Identifying and preventing burnout in young oncologists, an overwhelming challenge in the COVID-19 era: a study of the Spanish Society of Medical Oncology (SEOM).

BACKGROUND: Young oncologists are at particular risk of professional burnout, and this could have a significant impact on their health and care of their patients. The coronavirus disease 2019 (COVID-19) pandemic has forced rapid changes in professionals' jobs and training, with the consequent physical and psychological effects. We aimed to characterize burnout levels and determinants in young oncologists, and the effects of the pandemic on their training and health. METHODS: Two online surveys were conducted among oncology residents and young oncology specialists in Spain. The first addressed professional burnout and its determinants before the COVID-19 pandemic, while the second analyzed the impact of the pandemic on health care organization, training, and physical and psychological health in the same population. RESULTS: In total, 243 respondents completed the first survey, and 263 the second; 25.1% reported significant levels of professional burnout. Burnout was more common among medical oncology residents (28.2%), mainly in their second year of training. It was significantly associated with a poor work-life balance, inadequate vacation time, and the burnout score. Nearly three-quarters of respondents (72%) were reassigned to COVID-19 care and 84.3% of residents missed part of their training rotations. Overall, 17.2% of this population reported that they had contracted COVID-19, 37.3% had scores indicating anxiety, and 30.4% moderate to severe depression. Almost a quarter of young oncologists (23.3%) had doubts about their medical vocation. CONCLUSIONS: Burnout affects a considerable number of young oncologists. The COVID-19 pandemic has had a profound impact on causes of burnout, making it even more necessary to periodically monitor it to define appropriate detection and prevention strategies.

SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020)

Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future (AU)

SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020).

Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future.

Metronomic oral vinorelbine in previously untreated advanced non-small-cell lung cancer patients unfit for platinum-based chemotherapy: results of the randomized phase II Tempo Lung trial.

BACKGROUND: To assess the efficacy and safety of a metronomic schedule of oral vinorelbine (mVNR) in advanced non-small-cell lung cancer (NSCLC) in patients unfit for platinum-based combination chemotherapy. PATIENTS AND METHODS: This was a multicenter, prospective, randomized, open-label phase II study in treatment-naive patients with TNM stage IIIB/IV NSCLC. Patients received mVNR at a fixed dose of 50 mg × 3 or standard schedule 60-80 mg/m2 weekly until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) without grade 4 toxicity (G4PFS; NCI-CTC v4). Main secondary objectives were safety, disease control rate (DCR) without grade 4 toxicity (G4DCR), DCR, PFS, overall survival (OS) and quality of life (QoL). RESULTS: A total of 167 patients were included, 83 and 84 patients in the mVNR and standard arms, respectively. The median G4PFS was 4.0 months [95% confidence interval (CI): 2.6-4.3] and 2.2 months (95% CI: 1.5-2.9), hazard ration (HR) = 0.63 (95% CI: 0.45-0.88), P = 0.0068 in favor of metronomic arm; G4DCR was 45.8% and 26.8% in the mVNR and standard arms, respectively. Grade 3-4 treatment-related adverse events were less frequent in the mVNR arm (25.3% versus 54.4%) mainly owing to a reduction in all grades (15.7% versus 51.9%) and grade 3-4 neutropenia (10.8% versus 42%). PFS was 4.3 (95% CI: 3.3-5.1) and 3.9 months (95% CI: 2.8-5.2) in mVNR and standard arms, respectively. No difference in median OS was observed. QoL was comparable between arms. CONCLUSIONS: Metronomic oral vinorelbine significantly prolonged median G4PFS in advanced NSCLC patients unfit for platinum combinations as first-line treatment. It was associated with a clear reduction in toxicity and may be considered as an important option in this challenging population.

Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic.

BACKGROUND: Brain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC. METHODS: We reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models. RESULTS: Although limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8+ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion. CONCLUSIONS: Discordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.

The Medical Oncology resident mentor: situation and workload.

PURPOSE: The Spanish Society for Medical Oncology (SEOM, for its acronym in Spanish) and the National Commission for the Specialty of Medical Oncology seek to highlight the important workload and unrecognized dedication entailed in working as a Medical Oncology (MO) resident mentor, as well as its relevance for the quality of teaching units and the future of the specialty. MATERIALS AND METHODS: The current situation and opinion regarding the activity of MO resident mentors was analyzed by reviewing the standing national and autonomic community regulations and via an online survey targeting mentors, residents, and physicians who are not MO mentors. The project was supervised by a specially designated group that agreed on a proposal containing recommendations for improvement. RESULTS: Of the MO mentors, 90% stated that they did not have enough time to perform their mentoring duties. An estimated 172 h/year on average was dedicated to mentoring, which represents 10.1% of the total time. MO mentors dedicate an average of 6.9 h/month to these duties outside their workday. Forty-five percent of the mentors feel that their role is scantly recognized, if at all. CONCLUSIONS: The study reveals the substantial dedication and growing complexity of MO resident mentoring. A series of recommendations are issued to improve the conditions in which it is carried out, including the design of systems that adapt to the professional activity in those departments that have time set aside for mentoring tasks.

