Capecitabine/cisplatin combined with concurrent intensity-modulated radiation therapy: a feasible therapeutic strategy for anal squamous cell carcinoma

Purpose To evaluate the efficacy and safety of capecitabine/cisplatin (XP) combined with intensity-modulated radiation therapy (IMRT) in patients with non-metastatic anal squamous cell carcinoma (ASCC). Method and materials All patients with ASCC who received radical concurrent chemoradiotherapy in the past 8 years were screened. Patients who received XP or mitomycin/5-fluorouracil (MF) were selected and analyzed retrospectively. Results ASCC is an uncommon cancer, there were 36 patients were included in our study. The XP group and MF group included 18 patients each. The clinical complete response (cCR) rates in the XP group and the MF group were 94.4% and 88.9%, respectively (P = 1). The 2-year local control (LC), disease-free survival (DFS), and colostomy-free survival (CFS) rates were higher in the XP group than in the MF group (100% vs 93.3%, P = 0.32). Hematologic toxicities, especially grade ≥ 3 leukopenia (11.1% vs 44.4%, P = 0.06) and neutropenia (5.6% vs 61.1%, P = 0.001), were lower in the XP group than MF group. As a result of fewer side effects, fewer patients in the XP group demanded the dose reduction of chemotherapy (11.1% vs 50%, P = 0.03) and radiation interruption (55.6% vs 77.8%, P = 0.289). Delayed radiotherapy was shorter in the XP group (2.5 vs 6.5 days, P = 0.042) than in the MF group. Conclusion The XP regimen was as effective as the MF regimen in non-metastatic ASCC. Compared with the standard MF regimen, XP combined with IMRT showed higher treatment completion and lower toxicities. It could be considered a feasible alternative for patients with non-metastatic ASCC (AU)

Neoadjuvant chemotherapy with dose-dense MVAC in muscle-invasive bladder cancer: a tertiary center experience

Purpose Neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) patients has proven beneficial in overall survival. However, the optimal regimen is still a matter of debate. Materials and method In this retrospective analysis, we evaluate the results obtained in 42 patients treated in our center with 4 cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) followed by radical cystectomy from August 2015 to October 2020. All patients had cT2 or higher non-metastatic MIBC. Clinical and pathological outcomes are reported. Results Of the 42 patients, 90.5% were men (n = 38) and the mean age was 65 years. All of them had ECOG 0–1 at diagnosis and most tumors had an initial clinical stage T2N0 (76%). Thirty-six patients (85.7%) completed 4 cycles of neoadjuvant treatment, and 21.4% required a dose reduction. The most frequent adverse event (AE) was grade 1–2 asthenia (81%), while neutropenia was the most frequent grade 3 or higher AE (38%). Complete pathological response (ypT0, ypN0) was achieved in 50% of patients (n = 21), and down-staging was observed in 57.1% (n = 24). Only one patient presented radiological progressive disease during neoadjuvant treatment (2.4%), and after a mean follow-up time of 31.5 months, 33.3% of patients experienced disease recurrence. Conclusions Neoadjuvant chemotherapy with 4 cycles of dd-MVAC is an effective regimen with high rates of pathological complete responses and down-staging along with an acceptable toxicity profile. DD-MVAC should be considered as an alternative to cisplatin and gemcitabine in patients with good clinical performance status (AU)

Optimal cisplatin cycles in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy

