective Studies; Quality of Life; Treatment Outcome; Weight Loss
PubMed: 10027319
DOI: 10.1038/sj.bjc.6690077 -
Asian Pacific Journal of Cancer... 2015We conducted a retrospectively reviewed of the literature published of patients underwent fertility-preserving treatments for cervical, endometrial and ovarian cancers... (Review)
Review
We conducted a retrospectively reviewed of the literature published of patients underwent fertility-preserving treatments for cervical, endometrial and ovarian cancers using the WANFANG database in Chinese. A majority were retrospective studies and case reports. With cervical cancer, radical trachelectomy(RT) in combination with pelvic lymphadenectomy could preserve the fertility of patients with early stage IA1-IB1 cancers, Tumor size≤2 cm should be emphasized as the indication of RT in considering of the higher recurrent rate in patients with tumor size>2 cm. For endometrial cancers, there is much experience on it. Given accurate pretreatment assessment, hormonal therapy is feasible management option to preserve fertility in young patients with early stage lesions that limited to the endometrium and well differentiated. High dose progestin have been applied, oral medroxyprogesterone acetate (MPA), 250-500 mg/day, megestrol acetate 160-480 mg/day. Other therapies that have been used in a limited number of cases include GnRH analog, intrauterine devices (IUDS) containing progestogen, usually combination of these therapies. All patients should be followed up by ultrasound and/or MRI evaluation, and endometrial curettage at intervals of 3 months. With ovarian cancer, in China, fertility- preserving surgery in patients with stage IA (grade G1) of epithelial ovarian tumor and patients with germ cell tumor and borderline ovarian tumor have been successfully performed.
Topics: Female; Fertility Preservation; Genital Neoplasms, Female; Humans; Infertility, Female; Prognosis; Survival Rate
PubMed: 26163600
DOI: 10.7314/apjcp.2015.16.12.4839 -
Cancer Oct 2005New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in... (Comparative Study)
Comparative Study Review
BACKGROUND
New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC.
METHODS
The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods.
RESULTS
No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance.
CONCLUSIONS
This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI.
Topics: Aged; Anastrozole; Androstenedione; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Carcinoma; Clinical Trials, Phase III as Topic; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Fadrozole; Female; Humans; Letrozole; Middle Aged; Neoplasm Staging; Neoplasms, Hormone-Dependent; Nitriles; Postmenopause; Probability; Prognosis; Remission Induction; Risk Assessment; Survival Analysis; Triazoles
PubMed: 16088965
DOI: 10.1002/cncr.21339 -
The Journal of Nutrition, Health & Aging Jun 2024Anorexia of aging (AoA) is a prevalent geriatric syndrome characterized by a multifactorial decline in appetite and reduced food intake associated with the aging... (Review)
Review
BACKGROUND AND OBJECTIVES
Anorexia of aging (AoA) is a prevalent geriatric syndrome characterized by a multifactorial decline in appetite and reduced food intake associated with the aging process. This systematic review aims to investigate the use and outcomes of cannabinoids in addressing AoA, with the goal of providing a comprehensive understanding and discussing their potential integration into daily clinical practice.
METHODS
A thorough search of databases (Embase Ovid, Scopus, PubMed, Cochrane Library, and Web of Science) identified 6100 studies. After eliminating duplicates and screening titles and abstracts, 25 studies underwent full appraisal. Two reviewers assessed inclusion suitability, and study methodologies were evaluated using the Newcastle-Ottawa Scale (NOS) for observational studies and the modified Jadad Scoring Scale for randomized controlled trials. Ultimately, six studies published between 2002 and 2019, involving 869 participants, were included in the review.
RESULTS
Out of the 6 fin. l papers selected, 5 were randomized trials, and 1 was a prospective study. Megestrol acetate (800 mg/d) proved to be more effective than dronabinol 2.5 mg twice a day in increasing appetite. Nabilone (at a dosage of 0.5 mg per day) did not show superiority over placebo in alleviating symptoms such as pain, nausea, loss of appetite, and weight. However, with a double dosage followed by 1.0 mg/6 weeks, after eight weeks of treatment, patients recorded a significant increase in calorie intake and carbohydrate consumption compared to the placebo group, with some patients also experiencing substantial weight gain. Regarding delta-9-tetrahydrocannabinol (THC), a weight increase of ≥10% was observed in 17.6% of patients with doses of 5 mg or 10 mg capsules daily, without significant side effects. Additionally, patients treated with THC 2.5 mg reported improved chemosensory perception and increased appetite before meals compared to placebo. No significant side effects were reported in older adults taking cannabinoids.
