Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy.

BACKGROUND: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. PATIENTS AND METHODS: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. RESULTS: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. CONCLUSION: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.

Gender differences and health inequality: Evolution of cardiovascular risk in workers.

The aim was to find out if there are any such differences due to gender in a cohort of workers followed for ten years, comparing their lifestyles and following the evolution of the main cardiovascular risk factors (CVRF) and their impact on cardiovascular risk. An observational longitudinal study of 698 civil servants workers (186 women and 512 men) of a local government office from Córdoba (Spain), was conducted over the period 2003-2014. We compared the initial and final prevalence of physical activity, smoking, obesity, hypertension, metabolic syndrome and diabetes. Cardiovascular risk was also assessed using the REGICOR (Registre Gironí del Cor) and SCORE (Systematic Coronary Risk Evaluation) equations. There was a greater rise in the prevalence of hypertension and hypercholesterolemia in the cohort in women than in men (94.2% vs. 38% and 92% vs 21.1%), while the reduction in smoking also differed by gender (26.4% vs. 36.5%). It could be that since women present a lower cardiovascular risk profile, they are treated less or less effort is made to keep the risk factors low, resulting in a worse evolution of smoking, hypercholesterolemia and hypertension in women.

Epidermal growth factor receptor and epididymis invasion as prognostic biomarkers in clinical stage I testicular germ cell tumours.

BACKGROUND: Inguinal orchiectomy is curative in 70-80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT. METHODS: Fifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays. RESULTS: Classical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3-9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations. CONCLUSIONS: Epididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT.

Benefit of on nephrectomy for treating metastatic renal cell carcinoma. / Beneficio de la nefrectomía en el tratamiento del carcinoma de células renales metastásico.

INTRODUCTION: Systemic treatment for metastatic renal cell carcinoma (mRCC) has changed with the new therapies, and it is not clear if nephrectomy (NEP) has a survival benefit in this kind of patients. OBJECTIVE: To investigate if NEP associated to systemic treatment improves overall survival (OS) and progression-free survival (PFS). MATERIAL AND METHODS: A retrospective, observational, descriptive study of 45 patients with diagnosis of mRCC between 2006-2014. Advanced cases with only palliative care were excluded, also patients with solitary metastasis who were managed with surgical resection. RESULTS: Finally 34 patients were treated with systemic treatment. Twenty-six also with surgery associated. Seventy percent were intermediate/low risk at the Motzer classification and>80% Karnofsky performance status. PFS was 7m. NEP improves PFS (10 vs. 4m). High risk Motzer decreased PFS (P<.001). The OS was 11.5m. Patients with Karnofsky performance status>80, intermediate or low risk Motzer treated with NEP and mTOR as second line treatment, increased the OS (14 vs. 3m, P=.0001; 14 vs. 6m, P=.001; and 9 vs. 5m, P=.003, respectively). In the multivariate analysis only NEP (P=0,006; HR 4.5) and intermediate/low risk at the Motzer classification(P=.020; HR 8.9) demonstrated significant improvement in OS. CONCLUSIONS: Patients treated with NEP associated to systemic treatment and with an intermediate/low risk in the Motzer classification had a better PFS and OS. The OS also improves in patients treated with mTOR in second line, and Karnofsky performance status>80%in the univariate study, but not in the multivariable one.

A short CD3/CD28 costimulation combined with IL-21 enhance the generation of human memory stem T cells for adoptive immunotherapy.

BACKGROUND: Immunotherapy based on the adoptive transfer of gene modified T cells is an emerging approach for the induction of tumor-specific immune responses. Memory stem T cells, due to their enhanced antitumor and self-renewal capacity, have become potential candidate for adoptive T cell therapy of cancer. Methods to generate memory stem T cells ex vivo rely on CD3/CD28 costimulation and the use of cytokines such as IL-7 and IL-15 during the entire culture period. However, a strong costimulation may induce differentiation of memory stem T cells to effector memory T cells. Here we show that manipulation of the length of the costimulation and addition of IL-21 enhance the ex vivo expansion of memory stem T cells. METHODS: Purified naïve T cells from healthy donors were cultured in the presence of anti-CD3/CD28 coated beads, IL-7, IL-15 and/or IL-21 (25 ng/ml). T cells phenotype from the different memory and effector subpopulations were analyzed by multiparametric flow cytometry. RESULTS: A short anti-CD3/CD28 costimulation of naïve T cells, combined with IL-7 and IL-15 significantly increased the frequencies of CD4(+) and CD8(+) memory stem T cells ex vivo, compared to a prolonged costimulation (34.6 ± 4.4 % vs 15.6 ± 4.24 % in CD4(+); p = 0.008, and 20.5 ± 4.00 % vs 7.7 ± 2.53 % in CD8(+); p = 0.02). Moreover, the addition of IL-21 to this condition further enhanced the enrichment and expansion of CD4(+) and CD8(+) memory stem T cells with an increase in the absolute numbers (0.7 × 10(6) ± 0.1 vs 0.26 × 10(6) ± 0.1 cells for CD4(+); p = 0.002 and 1.1 × 10(6) ± 0.1 vs 0.27 × 10(6) ± 0.1 cells for CD8(+); p = 0.0002; short + IL-21 vs long). CONCLUSIONS: These new in vitro conditions increase the frequencies and expansion of memory stem T cells and may have relevant clinical implications for the generation of this memory T cell subset for adoptive cell therapy of patients with cancer.

[Orbital metastases in colorectal cancer: a case report]. / Metástasis orbitarias en carcinoma colorrectal: a propósito de un caso.

CLINICAL CASE: A 32-year-old male, with colon cancer stage IV, resistant to chemotherapy, was referred to our department due to palpebral oedema, conjunctival chemosis, severe exophthalmos, complete ptosis in left eye, and limitation in eye movements, mainly in abduction and supraversion. In the orbital MR scan we observed two nodular lesions in the left orbital, with involvement of the superior rectus-elevator muscle of upper eyelid complex and external rectus muscle, suggestive of metastases. Due to the patient generally feeling unwell, radiotherapy was not considered, and an intravenous bolus of corticoids was given, without response, resulting in the death of the patient. DISCUSSION: Orbital metastases usually originate from breast and lung cancer, with those secondary to colon cancer being much less frequent. The treatment is palliative, based on intravenous corticoids, and, above all, radiotherapy, and, only in cases with a long-term survival, surgery.