Use of CYP2D6 substrates and inhibitors during pain management with analgesic opioids: Drug-drug interactions that lead to lack of analgesic effectiveness.

BACKGROUND: Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes. MATERIALS AND METHODS: An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded. RESULTS: The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present. CONCLUSION: The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management.

Nadir prostate-specific antigen after salvage cryotherapy as a potential prognostic factor for oncologic outcomes.

PURPOSE: To report oncologic outcomes of patients undergoing salvage cryotherapy (SCT) for local recurrence of prostate cancer (PCa) and to establish a nadir PSA (nPSA) value that best defines long-term oncologic success. METHODS: Retrospective study of men who underwent SCT for local recurrence of PCa between 2008 and 2020. SCT was performed in men with biochemical recurrence (BCR), after primary treatment and with biopsy-proven PCa local recurrence. Survival analysis with Kaplan-Meier and Cox models was performed. We determined the optimal cutoff nPSA value after SCT that best classifies patients depending on prognosis. RESULTS: Seventy-seven men who underwent SCT were included. Survival analysis showed a 5-year biochemical recurrence-free survival (BRFS), androgen deprivation therapy-free survival (AFS), and metastasis-free survival (MFS) after SCT of 48.4%, 62% and 81.3% respectively. On multivariable analysis for perioperative variables associated with BCR, initial ISUP, pre-SCT PSA, pre-SCT prostate volume and post-SCT nPSA emerged as variables associated with BCR. The cutoff analysis revealed an nPSA < 0.5 ng/ml to be the optimal threshold that best defines success after SCT. 5-year BRFS for patients achieving an nPSA < 0.5 vs nPSA ≥ 0.5 was 64% and 9.5% respectively (p < 0.001). 5-year AFS for men with nPSA < 0.5 vs ≥ 0.5 was 81.2% and 12.2% (p < 0.001). Improved 5-year MFS for patients who achieved nPSA < 0.5 was also obtained (89.6% vs 60%, p = 0.003). CONCLUSION: SCT is a feasible rescue alternative for the local recurrence of PCa. Achieving an nPSA < 0.5 ng/ml after SCT is associated with higher long-term BRFS, AFS and MFS rates.

Postmenopausal sexual function and steroid hormone levels: a hospital-based cross-sectional study.

OBJECTIVE: Steroid hormone levels, particularly androgens, play an important role in sexual function in premenopausal women, but this relationship is not so well determined after menopause. This study aimed to assess the association between steroid hormone levels and sexual function in postmenopausal women. METHODS: A total of 84 postmenopausal women with intact ovaries, who had never used systemic hormone therapy, were enrolled in a cross-sectional study. Sexual function was assessed using the Female Sexual Function Index (FSFI) questionnaire and serum levels of steroid hormones were quantified by gas chromatography and tandem mass spectrometry. Associations between estradiol, testosterone, dehydroepiandrosterone, androstenedione and FSFI domain scores were evaluated. RESULTS: After adjustment for confounding variables, the analysis revealed a statistically significant association between androstenedione and overall sexual function (ß = 1.23, 95% confidence interval [CI] [0.37; 1.98], p = 0.010), arousal (ß = 0.19, 95% CI [0.02; 0.37], p = 0.034), orgasm (ß = 0.33, 95% CI [0.15; 0.45], p = 0.001) and satisfaction (ß = 0.25, 95% CI [0.11; 0.36], p = 0.001). No associations were found between the other hormones and FSFI domains. CONCLUSION: The main finding of this study is the association of androstenedione with sexual function in postmenopausal women, not verified for other steroid hormones. Further studies are necessary to determine the importance of androstenedione for postmenopausal sexual function.

Microextraction by Packed Sorbent as a Clean-up Approach for the Determination of Ketamine and Norketamine in Hair by Gas Chromatography--Tandem Mass Spectrometry.

The use of new psychoactive substances has been increasing and constitutes a social and public health problem, and hence, toxicological analysis has become of utmost importance for the detection of such substances. In this article, we present the development and full validation of a simple, user and environmentally friendly, cheap and suitable method for the determination of ketamine and its main metabolite norketamine in hair samples. The procedure included using a miniaturized procedure-microextraction by packed sorbent with mixed-mode sorbent-for sample clean-up. Organic solvents use was minimal, and it was possible to obtain a linear method (0.05-10 ng/mg for both analytes). The extraction efficiency ranged from 32 to 61%, which did not impair sensitivity. The method proved to be selective, precise, accurate and suitable for routine analysis for the determination of said compounds in 50-mg hair samples.

