Intercalated Chemotherapy and Epidermal Growth Factor Receptor Inhibitors for Patients With Advanced Non–Small-cell Lung Cancer: A Systematic Review and Meta-analysis

Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non–small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G₁ cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P < .00001), and objective response rate (ORR; odds ratio [OR], 2.70; 95% CI, 2.08-3.49; P < .00001). Considering only first-line trials, similar differences were found in OS (HR, 0.85; 95% CI, 0.72-1.00; P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P < .00001), and ORR (OR, 2.21; 95% CI, 1.65-2.95; P < .00001). In EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P < .00001) and ORR (168 patients; OR, 11.59; 95% CI, 5.54-24.25; P < .00001). In patients with advanced NSCLC, chemotherapy plus intercalated EGFR-TKIs was superior to chemotherapy alone, although a definitive interpretation was jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.     

Challenges to treat hypogonadism in prostate cancer patients: implications for endocrinologists,urologists and radiotherapists

The literature suggests that the serum testosterone level required for maximum androgen receptor (AR) binding may be in the range of nanomolar and above this range of concentrations; this sexual hormone may not significantly affect tumour biology. This assumption is supported by clinical studies showing that cell proliferation markers did not change when serum T levels increased after exogenous T treatment in comparison to subjects treated with placebo. However, a considerable part of the global scientific community remains sceptical regarding the use of testosterone replacement therapy (TRT) in men suffering from hypogonadism and prostate cancer (Pca). The negative attitudes with respect to testosterone supplementation in men with hypogonadism and Pca may be justified by the relatively low number of clinical and preclinical studies that specifically dealt with how androgens affect Pca biology. More controversial still is the use of TRT in men in active surveillance or at intermediate or high risk of recurrence and treated by curative radiotherapy. In these clinical scenarios, clinicians should be aware that safety data regarding TRT are scanty limiting our ability to draw definitive conclusions on this important topic. In this review we critically discuss the newest scientific evidence concerning the new challenges in the treatment of men with hypogonadal condition and Pca providing new insights in the pharmacological and psychological approaches.     

The Gynogram: A Multicentric Validation of a New Psychometric Tool to Assess Coital Pain Associated With VVA and Its Impact on Sexual Quality of Life in Menopausal Women

BackgroundVulvo-Vaginal Atrophy (VVA) affects about fifty percent of postmenopausal women, contributing more vulnerable sexual and psycho-relational equilibrium. To date, no psychometric instruments have been designed to assess the impact of coital pain associated with VVA on sexual quality of life.AimTo validate a new psychometric tool, the Gynogram, able to investigate coital pain and to quantify its impact on sexual well-being in menopause.Methods214 sexually active postmenopausal women were enrolled in the study during clinical consultations in gynecological outpatient clinics in Italy. After gynecological examination and evaluation of the presence of VVA, the study sample was divided in a clinical group (103 women with certified diagnosis of VVA) and in a control group (111 women without certified diagnosis of VVA) according to the Vaginal Health Index (VHI) cut-off. Factor, Reliability and Receiving Operating Characteristics (ROC) analysis were performed in order to validate our newly created Gynogram.OutcomesA structured questionnaire, named Gynogram, to assess coital pain and its impact, and the Female Sexual Function Index (FSFI).ResultsThe factor analysis performed on the original form (80 items) reduced the Gynogram to 24 items. Reliability analysis conducted with Cronbach's Alpha coefficients showed high values in all the components (ranging from .813 to .972), both in the long and in the short form. The sensitivity analysis demonstrated that the Gynogram, with a cut-off ≤93, is able to recognize a clinically significant coital pain. With respect to the FSFI, statistically significant differences were found for all the domains. In addition, statistically significant differences were found for all the twelve factors of the Gynogram, showing that VVA profoundly affects the sexual quality of life of women in post-menopause.Clinical TranslationThe utility of this tool consists in the possibility to improve prognosis, compliance/adherence and treatment outcomes.Strengths and LimitationsThe Gynogram is able to evaluate and to quantify the impact of coital pain associated with VVA. Moreover, it can also recognize the areas of biopsychosocial functioning being more affected by this clinical condition. The main limit of the study is the impossibility to evaluate both mental health and partner's general and sexual health.ConclusionsThe Gynogram is a new and validated psychometric tool able to detect the impact of symptomatic VVA on sexual quality of life among post-menopausal women, with a specific focus on the different areas of sexual functioning.Nappi RE, Graziottin A, Mollaioli A, et al. The Gynogram: A Multicentric Validation of a New Psychometric Tool to Assess Coital Pain Associated With VVA and Its Impact on Sexual Quality of Life in Menopausal Women. J Sex Med 2021;18:955–965.     

