RESUMO
BACKGROUND: Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs. METHODS: Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report. RESULTS: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1-6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7-1.5 months), and median overall survival was 2.9 months 95% CI (1.5-4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. CONCLUSIONS: This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Cisplatino/uso terapêutico , Dissulfiram/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológicoRESUMO
Background Patients with multiple relapsed/refractory germ cell tumours (GCTs) have an extremely poor prognosis. PARP (poly-ADP-ribose polymerase) is overexpressed in GCTs compared to normal testes, and PARP overexpression is an early event in GCT development. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and the PARP inhibitor veliparib in patients with multiple relapsed/refractory GCTs. Methods Fifteen patients with multiple relapsed/refractory GCTs were enrolled in this phase II study from October 2016 to October 2020. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 every 3 weeks; carboplatin at a target AUC of 4 on day 1 every 3 weeks; and veliparib at a dose of 250 mg b.i.d. throughout. The primary end point was 12-month progression-free survival (PFS). Results The median number of treatment cycles was 4 (range 2-8). Twelve-month PFS was achieved in 1 (6.7 %) patient. The median PFS was 3.1 months (95 % CI 2.2-3.9), and the median overall survival was 10.5 months (95 % CI 8.9-11.1). Partial remission was achieved in 4 (26.7 %) patients, and disease stabilization was observed in 5 (33.3 %) patients. A favourable response was achieved in 3 (20.0 %) patients. Treatment was well tolerated; however, 11 (73.3 %) patients experienced grade 3/4 neutropenia, 10 (66.7 %) experienced thrombocytopenia, 5 (33.3 %) anaemia and 2 (13.3 %) febrile neutropenia. Conclusions This study failed to achieve its primary endpoint, and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib for multiple relapsed/refractory GCTs. ClinicalTrials.gov Identifier: NCT02860819, registered August 9, 2016.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/uso terapêutico , Carboplatina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Adulto Jovem , GencitabinaRESUMO
BACKGROUND: Translocation renal cell carcinoma (TRCC) is a rare form of RCC affecting mostly children and young adults with the occurrence of only 1-5% of all renal cell carcinomas. These carcinomas are associated with different translocations on a short arm of chromosome X in the region 11.2, which results in genetic modification of the p arm containing the transcription factor E3 gene. METHODS: Herein we report a case of a patient who was dia-gnosed with TRCC with c-Met overexpression and was treated with multiple targeted therapy agents and immunotherapy. CASE: A 28-year old woman without a significant past medical history underwent left sided total nephrectomy for TRCC. Seven months later, she developed systemic relapse and was treated with multiple lines of targeted therapy including sunitinib, everolimus, sorafenib, crizotinib, and pazopanib as well as with anti-PD-L1 antibody nivolumab, with stable disease as a best response. The most pronounced disease stabilization was achieved with sorafenib, which lasted 18 months. The patient died 81 months after initial dia-gnosis and 74 months from the dia-gnosis of metastatic disease. CONCLUSION: Improved survival observed in our patient could be related to the effectivity of tyrosine-kinase inhibitors, but notm-TOR inhibitors, even though disease stabilisation was observed as a best response. Identification of new treatment targets are warranted in this rare disease.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Cromossomos Humanos X , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Crizotinibe/uso terapêutico , Progressão da Doença , Everolimo/uso terapêutico , Evolução Fatal , Feminino , Humanos , Indazóis/uso terapêutico , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/genética , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Pirimidinas/uso terapêutico , Sorafenibe/uso terapêutico , Sulfonamidas/uso terapêutico , Sunitinibe/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Metastatic germ cell cancer of the testis is characterized by favorable prognosis since effective treatment methods are available even in cases of extensive disease. Retroperitoneal masses frequently encroach major blood vessels requiring a vascular intervention usually performed in association with the post-chemotherapy retroperitoneal lymph node dissection (RPLND). Reported clinical case describes a successful pre-treatment endovascular surgery for abdominal aortic rupture allowing for full-dose systemic chemotherapy administration, and subsequent radical surgical intervention at primary tumor site as well as metastatic retroperitoneal lymph node dissection including the reconstruction of inferior caval vein. CASE PRESENTATION: Patient presented with left-sided testicular tumor and voluminous retroperitoneal mass with vascular involvement. Soon after the patient had been admitted for the first cycle of cisplatin-based chemotherapy, computed tomographic angiography (CTA) revealed a dorsal aortic wall rupture with active extravasation and irregular pseudoaneurysmatic dilatation of the aorta below the leak area. Retroperitoneal intratumoral hemorrhage associated with the bilateral iliac venous thrombosis required an endovascular repair procedure of infrarenal abdominal aorta. CONCLUSIONS: Following the successful endovascular aortic repair 3 cycles of BEP (bleomycin, etoposide, cisplatin) regimen were administered with subsequent delayed left radical orchiectomy and RPLND associated with vena cava inferior (VCI) resection. Reconstruction of VCI was originally not deemed necessary as collateral blood flow appeared sufficient, however, intraoperative complications resulted in the need for unilateral VCI reconstruction, using the interposed bypass between right common iliac vein and infrarenal segment of VCI. Histopathologic examination of the attained specimen detected no vital cancer structures. The patient remains disease-free 18 months after the RPLND.