Efectividad y seguridad del tratamiento con panitumumab en cáncer colorrectal metastásico / Effectiveness and safety of panitumumab for metastatic colorectal cancer treatment

Objetivos: Evaluar la efectividad y seguridad de panitumumab en los pacientes con cáncer colorrectal metastásico y comparar los resultados obtenidos con los publicados en los ensayos clínicos.Material y métodos: Estudio observacional retrospectivo de los pacientes con cáncer colorrectal metastásico en tratamiento con panitumumab desde junio de 2010 hasta septiembre de 2017. Se recogieron de la historia clínica informatizada datos demográficos, clínicos y terapéuticos. Las variables principales de efectividad fueron: supervivencia libre de progresión, supervivencia global y tipo de respuesta al tratamiento. Los efectos adversos presentados y su gravedad establecieron el perfil de seguridad al mismo.Resultados: Se incluyeron 85 pacientes, 60 varones. La tasa de respuesta global fue de 17,8%, de las cuales el 15,3% fueron respuestas parciales. El 14% presentaron estabilización de la enfermedad y el 51,8% progresión de la misma. La mediana de supervivencia libre de progresión fue de 6 meses (IC 95% 4,7-6,2). El tratamiento fue, en general, bien tolerado. La toxicidad más frecuente fue la cutánea, afectando al 82,4% de los pacientes.Conclusiones: Panitumumab constituye una terapia con una efectividad y tolerabilidad aceptable en el tratamiento del CCRm en la población KRAS WT. La combinación del fármaco con esquemas de quimioterapia produce una mejora significativa en la supervivencia libre de progresión. (AU)

Objectives: To evaluate the effectiveness and safety of panitumumab in patients with metastatic colorectal cancer and to compare the results obtained with those published in clinical trials.Material and methods: Retrospective observational study of patients with metastatic colorectal cancer treated with panitumumab from June 2010 to September 2017. Demographic, clinical and therapeutic data were collected from the computerised clinical history. The main effectiveness endpoints were: progression-free survival, overall survival and type of response to treatment. Adverse events and their severity established the safety profile.Results: 85 patients, 60 males, were included. The overall response rate was 17.8%, of which 15.3% were partial responses. Disease stabilisation occurred in 14% and disease progression in 51.8%. Median progression-free survival was 6 months (95% CI 4.7-6.2). Treatment was generally well tolerated. The most frequent toxicity was skin toxicity, affecting 82.4% of patients.Conclusions: Panitumumab is a therapy with acceptable effectiveness and tolerability in treatment of mRCC in KRAS WT population. The combination of the drug with chemotherapy regimens produces a significant improvement in progression-free survival. (AU)

SEOM clinical guidelines for the treatment of advanced prostate cancer (2020)

The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy (AU)

Eustigmatophyte strains with potential interest in cancer prevention and treatment: partial chemical characterization and evaluation of cytotoxic and antioxidant activity.

The interest in bioactive compounds from microalgae is increasing since they have medicinal and nutritional areas. The present work aims to evaluate the potential pharmaceutical interest of extracts from three eustigmatophyte strains from the Coimbra Collection of Algae (ACOI): Chlorobotrys gloeothece, Chlorobotrys regularis and Characiopsis aquilonaris. Antioxidant and antiproliferative activities were determined as well as chlorophyll a, carotenoid and phenolic total contents. In addition, major pigments and sterols were identified and quantified. The three strains were grown until the stationary phase and then the biomass was extracted. Antioxidant activity was measured by TEAC, DPPH and FRAP assays and antiproliferative effect was assessed by the MTT method on MCF-7, PC-3 and NHDF cells. The pigment and phenolic total contents were determined by spectrophotometry. Of these strains, C. aquilonaris showed the highest antioxidant activity measured by TEAC and FRAP assays (23.98 ± 0.01 µmol TE eq g-1 DW and 42.57 ± 0.04 µmol TE eq g-1 DW, respectively), a selective effect in reduting MCF-7 cells proliferation and a larger amount of chlorophyll a, carotenoids and phenolic content (18.40 ± 0.00 µg chlorophyll a mg-1 DW, 2.27 ± 0.00 mg carotenoids g-1 DW and 6.23 ± 0.01 mg GAE g-1 DW, respectively). A positive correlation between chlorophyll a and TEAC assay was observed, as well as between carotenoids and TEAC and FRAP assays, suggesting these compounds as important contributors to significant antioxidant activity. Violaxanthin, cholesterol and stigmasterol were present in larger amount in C. aquilonaris while C. regularis showed a higher amount of ß-carotene. These results suggest that these three ACOI eustigmatophytes are promising for applications in the improvement of human health, particularly in cancer prevention and treatment.