Purpose To analyze the effect of cisplatin cycles on the clinical outcomes of patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT). Methods This study included 749 patients with LACC treated with CCRT between January 2011 and December 2015. A receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off of cisplatin cycles in predicting clinical outcomes. Clinicopathological features of the patients were compared using the Chi-square test. Prognosis was assessed using log-rank tests and Cox proportional hazard models. Toxicities were compared among different cisplatin cycle groups. Results Based on the ROC curve, the optimal cut-off of the cisplatin cycles was 4.5 (sensitivity, 64.3%; specificity, 54.3%). The 3-year overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival for patients with low-cycles (cisplatin cycles < 5) and high-cycles (≥ 5) were 81.5% and 89.0% (P < 0.001), 73.4% and 80.1% (P = 0.024), 83.0% and 90.8% (P = 0.005), and 84.9% and 86.8% (P = 0.271), respectively. In multivariate analysis, cisplatin cycles were an independent prognostic factor for overall survival. In the subgroup analysis of high-cycle patients, patients who received over five cisplatin cycles had similar overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival to patients treated with five cycles. Acute and late toxicities were not different between the two groups. Conclusion Cisplatin cycles were associated with overall, disease-free, and loco-regional relapse-free survival in LACC patients who received CCRT. Five cycles appeared to be the optimal number of cisplatin cycles during CCRT (AU)

Validation of a prognostic model for predicting larynx preservation outcome (TALK score) in a Southern European population

Objective Larynx preservation is the current standard for locally advanced (LA) laryngeal/hypopharyngeal tumors, but not all patients respond as expected. TALK score model measures four variables (T-staging, albumin levels, liquor consumption and Karnofsky score) to determine which cases are best suited to preservation treatment scheme. We aimed to validate this prognostic model in a Southern European population. Methods We retrospectively evaluated 175 patients diagnosed from July 2008 to December 2015 with LA laryngeal/hypopharyngeal carcinoma and treated with a laryngeal preservation scheme comprising induction chemotherapy followed by concomitant chemotherapy and radiotherapy. We applied the TALK score model to predict larynx preservation rate. Results Of the 175 patients evaluated, 96.6% were men, 98.3% were smokers and 77.1% misused alcohol. Tumors were laryngeal 66.3% vs 33.7% in hypopharynx, and all were either stage III (37.7%) or stage IV (62.3%). TALK prognostic subgroups were: good risk 40.0%; intermediate risk 52.5%; and poor risk 7.5%. With a median follow-up of 40.1 months, larynx preservation rate, laryngectomy-free survival and overall survival at 3 years was 84.5%, 63.7% and 68.2%, respectively. Although TALK score was not predictive of 3-year larynx preservation rate (good risk 85.5%; intermediate risk 83.1%; poor risk 91.6%), it was predictive of 3-year overall survival (good risk 81.9%; intermediate risk 62.9%; poor risk 33.5%) and 3-year laryngectomy-free survival (good risk 75.6%; intermediate risk 59.6%; poor risk 30.7%) Conclusion TALK model could predict OS and laryngectomy-free survival, helping clinicians to decide which patients should avoid laryngeal preservation and undergo laryngectomy after diagnosis (AU)

Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1a

Background Cancer-associated fibroblasts (CAFs), one of the main members of stromal cells in tumor microenvironment are proposed to play a central role in promoting tumor metastasis. It is unclear whether and how CAFs mediates tumor metastasis or chemoresistance in human ovarian cancer. Methods CAFs were extracted from human ovarian cancer tissues (OCs) of patients with different kinds of histological types. Results We found that CAFs showed more aggressive potency than those tumor cells, both of which were isolated from the same ovarian cancer specimen. Moreover, when co-cultured with CAFs, cell migration abilities of ovarian cancer cells (SKOV3, OVCAR3 and HEY) were significantly increased. Next, we preliminarily detected a higher CAFs density in sections of metastatic lesions than those in primary tumor site of primary OCs clinically. However, no significant difference of stromal derived factors-1α (SDF-1α) production from CAFs was found between primary and metastatic lesions. Additionally, in contrast with tumor cells, CAFs exhibited obvious apoptosis resistance when treated with cisplatin. Furthermore, we found that cisplatin-induced cytotoxicity and apoptosis were significantly inhibited by co-cultured with recombinant human SDF-1α in SKOV3 in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100. Conclusions CAFs might be involved in the malignant metastasis in human ovarian cancer through promoting cell migration in tumor cells. And their resistance to cytotoxic agents might be mediated by paracrine SDF-1α/CXCR4 signaling in ovarian cancer (AU)