The multimodal management of locally advanced N2-non-small cell lung cancer: is there a role for surgical resection? A single institution's experience

BACKGROUND: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone. METHODS: From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test. RESULTS: Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group. CONCLUSIONS: The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found (AU)

Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour cells.

BACKGROUND: In addition to the mutational status of KRAS, the epidermal growth factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG) might function as bona fide biomarkers of cetuximab (Ctx) sensitivity for most EGFR-driven carcinomas. METHODS: Lentivirus-delivered small hairpin RNAs were employed to specifically reduce AREG or EREG gene expression in wild-type KRAS A431 squamous cell carcinoma cells. Colony-forming assays were used to monitor the impact of AREG and EREG knockdown on Ctx efficacy. Amphiregulin and EREG protein expression levels were assessed by quantitative ELISA in parental A431 cells and in pooled populations of A431 cells adapted to grow in the presence of Ctx. A phosphoproteomic platform was used to measure the relative level of phosphorylation of 42 distinct receptor tyrosine kinases before and after the acquisition of resistance to Ctx. RESULTS: Stable gene silencing of either ligand was found to notably reduce the expression of the other ligand. Parental A431 cells with normal expression levels of AREG/EREG exhibited significantly increased growth inhibition in response to Ctx, compared with derivatives that are engineered to produce minimal AREG/EREG. The parental A431 cells acutely treated with Ctx exhibited reduced basal expression levels of AREG/EREG. Pooled populations of Ctx-resistant A431 cells expressed significantly lower levels of AREG/EREG and were insensitive to the downregulatory effects of Ctx. Phosphoproteomic screen identified a remarkable hyperactivation of FGFR3 in Ctx-resistant A431 cells, which gained sensitivity to the cytotoxic and apoptotic effects of the FGFR3 TK inhibitor PD173074. The A431 parental cells acutely treated with Ctx rapidly activated FGFR3 and their concomitant exposure to Ctx and PD173074 resulted in synergistic apoptosis. CONCLUSION: Cross-suppression of AREG/EREG expression may explain the tight co-expression of AREG and EREG, as well as their tendency to be more highly expressed than other EGFR ligands to determine Ctx efficacy. The positive selection for Ctx-resistant tumour cells exhibiting AREG/EREG cross-suppression may have an important role in the emergence of Ctx resistance. As de-repression of FGFR3 activity rapidly replaces the loss of EGFR-ligand signalling in terms of cell proliferation and survival, combinations of Ctx and FGFR3-targeted drugs may be a valuable strategy to enhance the efficacy of single Ctx while preventing or delaying acquired resistance to Ctx.

Direct antitumour activity of zoledronic acid: preclinical and clinical data

Bisphosphonates (BPs) are widely used in the management of metastatic bone disease to reduce skeletal morbidity. Zoledronic acid (ZA), the most potent BP in clinical use, has demonstrated clinical utility in multiple tumour types. Preclinical data indicate that ZA may have direct antitumour activity, as has been demonstrated preclinically in both in vitro and in vivo experiments. The majority of preclinical studies showing antitumour effects have used high doses of ZA, making it difficult to translate these data to the clinical setting. This review summarises the published data on antitumour effects of ZA in tumour cell lines, mice experiments, and human clinical trials. Translational questions regarding drug dose, dose interval, and sequence with chemotherapy treatment are also addressed (AU)

Alucinaciones visuales y dolor inusual en relación a hipomagnesemia en un paciente con cáncer avanzado / Visual hallucinations and unusual pain related to hypomagnesemia in an advanced cancer patient

La hipomagnesemia se ha relacionado con dosis acumuladas altas de cisplatino y su presentación clínica se caracteriza por alteraciones neuromusculares y cardiovasculares. Presentamos el caso de un paciente con cáncer avanzado que había recibido varias líneas de tratamiento de quimioterapia y recibía tratamiento analgésico opioide. Durante su estancia en el hospital presentó alucinaciones visuales y un intenso e inexplicado dolor en el hombro. La sintomatología revirtió tras la normalización de los niveles de magnesio en sangre, que eran bajos. Consideramos que los niveles séricos de magnesio deberían monitorizarse en los pacientes oncológicos con dolor inusual o síntomas neurológicos o psiquiátricos no explicables (AU)

Hypomagnesemia has been related to high accumulated doses of cisplatin, and its clinical presence is characterized by neuromuscular and cardiovascular alterations. We present the case of an advanced cancer patient who had received successive lines of chemotherapy and who was receiving opioid treatment for cáncer pain. During his hospital stay, he experienced visual hallucinations and very intense, unexplained pain in one shoulder. Symptoms reverted with the normalization of his plasma magnesium levels, which were low. We consider that plasma magnesium levels should be monitored in oncology patients with neurological or psychiatric symptoms or with unusual pain (AU)