Impact of the COVID-19 pandemic on tuberculosis management in Spain.

BACKGROUND: The impact of COVID-19 on the diagnosis and management of tuberculosis (TB) patients is unknown. METHODS: Participating centres completed a structured web-based survey regarding changes to TB patient management during the COVID-19 pandemic. The study also included data from participating centres on patients aged ≥18 diagnosed with TB in 2 periods: March 15 to June 30, 2020 and March 15 to June 30, 2019. Clinical variables and information about patient household contacts were retrospectively collected. RESULTS: A total of 7 (70%) TB units reported changes in their usual TB team operations. Across both periods of study, 169 patients were diagnosed with active TB (90 in 2019, 79 in 2020). Patients diagnosed in 2020 showed more frequent bilateral lesions in chest X-ray than patients diagnosed in 2019 (P = 0.004). There was a higher percentage of latent TB infection and active TB among children in households of patients diagnosed in 2020, compared with 2019 (P = 0.001). CONCLUSIONS: The COVID-19 pandemic has caused substantial changes in TB care. TB patients diagnosed during the COVID-19 pandemic showed more extended pulmonary forms. The increase in latent TB infection and active TB in children of patient households could reflect increased household transmission due to anti-COVID-19 measures.

Consensus statement of the Spanish Society of Internal Medicine and the Spanish Society of Medical Oncology on secondary thromboprophylaxis in patients with cancer

Up to 20% of cancer patients will develop some manifestation of venous thromboembolic disease (VTD) during their clinical course. VTD greatly impacts morbidity, mortality, quality of life and pharmaceutical expenditure. In addition, both thrombotic relapse and major haemorrhages derived from VTD treatment are more likely in oncological patients. To make the decision to establish secondary thromboprophylaxis as an indefinite treatment in these patients, it is important to review all the risk factors involved, whether related to the disease, the patient or the prior thrombotic event. The objectives of this consensus of the Spanish Society of Internal Medicine (Sociedad Española de Medicina Interna—SEMI) and the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica—SEOM) are to establish recommendations that help assess the risk of recurrence of VTD and haemorrhagic risk in patients with cancer, as well as to analyse the evidence that exists on the currently available drugs, which will allow the establishment of a protocol for shared decision-making with the informed patient (AU)

Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies

Background The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. Materials and methods We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. Results Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. Conclusion Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab (AU)

Clinical and molecular characterization of Chilean patients with X-linked hypophosphatemia.

We report the most comprehensive clinical and molecular characterization of XLH patients performed in Chile. We show high prevalence of musculoskeletal burden and pain, associated with significantly impaired physical capacity and quality of life, with many relevant complications presenting more frequently than previously reported in cohorts from developed countries. INTRODUCTION: Our current understanding of the clinical presentation and natural history of X-linked hypophosphatemia (XLH) comes mainly from cohorts from developed countries, with limited data on the clinical and genetic abnormalities of XLH patients in South America. OBJECTIVE: To describe the clinical, biochemical, and molecular presentation of patients with XLH in Chile. METHODS: Patients with XLH referred by endocrinologist throughout Chile were included. Demographic data and clinical presentation were obtained from a clinical interview. Surveys were applied for quality of life (QoL), pain, and functionality. FGF23 was measured by ELISA, and genetic testing was performed. Imaging studies were conducted to assess skeletal and renal involvement. RESULTS: We included 26 patients, aged 2-64 years, from 17 unrelated Chilean families. All pediatric patients but only 40% of adults were receiving conventional therapy, while 65% of all patients had elevated alkaline phosphatase. All patients had mutations in PHEX, including 5 novel variants. Radiographic skeletal events (RSE) and enthesopathies in adults were frequent (34% and 85%, respectively). The duration of treatment was associated with fewer RSE (p < 0.05). Most adults reported pain and impaired QoL, and 50% had impaired physical capacity. The number of enthesopathies was associated with worse pain and stiffness scores (p < 0.05). CONCLUSION: Chilean patients with XLH have a high prevalence of musculoskeletal burden associated with pain and impaired physical capacity and QoL, especially in adults who were generally undertreated. These data identify a significant unmet need, inform our understanding of the current status of patients, and can guide care for XLH patients in similarly socioeconomically defined countries.