Platin desensitizations in thoracic malignancies and risk factors for breakthrough reactions

Although platin desensitization is a safe and effective alternative for patients with hypersensitivity reactions (HSRs), sometimes breakthrough reactions (BTRs) can be encountered. However, data about the risk factors for BTRs are limited. The aim of this study is to define the outcomes of desensitization, the characteristics of BTRs, and to identify the risk factors for BTRs with platins in thoracic malignancies. This is a retrospective report of patients with thoracic malignancies who underwent platin desensitization. Patients’ demographics, initial HSR characteristics, skin test results, desensitization outcomes, and BTR characteristics were recorded. Thirty-three lung cancer and 14 malignant pleural mesothelioma (MPM) patients were included in the study. The culprit drug was cisplatin in 29 and was carboplatin in 18 patients. Skin test positivity was 43.5% with cisplatin, 50% with carboplatin, and it was found to be higher if the interval between the initial HSR and skin testing (ST) was ˃20 days (p = 0.027). One hundred and five desensitization courses were performed. Twenty-two patients had 33 BTRs. Skin test positivity was higher in the BTR-positive group (p = 0.025). BTRs (18.2%; n = 6) were more severe than initial HSR. In the case of epinephrine administration during initial HSR, epinephrine administration during the first BTR was found to be more (p = 0.036). The target dose was achieved in 92.4% of desensitization courses. The number of previous platin infusions ≥10 was found to be an independent risk factor for BTR development (p = 0.036 OR:17.641, 95% CI: 1.211–256.971). Identification of risk factors for BTR will guide appropriate management and desensitization approaches for platin HSRs (AU)

Establishment of an acquired lorlatinib-resistant cell line of non-small cell lung cancer and its mediated resistance mechanism

Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs’ drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung cancer (NSCLC) patients was still unknown.MethodsA lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order. (AU)

Ototoxicidad en la edad pediátrica: recomendaciones de la CODEPEH (Comisión para la Detección Precoz de la Hipoacusia infantil) para su prevención y diagnóstico precoz / Ototoxicity in childhood: Recommendations of the CODEPEH (Commission for the Early Detection of childhood Hearing Loss) for prevention and early diagnosis

La ototoxicidad se define como el daño, reversible o irreversible, producido sobre el oído interno por diversas sustancias que se denominan ototóxicos y que causan una hipoacusia y/o una alteración del sistema vestibular.La hipoacusia permanente afecta significativamente a la calidad de vida y es especialmente importante en el caso de niños. Es frecuente la falta o el retraso en su detección, dado que muchas veces progresa de forma poco llamativa hasta que afecta a la comunicación y al desarrollo global. Este impacto puede minimizarse siguiendo una estrategia de monitorización audiológica de la ototoxicidad, que permita su detección y tratamiento precoz. Se recomienda implantar dicha monitorización en los niños que van a ser tratados con cisplatino o aminoglucósidos.Este documento de revisión y recomendaciones de la CODEPEH se enfoca a la detección precoz, la profilaxis, la otoprotección, el seguimiento y el tratamiento de la ototoxicidad por aminoglucósidos y antineoplásicos derivados del platino en la población pediátrica. (AU)

Ototoxicity is defined as the damage, reversible or irreversible, produced in the inner ear by various substances that are called ototoxic and that can cause hearing loss and/or an alteration of the vestibular system.Permanent hearing loss significantly affects quality of life and is especially important in children. The lack or delay in its detection is frequent, since it often progresses in an inconspicuous manner until it affects communication and overall development. This impact can be minimized by following a strategy of audiological monitoring of ototoxicity, which allows for its early detection and treatment. This document recommends that children who are going to be treated with cisplatin or aminoglycosides be monitored.This CODEPEH review and recommendation document focuses on the early detection, prophylaxis, otoprotection, monitoring and treatment of ototoxicity caused by aminoglycosides and platinum-based antineoplastics in the paediatric population. (AU)