La vía de la insulina y el factor de crecimiento similar a la insulina, una nueva diana terapéutica en oncología / Insulin and insulin-like growth factor pathway, a new targeted therapy in oncology

La biología molecular del cáncer ha permitido identificarnuevas dianas para atacar las células tumorales.Recientemente se ha propuesto la vía de señalizaciónde la insulina y el factor de crecimiento similar a la insulinacomo una de estas dianas. En esta revisión sedescribe su función biológica, los datos de laboratorioy estudios poblacionales que alertan de su papel enel cáncer y se describen los elementos claves de estavía de señalización: los ligandos (insulina, IGF1, IGF2),sus receptores y la cascada de señales intracelular quedesencadena su activación. Así mismo se revisan lasdistintas estrategias que se están investigando parabloquearla, algunas de las cuales ya se encuentran enestudios avanzados fase III. Los datos preliminares indicanque los fármacos diseñados para bloquear esta víapueden ser una nueva arma terapéutica para los pacientesoncológicos en un futuro próximo(AU)

The molecular biology of cancer has made it possibleto identify new targets for attacking tumourouscells. One of these recently proposed targets is the insulinand insulin-like growth factor signaling pathway.This review describes its biological function, laboratorydata, population studies that warn of its role incancer, and the key elements of this signaling pathway:the ligands (insulin, IGF1, IGF2), its receptors and thecascade of intracellular signals that trigger its activation.Also reviewed are the different strategies underinvestigation for blocking it, some of which are alreadyin phase III advanced studies. The preliminary data indicatethat the medicines designed for blocking this pathwaymight be a new therapeutic weapon for oncologypatients in the near future(AU)

Sensory-motor axonal peripheral neuropathy in an advanced breast cancer patient treated with ixabepilone

Ixabepilone is a novel microtubule-stabilising agent used as monotherapy or in combination with capecitabine to treat taxane- and anthracycline-refractory breast cancer. We report the case of a patient who experienced an unusual motor neuropathy after the first cycle. This is a very uncommon secondary effect, but it must be taken into account as a possible complication of treatment with ixabepilone (AU)

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[Insulin and insulin-like growth factor pathway, a new targeted therapy in oncology]. / La vía de la insulina y el factor de crecimiento similar a la insulina, una nueva diana terapéutica en oncología.

The molecular biology of cancer has made it possible to identify new targets for attacking tumourous cells. One of these recently proposed targets is the insulin and insulin-like growth factor signaling pathway. This review describes its biological function, laboratory data, population studies that warn of its role in cancer, and the key elements of this signaling pathway: the ligands (insulin, IGF1, IGF2), its receptors and the cascade of intracellular signals that trigger its activation. Also reviewed are the different strategies under investigation for blocking it, some of which are already in phase III advanced studies. The preliminary data indicate that the medicines designed for blocking this pathway might be a new therapeutic weapon for oncology patients in the near future.

[Stem cells and cancer: elucidating the origin of the cancer stem cell]. / Células madre y cáncer: dilucidando el origen de la célula madre tumoral.

Stem cell therapy is currently at the frontier of biomedical research. A considerable volume of evidence indicates that cancer stem cells are responsible for the development of different types of tumors. Malignant transformation of stem cells may be due to the loss of normal asymmetric division processes, cell fusion, microenviromental factors, generic and epigenetic mechanisms or carcinogenics already implicated in cancer development. A better understanding of these transforming events will allow more rational design of new specific therapeutic strategies targeting the cancer stem cell.

Células madre y cáncer: dilucidando el origen de la célula madre tumoral / No disponible

La terapia con células madre está en la vanguardia de la investigación biomédica actual. Cada vez hay más evidencias de que la célula madre tumoral puede estar implicada en el origen del cáncer como se propone en el modelo jerárquico. La célula madre puede transformarse en maligna por procesos de pérdida de la división asimétrica, transferencia genética horizontal, fusión celular, factores microambientales y los agentes carcinógenos ya descritos para las células diferenciadas. Conocer mejor cómo se produce esta transformación permitirá diseñar abordajes de terapia celular más seguros y nuevos tratamientos específi cos contra estas células madre tumorales

Stem cell therapy is currently at the frontier of biomedical research. A considerable volume of evidence indicates that cancer stem cells are responsible for the development of different types of tumors. Malignant transformation of stem cells may be due to the loss of normal asymmetric division processes, cell fusion, microenviromental factors, generic and epigenetic mechanisms or carcinogenics already implicated in cancer development. A better understanding of these transforming events will allow more rational design of new specifi c therapeutic strategies targeting the cancer stem cell