SEOM clinical guidelines for the treatment of advanced prostate cancer (2020).

The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy.

Consensus statement of the Spanish Society of Internal Medicine and the Spanish Society of Medical Oncology on secondary thromboprophylaxis in patients with cancer.

Up to 20% of cancer patients will develop some manifestation of venous thromboembolic disease (VTD) during their clinical course. VTD greatly impacts morbidity, mortality, quality of life and pharmaceutical expenditure. In addition, both thrombotic relapse and major haemorrhages derived from VTD treatment are more likely in oncological patients. To make the decision to establish secondary thromboprophylaxis as an indefinite treatment in these patients, it is important to review all the risk factors involved, whether related to the disease, the patient or the prior thrombotic event. The objectives of this consensus of the Spanish Society of Internal Medicine (Sociedad Española de Medicina Interna-SEMI) and the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) are to establish recommendations that help assess the risk of recurrence of VTD and haemorrhagic risk in patients with cancer, as well as to analyse the evidence that exists on the currently available drugs, which will allow the establishment of a protocol for shared decision-making with the informed patient.

Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies.

BACKGROUND: The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. MATERIALS AND METHODS: We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. RESULTS: Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. CONCLUSION: Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

Microextraction by Packed Sorbent as a Novel Strategy for Sample Clean-Up in the Determination of Methadone and EDDP in Hair.

A microextraction by packed sorbent (MEPS) procedure for rapid concentration of methadone and its primary metabolite (EDDP) in hair samples was developed. The miniaturized approach coupled to gas chromatography with tandem mass spectrometry (GC-MS-MS) was successfully validated. Hair samples (50 mg) were incubated with 1 mL of 1 M sodium hydroxide for 45 min at 50°C, time after which the extract was neutralized by adding 100 µL of 20% formic acid. Subsequently, MEPS was applied using a M1 sorbent (4 mg; 80% C8 and 20% strong cation-exchange (SCX)), first conditioned with three 250-µL cycles of methanol and three 250-µL cycles of 2% formic acid. The extract load occurred with nine 150-µL cycles followed by a washing step involving three 50-µL cycles with 3.36% formic acid. For the elution of the analytes, six 100-µL cycles of 2.36% ammonium hydroxide in methanol were applied. The method was linear from 0.01 to 5 ng/mg, for both compounds, presenting determination coefficients greater than 0.99. Precision and accuracy were in accordance with the statements of international guidelines for method validation. This new miniaturized approach allowed obtaining recoveries ranging from 73 to 109% for methadone and 84 to 110% for EDDP, proving to be an excellent alternative to classic approaches, as well as other miniaturized procedures.

Latest progress in molecular biology and treatment in genitourinary tumours.

The management of genitourinary cancer, including bladder, prostate, renal and testicular cancer, has evolved dramatically in recent years due to a better understanding of tumour genetic mutations, alterations in molecular pathways, and to the development of new kinds of drugs such as targeted therapies and immunotherapies. In the field of immunotherapy, new drugs focused on stimulating, enhancing and modulating the immune system to detect and destroy cancer, have been recently discovered. Research in oncology moves quickly and new data of great relevance for clinical practice are communicated every year. For this reason, a group of experts, focused exclusively on the treatment of genitourinary tumours and who get together every year in the BestGU conference to assess the latest progress in this field have summarized the most important advances in a single review, along with a critical assessment of whether these results should alter daily clinical practice.

SEOM clinical guideline thyroid cancer (2019).

Thyroid carcinoma is the most frequent endocrine malignancy and accounts for around 3% of global cancer incidence. Different histologies and clinical scenarios make necessary a multidisciplinary approach that includes new diagnostic methods and surgical, radiopharmaceutical and systemic therapies. This guideline updates several aspects of management of thyroid cancer.