Resveratrol enhanced chemosensitivity by reversing macrophage polarization in breast cancer

BackgroundResveratrol, a naturally occurring polyphenolic compound, has been shown to inhibit cancer growth by targeting several cancer-related signalling pathways. In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) are the most abundant leukocyte population that are associated with poor prognosis in over 80% of breast cancer cases. However, little is known about the effect of resveratrol in the TME.MethodsIn this study, MDA-MB-231(MB231), cisplatin resistance MDA-MB-231 (cisR), and T47D were used to examine the antitumor effect of resveratrol. The effectiveness of resveratrol, together with cisplatin as breast cancer treatment was investigated in vivo. Gene expressions of M1 (iNOS and CXCL10) and M2 (ARG1, CD163 and MRC1) markers in differentiated macrophages derived from THP-1 cells were examined to investigate the effect of resveratrol on TAM polarization in breast cancer progression.ResultsOur results demonstrated that resveratrol significantly reduced cell proliferation and enhanced chemosensitivity in breast cancer cells by inhibiting production of IL-6 and STAT3 activation. Treatment of resveratrol increased CXCL10 (M1 marker) expression. Further, resveratrol decreased IL-6 levels in LPS-treated differentiated macrophages. The use of resveratrol with cisplatin inhibited suppressed tumor growth when compared with cisplatin alone.ConclusionThis study revealed that resveratrol inhibited breast cancer cell proliferation by promoting M1/M2 macrophage polarization ratio and suppressing IL-6/pSTAT3 pathway.

SEOM-SOGUG clinical guideline for localized muscle invasive and advanced bladder cancer (2021)

Most muscle-invasive bladder cancer (BC) are urothelial carcinomas (UC) of transitional origin, although histological variants of UC have been recognized. Smoking is the most important risk factor in developed countries, and the basis for prevention. UC harbors high number of genomic aberrations that make possible targeted therapies. Based on molecular features, a consensus classification identified six different MIBC subtypes. Hematuria and irritative bladder symptoms, CT scan, cystoscopy and transurethral resection are the basis for diagnosis. Radical cystectomy with pelvic lymphadenectomy is the standard approach for muscle-invasive BC, although bladder preservation is an option for selected patients who wish to avoid or cannot tolerate surgery. Perioperative cisplatin-based neoadjuvant chemotherapy is recommended for cT2-4aN0M0 tumors, or as adjuvant in patients with pT3/4 and or pN + after radical cystectomy. Follow-up is particularly important after the availability of new salvage therapies. It should be individualized and adapted to the risk of recurrence. Cisplatin–gemcitabine is considered the standard first line for metastatic tumors. Carboplatin should replace cisplatin in cisplatin-ineligible patients. According to the EMA label, pembrolizumab or atezolizumab could be an option in cisplatin-ineligible patients with high PD-L1 expression. For patients whose disease respond or did not progress after first-line platinum chemotherapy, maintenance with avelumab prolongs survival with respect to the best supportive care. Pembrolizumab also increases survival versus vinflunine or taxanes in patients with progression after chemotherapy who have not received avelumab, as well as enfortumab vedotin in those progressing to first-line chemotherapy followed by an antiPDL1/PD1. Erdafitinib may be considered in this setting in patients with FGFR alterations. An early onset of supportive and palliative care is always strongly recommended.