Ligand-based chemoinformatic discovery of a novel small molecule inhibitor targeting CDC25 dual specificity phosphatases and displaying in vitro efficacy against melanoma cells

CDC25 phosphatases are important regulators of the cell cycle and represent promising targets for anticancer drug discovery. We recently identified NSC 119915 as a new quinonoid CDC25 inhibitor with potent anticancer activity. In order to discover more active analogs of NSC 119915, we performed a range of ligand-based chemoinformatic methods against the full ZINC drug-like subset and the NCI lead-like set. Nine compounds (3, 5–9, 21, 24, and 25) were identified with K_i values for CDC25A, -B and -C ranging from 0.01 to 4.4 μM. One of these analogs, 7, showed a high antiproliferative effect on human melanoma cell lines, A2058 and SAN. Compound 7 arrested melanoma cells in G2/M, causing a reduction of the protein levels of CDC25A and, more consistently, of CDC25C. Furthermore, an intrinsic apoptotic pathway was induced, which was mediated by ROS, because it was reverted in the presence of antioxidant N-acetyl-cysteine (NAC). Finally, 7 decreased the protein levels of phosphorylated Akt and increased those of p53, thus contributing to the regulation of chemosensitivity through the control of downstream Akt pathways in melanoma cells. Taken together, our data emphasize that CDC25 could be considered as a possible oncotarget in melanoma cells and that compound 7 is a small molecule CDC25 inhibitor that merits to be further evaluated as a chemotherapeutic agent for melanoma, likely in combination with other therapeutic compounds.     

Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire

Patient satisfaction in performing activities of daily living (ADL) was assessed by using a self-administered questionnaire modified from the Stanford Health Assessment Questionnaire (HAQ). The HAQ includes questions to determine a patient's degree of difficulty and need for help and assistive devices in ADL. A modification of the HAQ (MHAQ) was developed to include questions concerning perceived patient satisfaction regarding the same ADL, along with perceived change in degree of difficulty. In order to add additional questions while maintaining the length of the questionnaire in a format suitable in routine care, the number of ADL included in the MHAQ was reduced from 20 to 8. Information regarding degree of difficulty derived from 8 questions in the MHAQ is comparable with that derived from 20 questions in the HAQ. The response of a patient that a specific activity is associated with difficulty in functional capacity was not inevitably associated with the absence of patient satisfaction; 43.7% of patients responding "with some difficulty" and 19.1% of patients responding "with much difficulty" expressed satisfaction with their functional capacity. A major determinant of expression of patient satisfaction was perceived change in difficulty: 81.4% of patients noting that their function was "less difficult now," in contrast to 16.9% of patients responding "more difficult now," expressed satisfaction. These studies suggest that data regarding patient satisfaction and perceived change in difficulty can be assessed to more completely characterize patients' functional status in ADL.     

Controversies in Sexual Medicine: Clinical and Basic Science Research in Sexual Medicine Must Rely,in Part,on Pharmaceutical Funding?

IntroductionThe conflict of interest in sexual medicine (SM) is a never-ending debate between scientists who consider possible and fruitful the partnership between science and the pharmaceutical industry (pharma) and others who are afraid that such a relationship might contaminate the veracity of scientific research. The aim of this Controversy is to appreciate opinions from both perspectives.MethodsFour scientists (three from academic or private practice and one employee of the industry) with expertise in the area of SM were asked to contribute with their opinions.Main Outcome MeasureExpert opinion supported by the critical review of the currently available literature.ResultExpert #1, who is Controversy's section editor, and Expert #3 consider industry involvement in the field of SM problematic but potentially synergistic with the aim of science. On the other side, the Experts #2 and 4 argue that it is almost impossible to serve two masters. They believe that the pharma involved both in basic and applied research may jeopardize the independent evolution of the young SM.ConclusionsAfter reading this Controversy, The Journal of Sexual Medicine's readers should be able to judge by themselves the claims of the discussants and if the partnership between industry and SM is a risk or a potential benefit. Jannini EA, Eardley I, Sand M, and Hackett G. Clinical and basic science research in sexual medicine must rely, in part, on pharmaceutical funding?.