Assuntos
Ruptura Aórtica/cirurgia , Procedimentos Endovasculares/métodos , Hemorragia/cirurgia , Neoplasias Embrionárias de Células Germinativas , Neoplasias Retroperitoneais , Neoplasias Testiculares , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/patologia , Aorta Abdominal/cirurgia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/etiologia , Ruptura Aórtica/patologia , Bleomicina/administração & dosagem , Cisplatino/administração & dosagem , Angiografia por Tomografia Computadorizada , Etoposídeo/administração & dosagem , Hemorragia/diagnóstico por imagem , Hemorragia/etiologia , Humanos , Veia Ilíaca , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/diagnóstico por imagem , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/secundário , Neoplasias Embrionárias de Células Germinativas/cirurgia , Orquiectomia , Neoplasias Retroperitoneais/diagnóstico por imagem , Neoplasias Retroperitoneais/tratamento farmacológico , Neoplasias Retroperitoneais/secundário , Neoplasias Retroperitoneais/cirurgia , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia , Neoplasias Vasculares/diagnóstico por imagem , Neoplasias Vasculares/tratamento farmacológico , Neoplasias Vasculares/secundário , Neoplasias Vasculares/cirurgia , Veia Cava Inferior/cirurgia , Trombose Venosa/cirurgiaRESUMO
BACKGROUND: Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors. METHODS: GCT survivors (N = 170) from the National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5-32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%). RESULTS: In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m2 of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively). CONCLUSIONS: This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.
Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Embrionárias de Células Germinativas/terapia , Disfunções Sexuais Fisiológicas/epidemiologia , Neoplasias Testiculares/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobreviventes de Câncer/psicologia , Quimiorradioterapia Adjuvante/efeitos adversos , Cisplatino/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/complicações , Neoplasias Embrionárias de Células Germinativas/mortalidade , Orquiectomia/efeitos adversos , Orgasmo/efeitos dos fármacos , Orgasmo/efeitos da radiação , Ereção Peniana/efeitos dos fármacos , Ereção Peniana/efeitos da radiação , Estudos Prospectivos , Qualidade de Vida , Autorrelato/estatística & dados numéricos , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/efeitos da radiação , Disfunções Sexuais Fisiológicas/diagnóstico , Disfunções Sexuais Fisiológicas/etiologia , Eslováquia/epidemiologia , Neoplasias Testiculares/complicações , Neoplasias Testiculares/mortalidade , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE OF THE STUDY The aim of our study is to show the pitfalls of performing skull X-rays in patients with head injuries and the lack of accuracy of this examination nowadays, and to clarify the current trend in the MTBI investigation algorithm. MATERIAL AND METHODS A retrospective study of 3,950 patients treated for acute head injury at the Department of Trauma Surgery (University Hospital Brno) in the period from 2015 to 2016. Inclusion criteria were the following: mild brain injury (GCS = 15), primary skull X-ray design in head injury diagnosis. Patients with a positive skull X-ray finding underwent a head CT evaluation up to 24-hours from the injury except for the patients with an isolated nose bone fracture. A CT head scan was also performed in patients indicated by the neurologist at the initial examination based on the anamnestic data and an objective finding. RESULTS Inclusion criteria were met by 1,938 patients. In 1806 (93.2%) cases the X-ray was negative, in 132 (6.8%) patients the X-ray was positive, of which in 62% of patients a nasal fracture was detected. A skull fracture reported in 16 cases. Once the CT scan of the head was obtained, all of these cases were classified as false negative. After the CT scan of the head, intracranial bleeding was observed in 12 patients, in 4 cases accompanied by fractures of the skull, not visible on the X-ray images. After the statistical evaluation, the sensitivity and specificity of the X-ray examination compared to the CT scan of the head was determined to be 0.00 and 0.94, respectively. DISCUSSION The aim of MTBI diagnostics is primarily to detect serious intracranial lesions requiring neurosurgical intervention. A simple X-ray of the skull shows fractures only and does not allow to visualize both the brain and any traces of bleeding that would show an intracranial injury. Hofman, in his meta-analysis, points out that a simple X-ray image of the skull has only very little noticeable value when diagnosing MTBI. The prevalence of intracerebral hematoma (ICH) over MTBI is 0.083. The sensitivity of a radiographic finding of skull fracture in the diagnosis of ICH based on the CT verification is only 0.38 with a specificity of 0.95, which is consistent with our study where the sensitivity of the radiographic finding was 0.00 with a specificity of 0.94 relative to CT. Thus, the question is not whether to perform an X-ray of the skull in mild head injuries, but rather when to indicate a CT scan of the brain, when to admit the patient to the hospital for observation, and for how long or when the patient can be safely discharged into home care. The purpose of MTBI diagnostics, however, should not be a rashly decision to perform a brain CT scan, but to put into practice the CT indication criteria in MTBI applying and respecting the validated guidelines known worldwide. CONCLUSIONS Our study, in which no X-ray examination revealed possible intracranial bleeding, clearly shows that nowadays the plain radiograph of the skull does not bring any benefit in the diagnosis of minor traumatic brain injury. Key words:skull X-ray, CT of the head, head injury, minor traumatic brain injury.