Ototoxicidad en pacientes oncológicos: experiencia y propuesta de un protocolo de vigilancia / Ototoxicity in cancer survivors: experience and proposal of a surveillance protocol

Introducción: La ototoxicidad se presenta en diversos porcentajes según estudios tras el tratamiento con quimioterapia basada en platino y/o radioterapia craneal. El objetivo es mostrar nuestra experiencia en la monitorización de la ototoxicidad. Material y métodos: Se realizó una revisión del 1999 al 2019 en el registro de pacientes oncológicos pediátricos de nuestro hospital y remitidos a la Unidad de Hipoacusia Infantil. Resultados: 46 pacientes fueron remitidos a nuestra unidad. 41 pacientes recibieron platinos como parte de su tratamiento, 17 pacientes fueron sometidos a una intervención neuroquirúrgica y 18 pacientes recibieron radioterapia craneal. A todos se les realizó una anamnesis y otoscopia, y la monitorización se llevó a cabo con una audiometría tono-verbal y/o productos de distorsión. Se objetivó una hipoacusia como secuela del tratamiento en ocho pacientes (21,05% de los pacientes remitidos para seguimiento audiológico). Fue imposible determinar la situación audiológica al finalizar el tratamiento en ocho pacientes. La adaptación audioprotésica fue necesaria en dos pacientes. En la coordinación con Oncología Pediátrica, se consideró oportuno el cambio de cisplatino por carboplatino por ototoxicidad importante durante el tratamiento en un único paciente. Conclusión: Es imprescindible una adecuada coordinación con Oncología Pediátrica para realizar una vigilancia activa de la ototoxicidad y modificar, si es posible, la dosificación o el tipo de quimioterápico en caso de verse afectada la audición. En nuestra experiencia, y siguiendo las recomendaciones actuales, realizamos una valoración pretratamiento, una monitorización durante el tratamiento, al finalizarlo y después de forma anual por el riesgo de desarrollo diferido de una hipoacusia. (AU)

Introduction: Ototoxicity occurs in different percentages in patients after treatment with platinum-based chemotherapy or cranial radiation therapy. The aim of this study was to present experience in ototoxicity monitoring. Material and methods: A review was made of the registry of paediatric cancer patients referred to the Children's Hearing Loss Unit from 1999 to 2019. Results: Of the 46 patients referred to this unit, 41 had received platinum as part of their treatment, 17 patients underwent neurosurgery, and 18 patients received cranial radiation therapy. An anamnesis and otoscopy were performed on all of them, and the monitoring was carried out with tone-verbal audiometry and/or distortion products. Hearing loss was observed in eight patients (21.05% of patients referred for audiological follow-up) as a consequence of the treatment. It was impossible to determine the audiological situation in eight patients at the end of treatment. Hearing aid adaption was necessary in two patients. In coordination with Paediatric Oncology, a change from cisplatin to carboplatin due to bilateral grade two ototoxicity was considered appropriate during treatment in one patient. Conclusion: Adequate coordination with Paediatric Oncology is essential to carry out active surveillance for ototoxicity and to modify, if possible, the dosage or type of chemotherapy in case hearing is affected. In our experience, and following current recommendations, a pre-treatment assessment is usually performed, as well as monitoring during treatment, at the end of treatment, and annually thereafter due to the risk of a later development of hearing loss. (AU)

Randomized placebo-controlled phase II trial of high-dose melatonin mucoadhesive oral gel for the prevention and treatment of oral mucositis in patients with head and neck cancer undergoing radiation therapy concurrent with systemic treatment