CONCLUSIONS
Cannabinoids offer promise in enhancing the quality of life for older individuals with active neoplastic disease. However, to establish comprehensive guidelines, further research with larger sample sizes is essential. Only through this approach can we fully grasp the potential and application of cannabinoids in addressing the nutritional concerns associated with neoplastic diseases.
PubMed: 38917597
DOI: 10.1016/j.jnha.2024.100299 -
Canadian Journal of Veterinary Research... Jan 1987The major purpose of this investigation was to determine the effect of prednisolone and megestrol acetate in cats on the adrenal cortisol response to exogenous...
Suppression of cortisol responses to exogenous adrenocorticotrophic hormone, and the occurrence of side effects attributable to glucocorticoid excess, in cats during therapy with megestrol acetate and prednisolone.
The major purpose of this investigation was to determine the effect of prednisolone and megestrol acetate in cats on the adrenal cortisol response to exogenous adrenocorticotrophic hormone during drug administration at dose rates employed for management of some inflammatory feline dermatoses. Prednisolone (at least 2 mg/kg/day) and megestrol acetate (5 mg/cat/day) were each administered orally to seven cats from days 1 to 16. Three additional cats received no therapy. Basal and stimulated cortisol concentrations, food and water intake, hematology, blood biochemistry, urinalyses, and hepatic and cutaneous histology were studied in all cats before, during, and two weeks following the end of treatment. Cats given prednisolone or megestrol acetate had significant suppression of stimulated cortisol levels on day 8. This change was more marked on day 15, when the suppression in cats given megestrol acetate was also significantly more severe than in those receiving prednisolone. Recovery of adrenal reserve was considered present on day 30 in six of seven cats given prednisolone, but in only three of seven receiving megestrol acetate. Eosinopenia, glycosuria and hepatocyte swelling from glycogen deposition were occasionally recorded in treated cats of both groups, providing additional circumstantial evidence for glucocorticoid activity of megestrol acetate in cats. It is advised that abrupt withdrawal of prednisolone or megestrol acetate therapy be avoided in this species to reduce the chance of precipitating clinical signs of hypoadrenocorticism, even after treatment for as little as one week.
Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Cats; Female; Hydrocortisone; Liver; Male; Megestrol; Megestrol Acetate; Prednisolone; Skin
PubMed: 3032391
DOI: No ID Found -
The Oncologist Mar 2015Endometrial cancer is the most common gynecologic cancer in developed countries. Approximately 3%-14% of endometrial cancers are diagnosed in young women under 40 who... (Review)
Review
Endometrial cancer is the most common gynecologic cancer in developed countries. Approximately 3%-14% of endometrial cancers are diagnosed in young women under 40 who want to preserve their fertility. The incidence of endometrial cancer in this age group is increasing, for which fertility-sparing therapy is increasingly used because it is one of the most important quality of life issues in these women. Progestin therapy is the most common type of fertility-sparing therapy. In this review, the most up-to-date findings regarding fertility-sparing progestin therapy for young women with primary and recurrent endometrial cancer is addressed in terms of diagnosis, treatment, follow-up, and oncologic and reproductive outcomes. Fertility-sparing progestin therapy is highly effective in selected young women with primary and recurrent endometrial cancer. The selection of appropriate patients through comprehensive pretreatment evaluation is of paramount importance to achieve the best outcomes without compromising survival. Because of the high rate of recurrence after successful fertility-sparing therapy, close surveillance is mandatory, and prophylactic hysterectomy is the best option for patients who have completed family planning. Pregnancy outcomes are very promising with the aid of assisted reproductive technologies. Continuous daily oral medroxyprogesterone acetate and megestrol acetate are the preferred progestins for fertility-sparing therapy, but future studies should be performed to determine the optimal dose and treatment duration of these agents.