Assuntos
Encéfalo/diagnóstico por imagem , Traumatismos Craniocerebrais/diagnóstico por imagem , Fraturas Cranianas/diagnóstico por imagem , Crânio/diagnóstico por imagem , Algoritmos , Lesões Encefálicas/diagnóstico por imagem , Traumatismos Craniocerebrais/complicações , Humanos , Estudos Retrospectivos , Fraturas Cranianas/etiologia , Tomografia Computadorizada por Raios X , Raios XRESUMO
Head and neck squamous cell carcinomas (HNSCC) are a highly heterogenous disease which can be induced by two main carcinogens - tobacco and/or alcohol, or by HR HPV infection. This work examined 60 paraffin-embedded biopsies of head and neck carcinomas after histological verification. HPV infection, including its specific types in various HNSCC areas, was studied using multiplex qPCR. Expression levels of p16INK4A and p53 were detected by subsequent IHC analysis as being potential diagnostic markers. Based on the assumption that patients with HNSCC could benefit from anti-EGFR therapy (cetuximab), but the predictors are not yet defined, analyses of point mutations of ras genes (Kras, Nras) were carried out using multiplex qPCR and sequence analysis of the Braf gene. All statistical data were processed by Chí-x2 test.HPV infection was detected in 23.34 % of cases with HNSCC, of which 100 % were HPV 16, which is the most frequently infection found in the oropharyngeal region. Using IHC analysis, a positive expression of P16INK4A was detected in 100 % of HPV-positive HNSCC while this expression was discovered to be highly correlated with HPV infection. Furthermore, a correlation between p53 and HPV-negative HNSCC was proved. The mutation incidence was the highest in the Kras gene (codon 12 and codon 146), Nras (codon 12) and Braf. A correlation between tumor location in the oropharyngeal region and Kras mutations was proved. The HPV infection correlated with Kras mutations in case of codon 146 but on the grounds of low amount of output data, these figures could be irrelevant. In one case, c.1808 G>A, protein 603 Arg>Gln mutation was found in the Braf gene but its correlation with head and neck carcinomas has not been described yet (Tab. 2, Fig. 2, Ref. 24). Keywords: head and neck carcinomas, biopsy, HPV types, PCR, p16INK4A, p53, molecular predictors, Kras, Nras, Braf.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas/virologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , GTP Fosfo-Hidrolases/genética , Neoplasias de Cabeça e Pescoço/virologia , Papillomavirus Humano 16 , Humanos , Imuno-Histoquímica , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Cancer-related mortality have been declining in the last decades. Approximately half of adults and more than two thirds of children oncological patients live longer than 5 years after diagnosis. However, this optimistic scenario has been counterbalanced by an increasing cardiovascular risk in cancer patients. Atherosclerotic damage has been underestimated in oncology practice for a long time, but recently a significant number of cancer patients with cardiovascular risk factors and serious artery disease during and after anticancer therapy has been reported. Complexity of atherosclerosis in cancer patients is challenging. Herein, we describe cardiovascular risk factors and pathophysiological mechanisms of atherosclerosis induced by selected classic chemotherapeutics, targeted cancer therapies, hormonal agents and radiotherapy and new clinical data regarding atherosclerosis, which received a particular attention in recent years (Tab. 1, Ref. 26). Keywords: cardiovascular disease, atherosclerosis, cardiotoxicity, risk factors, hypertension, hyperlipidemia.