Purpose The objective of this trial was to evaluate the safety and efficacy of melatonin oral gel mouthwashes in the prevention and treatment of oral mucositis (OM) in patients treated with concurrent radiation and systemic treatment for head and neck cancer. Methods Randomized, phase II, double-blind, placebo-controlled trial (1:1 ratio) of 3% melatonin oral gel mouthwashes vs. placebo, during IMRT (total dose ≥ 66 Gy) plus concurrent Q3W cisplatin or cetuximab. Primary endpoint: grade 3–4 OM or Severe Oral Mucositis (SOM) incidence by RTOG, NCI, and a composite RTOG-NCI scales. Secondary endpoints: SOM duration and grade 2–4 OM or Ulcerative Oral Mucositis (UOM) incidence and duration. Results Eighty-four patients were included in the study. Concurrent systemic treatments were cisplatin (n = 54; 64%) or cetuximab (n = 30; 36%). Compared with the placebo arm, RTOG-defined SOM incidence was numerically lower in the 3% melatonin oral gel arm (53 vs. 64%, P = 0.36). In patients treated with cisplatin, assessed by the RTOG-NCI composite scale, both SOM incidence (44 vs. 78%; P = 0.02) and median SOM duration (0 vs. 22 days; P = 0.022) were significantly reduced in the melatonin arm. Median UOM duration assessed by the RTOG-NCI scale was also significantly shorter in the melatonin arm (49 vs. 73 days; P = 0.014). Rate of adverse events and overall response rate were similar between the two arms. Conclusions Treatment with melatonin oral gel showed a consistent trend to lower incidence and shorter SOM duration and shorter duration of UOM. These results warrant further investigation in phase III clinical trial (AU)

Downregulation of HOXA11 enhances endometrial cancer malignancy and cisplatin resistance via activating PTEN/AKT signaling pathway

Purpose Endometrial cancer is the most common malignant tumor of female genital system worldwide. Homeobox A11 (HOXA11) is an evolutionarily conserved Homeobox gene closely implicated in carcinogenesis. However, the mechanisms of HOXA11 in the progression and cisplatin resistance of endometrial cancer remain unclear. Methods The expression of HOXA11 was analyzed based on 548 endometrial cancer and 35 control tissues from The Cancer Genome Atlas (TCGA) database. Transwell assay was performed to investigate the effect of HOXA11 on endometrial cell migration and invasion. TUNEL staining was carried out to assay the role of HOXA11 in endometrial cell apoptosis. Western blot was employed to detect the protein levels of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), cleaved caspase-3, matrix metalloproteinase-2/9 (MMP/9), phosphatase and tensin homolog (PTEN), protein kinase B (AKT) and p-AKT. Results TCGA data showed that HOXA11 expression was significantly down-regulated in endometrial cancer tissue samples. The overexpression of HOXA11 promoted the apoptosis, but inhibited the proliferation, migration and invasion of endometrial cancer cells. HOXA11 knockdown with small interfering RNA (siRNA) considerably repressed cell apoptosis, while promoted cell proliferation, migration, and invasion through PTEN/AKT signaling pathway. Interestingly, HOXA11 was lowly expressed in Ishikawa cells treated with cisplatin. In addition, HOXA11 knockdown increased the resistance of endometrial cancer to cisplatin through activating PTEN/AKT signaling pathway. Conclusion Low HOXA11 expression may promote the proliferation, migration, invasion of endometrial cancer cells, and increase their resistance to cisplatin through activating PTEN/AKT pathway (AU)

Use of nimotuzumab combined with cisplatin in treatment of nasopharyngeal carcinoma and its effect on expressions of VEGF and MMP-2

Purpose This paper aims to observe the expressions of VEGF and MMP-2 in patients with nasopharyngeal carcinoma treated by nimotuzumab combined with cisplatin. Methods Altogether, 104 patients with nasopharyngeal carcinoma treated in our hospital from April 2014 to August 2016 were selected as research subjects. Among them, 50 patients treated with cisplatin were divided into a control group and 54 patients treated with nimotuzumab combined with cisplatin were divided into an observation group. The two groups of patients were compared in terms of efficacy after treatment and incidence of adverse reactions. Changes of serum VEGF and MMP-2 concentrations before and after treatment were detected using enzyme-linked immunosorbent assay (ELISA), and the 3-year overall survival (OS) of patients was observed. Results Compared with the control group, patients in the observation group had significantly higher total remission rate (RR) (P < 0.05) and significantly lower incidence of adverse reactions (P < 0.05). Before treatment, there was no significant difference between the observation and control groups in the concentrations of VEGF and MMP-2 (P > 0.05). After treatment, the concentrations in the two groups were significantly lower than those before treatment (P < 0.05), and the concentrations in the observation group were significantly lower than those in the control group (P < 0.05). There was no significant difference in the 3-year OS between the observation and control groups (P > 0.05). Conclusions Nimotuzumab combined with cisplatin could improve the conditions of patients with nasopharyngeal carcinoma. After treatment, the expression of VEGF and MMP-2 decreased significantly. We speculated that it improves the survival rate of patients by reducing the expression of VEGF and MMP-2 (AU)