Topics: Adenocarcinoma; Antineoplastic Agents, Hormonal; Endometrial Neoplasms; Female; Fertility Preservation; Humans; Neoplasm Recurrence, Local; Patient Selection; Progestins; Quality of Life; Retreatment
PubMed: 25673106
DOI: 10.1634/theoncologist.2013-0445 -
Journal of the Advanced Practitioner in... Mar 2018RS, a 36-year-old female, presented to the emergency department (ED) of a large academic medical center upon the advice of her primary care provider because of 3 weeks... (Review)
Review
RS, a 36-year-old female, presented to the emergency department (ED) of a large academic medical center upon the advice of her primary care provider because of 3 weeks of progressive mental status changes, weakness, and decreased oral intake. According to her husband, RS was diagnosed with stage IIIA large cell lung cancer 8 months earlier and was treated with concurrent chemotherapy (carboplatin, pemetrexed, and bevacizumab) and radiation therapy that was completed 4 months prior to admission. No other specific information about her treatment or outside health records was available. According to her husband, RS had been in her usual state of health until approximately 3 weeks prior, when she began having significant mental status changes. She first exhibited some difficulty finding words and later was noted to be putting food in a coffee maker. This spontaneously resolved after approximately 1 week; however, she rapidly developed slurred speech and began to make nonsensical statements. These manifestations also slowly improved but were followed by worsening speech deficit, difficulty walking, and impaired balance. During one of these episodes, she had an occurrence of incontinence. Her husband also noted an incident where her "eyes were beating back and forth and the left side of her face was twitching." RS also had periods (according to her husband) where she "did not seem to be interacting with her environment." These progressively worsened during the last week, and she completely stopped walking and talking 2 days prior to coming to the ED. According to her husband, RS had rheumatoid arthritis and no surgical history. Her family history was unknown except that RS's mother had "seizures." RS had reportedly not used tobacco, alcohol, or drugs, and she was sexually active with her husband. Home medications included transdermal fentanyl 12 μg/hr patch changed every 72 hours; oxycodone-acetaminophen tablets 5-325 mg, two every 4 hours as needed for pain; prednisone 10 mg, one tablet daily; and megestrol 40 mg/mL suspension, 20 mL once daily for appetite stimulation. RS was admitted to an inpatient medical oncology service and evaluated by the oncology advanced practitioner (AP) on her second inpatient day. Upon exam, RS was nonverbal except for moaning in response to painful stimuli and to her sister's voice. Her vital signs were normal. She appeared ill but well-nourished, and she was mildly diaphoretic. Neurologic examination revealed that her pupils were slightly sluggish but equal, round, and reactive to light. Extraocular muscle movements were intact, but she did not move her eyes in response to commands. She tracked the AP and family members around the room with her eyes. Cranial nerve examination was intact with the exception of cranial nerves IX, X, and XI, which were difficult to examine given her inability to cooperate and open her mouth. Motor examination revealed increased tone throughout and intermittent, inconsistent resistance to passive movement. She was seen to move all four extremities spontaneously although not in response to commands. Deep tendon reflexes were intact and equal in all extremities. Examination of other body systems was as follows: there was dry, peeling skin on her lips, but her mucous membranes were moist and free of erythema or lesions. Her lungs were clear to auscultation bilaterally. Her heart rate and rhythm were regular, there were no murmurs, rubs, or gallops, and distal pulses were intact. Her abdomen was nondistended with normally active bowel sounds in all four quadrants. Her abdomen was soft, nontender to palpation, and without palpable masses. There was no peripheral discoloration, temperature changes, or edema, and examination of her skin was benign. On admission to the emergency department, serum laboratory studies were unrevealing for any potential causes of encephalopathy. Kidney and liver function were normal, making diagnoses of uremic and hepatic encephalopathies less likely. Cultures of the urine and blood were negative. Samples of cerebrospinal fluid (CSF) were obtained via lumbar puncture and were unrevealing for any abnormalities. Computed tomography (CT) of the head without contrast was negative for any acute intracranial process. Ultrasound of the right upper quadrant revealed a single, nonspecific, hypoechoic hepatic lesion. Computed tomography scans of the chest, abdomen, and pelvis demonstrated the primary malignancy in the upper lobe of the left lung, as well as possible metastatic disease within the left lung, right lung, and liver, and widespread osseous metastatic disease. Magnetic resonance imaging (MRI) of the brain performed 1 day after admission demonstrated numerous scattered punctate foci of enhancement throughout the supratentorial and infratentorial brain parenchyma, measuring at most 3 to 4 millimeters in diameter. There was no significant mass effect or midline shift. A paraneoplastic panel was sent to an outside laboratory and returned positive for antivoltage-gated potassium channel (VGKC) autoantibodies. Clinically, RS was exhibiting signs of encephalopathy, a broad term that indicates general brain dysfunction, the hallmark of which is altered mental status. Diagnosing encephalopathy is challenging, as many differential diagnoses must be considered. The clinician must consider metabolic derangements, toxic and infectious etiologies, psychiatric disorders, and less commonly, prion disorders and progressive dementia. Cultures of RS's blood and urine as well as other specialized endocrine tests were negative, decreasing the likelihood of a metabolic or infectious cause for her presentation. The abnormalities on her brain MRI were reviewed by a neuro-oncology team, who felt that the faint, nondescript nature of the visualized lesions was not suspicious for metastatic disease. Sequelae of seizures was also considered by neuro-oncology but dismissed given a grossly normal prolonged electroencephalogram. Some encephalopathies are caused by autoimmune or inflammatory mechanisms, which are confirmed by the presence of autoantibody markers and/or clear response to immunomodulatory treatment (Vernino, Geschwind, & Boeve, 2007). These types of encephalopathies have been seen in patients with cancer and have thus been termed paraneoplastic. The presence of anti-VGKC antibodies on RS's paraneoplastic panel directed the inpatient medical oncology team toward a paraneoplastic neurologic disorder (PND) as the most likely diagnosis.