Combination therapy with TiO2 nanoparticles and cisplatin enhances chemotherapy response in murine melanoma models

Background Despite recent progressions in the treatment of melanoma, the response to conventional therapies and the long-term survival in melanoma patients still remain poor. Recently, the use of nanoparticles (NPs) has been highlighted for promoting the chemotherapeutic effects of cytotoxic drugs in melanoma. The aim of this study is to mechanistically evaluate the potential of titanium dioxide (TiO2) nanoparticles (NPs) for enhancing chemotherapy effects in in vitro and in vivo models of murine melanoma. Methods The F10 melanoma cells were exposed to different concentrations of TiO2 NPs and/or cisplatin, then cell growth, cell viability, and cell death were evaluated. In parallel, C57BL/6 syngeneic melanoma mice were treated by TiO2 NPs and/or cisplatin, and then drug responses, tumor size and mice’s organs were studied pathologically. Autophagy was examined by evaluating the formation of autophagosomes and gene expression levels of autophagy markers (ATG5 and ATG6) by fluorescent microscopy and qPCR, respectively. Results Nontoxic concentrations of TiO2 NPs (50 µg/ml) promote anti-proliferative and cytotoxic effects of cisplatin in F10 melanoma cells, which is mediated through the induction of autophagy and necrotic cell death. Whereas TiO2 NPs have no cytotoxic or metastatic effects in melanoma mice, its combination with cisplatin enhances drug responses (up to 50%), leading to higher inhibition of tumor growth compared with each monotherapy. Conclusion The combination of TiO2 NP with cisplatin enhances chemotherapy response in both in vitro and in vivo melanoma models. In addition, autophagy plays an essential role during sensitizing melanoma cells to chemotherapy (AU)

Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial

Background Our previous phase-3 study (TTCC 2503) failed to show overall survival advantage of 2 induction chemotherapy (IC) regimens followed by standard concurrent chemoradiotherapy (CRT) over CRT alone in patients with unresectable locally advanced head and neck squamous-cell carcinoma (LAHNSCC). This study described the long-term survival of those patients. Materials and methods Long-term follow-up study of patients with untreated LAHNSCC assigned to IC (three cycles), with either docetaxel, cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CRT, or CRT alone, included in the previous TTCC 2503 trial. Results In the intention-to-treat population (n = 439), the median OS times were 25.4 (95% CI, 16.8–34.4), 26.2 (95% CI, 18.2–36.6) and 25.4 months (95% CI, 17.4–36.0) in the TPF-CRT, PF-CRT and CRT arms, respectively (log-rank p = 0.51). In the per-protocol population (n = 355), patients with larynx–hypopharynx primary tumors treated with IC (TPF or PF) followed by CRT had a longer median PFS than those who received CRT alone. Moreover, patients with ECOG 0 treated with IC (TPF or PF) followed by CRT had a better TTF than those with CRT alone. There were no statistically significant differences in terms of OS, PFS or TTF, according to the tumor load or affected nodes. Conclusion After a long follow-up, the TTCC 2503 trial failed to show the benefit of IC-CRT in unresectable LAHNSCC regarding the primary end point. However, fit patients with ECOG 0 and primary larynx–hypopharyngeal tumors may benefit from the use of IC if administered by an experienced team (AU)

Patterns of relapse and treatment outcome after active surveillance or adjuvant carboplatin for stage I seminoma: a retrospective study of the Spanish Germ Cell Cancer Group

Purpose Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. Methods We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. Results No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. Conclusion In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome (AU)