PubMed: 30588355
DOI: No ID Found -
Annals of Oncology : Official Journal... Mar 2001The aim of the present study was to summarise evidence from scientific studies on cancer anorexia-cachexia syndrome in order to assess and highlight the efficacy of... (Review)
Review
BACKGROUND
The aim of the present study was to summarise evidence from scientific studies on cancer anorexia-cachexia syndrome in order to assess and highlight the efficacy of high-dose progestins (megestrol acetate and medroxyprogesterone acetate) compared with placebo in patients with hormone-independent tumors.
MATERIALS AND METHODS
A systematic review of published randomised clinical trials was carried out by an extensive electronic and hand search through databases, relevant journals and books, congress, proceedings, reference lists, without any language or year of publication restriction. The research was conducted by two independent operators who collected the data in a form specifically designed for this review. Among the several possible outcomes, appetite and body weight were chosen.
RESULTS
Fifteen randomised clinical trials (more than 2000 patients) were retrieved for the review. There was a statistically significant advantage for high-dose progestins as regards improved appetite: pooled odds ratio (OR) = 4.23, 95% confidence interval (CI): 2.53-7.04. Although the effect of high-dose progestins on body weight was less impressive, statistical significance was also reached for this outcome: pooled OR = 2.66, 95% CI: 1.80-3.92. Treatment morbidity was very low, due to the brief period of the treatment in most of the studies.
CONCLUSIONS
The effects of high-dose progestins on appetite and body weight were clearly demonstrated. However, further studies are undoubtedly warranted to investigate other aspects of progestin activity, especially as regards dosage, duration and timing with best therapeutic index.
Topics: Anorexia; Appetite; Body Weight; Cachexia; Cross-Over Studies; Double-Blind Method; Humans; Neoplasms; Progestins; Prospective Studies; Randomized Controlled Trials as Topic; Syndrome
PubMed: 11332139
DOI: 10.1023/a:1011156811739 -
Cancer Nov 2002The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and... (Review)
Review
BACKGROUND
The newer generation, nonsteroidal aromatase inhibitors (AIs) anastrozole and letrozole have shown superior efficacy compared with tamoxifen as first-line treatments and compared with megestrol acetate as second-line therapy in postmenopausal women with advanced breast carcinoma. In an open-label, Phase II trial, it was reported that exemestane showed numerical superiority compared with tamoxifen for objective response and clinical benefit. Because these agents ultimately may be administered for periods of up to 5 years in the adjuvant setting, it is of increasing importance to assess their tolerability and pharmacologic profiles.
METHODS
In the absence of data from direct clinical comparisons, the published literature was reviewed for the clinical pharmacology, pharmacokinetic characteristics, and selectivity profiles of anastrozole, letrozole, and exemestane.
RESULTS
At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) were 41-48 hours, 2-4 days, and 27 hours, respectively. The time to steady-state plasma levels was 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have been reported only with exemestane. Anastrozole treatment had no impact on plasma lipid levels, whereas both letrozole and exemestane had an unfavorable effect on plasma lipid levels. In indirect comparisons, anastrozole showed the highest degree of selectivity compared with letrozole and exemestane in terms of a lack of effect on adrenosteroidogenesis.
CONCLUSIONS
All three AIs demonstrated clinical efficacy over preexisting treatments. However, there were differences in terms of pharmacokinetics and effects on lipid levels and adrenosteroidogenesis. The long-term clinical significance of these differences remains to be elucidated.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Female; Humans; Letrozole; Nitriles; Triazoles
PubMed: 12404296
DOI: 10.1002/cncr.10908