Assuntos
Antineoplásicos/efeitos adversos , Aterosclerose/complicações , Neoplasias/complicações , Humanos , Fatores de RiscoRESUMO
Head and neck paragangliomas Paragangliomas and pheochromocytomas are rare, mostly benign neuroendocrine tumors, which are embryologically derived from neural crest cells of the autonomic nervous system. Paragangliomas are essentially the extra-adrenal counterparts of pheochromocytomas. As such this family of tumors can be subdivided into head and neck paragangliomas, pheochromocytomas and thoracic and abdominal extra-adrenal paragangliomas. Ten out of fifteen genes that contribute to the development of paragangliomas are more susceptible to the development of head and neck paragangliomas when mutated. Gene expression profiling revealed that pheochromocytomas and paragangliomas can be classified into two main clusters (C1 and C2) based on transcriptomes. These groups were defined according to their mutational status and as such strongly associated with specific tumorigenic pathways. The influence of the main genetic drivers on the somatic molecular phenotype was shown by DNA methylation and miRNA profiling. Certain subunits of succinate dehydrogenase (SDHx), von Hippel-Lindau (VHL) and transmembrane protein 127 (TMEM127) still have the highest impact on development of head and neck paragangliomas. The link between RAS proteins and the formation of pheochromocytoma and paragangliomas is clear due to the effect of receptor tyrosine-protein kinase (RET) and neurofibromatosis type 1 (NF1) in RAS signaling and recent discovery of the role of HRAS. The functions of MYC-associated factor X (MAX) and prolyl hydroxylase 2 (PHD2) mutations in the contribution to the pathogenesis of paragangliomas still remain unclear. Ongoing studies give us insight into the incidence of germline and somatic mutations, thus offering guidelines to early detection. Furthermore, these also show the risk of mistakenly assuming sporadic cases in the absence of definitive family history in head and neck paragangliomas.
Assuntos
Neoplasias de Cabeça e Pescoço , Paraganglioma , Humanos , Neoplasias de Cabeça e Pescoço/genética , Mutação , Paraganglioma/genéticaRESUMO
BACKGROUND: Testicular germ cell tumours (GCTs) are the only universally curable solid malignancy. The long-term cure rate of >95% is attributed to the extraordinary sensitivity to cisplatin-based treatment but a proportion of patients die due to a progression of the chemotherapy-refractory disease. While treatment of a variety of solid cancers was significantly improved with recent immune therapies, the immunology and immunotherapy remained underinvestigated in GCTs. OBJECTIVES: In this narrative review, we summarize evidence about immune-related mechanisms and possible immune therapies in GCTs and provide insights and implications for future research and clinical practice. MATERIALS AND METHODS: We performed a comprehensive search of PubMed/MEDLINE to identify original and review articles reporting on immune mechanisms and immunotherapy in GCTs. Review articles were further searched for additional original articles. RESULTS: Clear link of immune surveillance and the presence of GCT have been identified with several novel immune-related prognostic biomarkers published recently. Several case reports, case series, and preliminary results from phase I-II studies are emerging to report on the efficacy of immune checkpoint inhibitors. DISCUSSION: Newly discovered immune biomarkers provide an evidence supporting the role of immune environment in the GCT biology. While these discoveries provide only an initial insight into the immunobiology, strong correlation with prognosis is evident. This provided a premise to investigate the treatment efficacy of novel immunotherapy. Some efficacy of these treatments has been reported in clinical setting; however, the results of published studies with immune checkpoint inhibitor monotherapy seem to be disappointing. CONCLUSION: Immune-related mechanisms and efficacy of immune checkpoint blockade in GCTs should be further investigated in preclinical and clinical studies.
Assuntos
Imunoterapia , Neoplasias Embrionárias de Células Germinativas/imunologia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Testiculares/imunologia , Neoplasias Testiculares/terapia , Humanos , MasculinoRESUMO
Background Germ cell tumors (GCTs) are highly curable diseases; however, not all patients can be cured. Patients in their second relapse have especially poor prognoses. PD-L1 expression is significantly higher in GCTs than in normal testicular tissue, and high PD-L1 expression is associated with a poor prognosis. This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs. Methods In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10 mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if <8 of 15 patients had 12-week PFS, the study was to be terminated. Here, we report the results of the first stage of the trial. Results From November 2017 to January 2018, 8 patients with a median age of 29 years (range, 22 to 52 months) were enrolled. Patients were pretreated with a median of 5 (range, 1 to 6) previous lines of platinum-based therapies; 5 tumors (62.5%) were absolutely refractory to cisplatin, and 5 patients (62.5%) had visceral nonpulmonary metastases. At a median follow-up period of 2.6 months (range, 0.3 to 14.4), all the patients experienced disease progression, and 7 patients (87.5%) died. The twelve-week PFS was 0%, median PFS was 0.9 months (95% CI 0.5-1.9), and median OS was 2.7 months (95% CI 1.0-3.3). Avelumab was well tolerated, and no severe adverse events were observed. Conclusions This study failed to achieve its primary endpoint. Our data suggest a lack of avelumab efficacy in unselected multiple relapsed/refractory GCTs.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Intervalo Livre de Progressão , Adulto JovemRESUMO
BACKGROUND: Growing teratoma syndrome (GTS) is an uncommon clinical finding in patients treated for testicular cancer. It is diagnosed during or after chemotherapy as an expanding tumour mass not responding to the treatment while the serum tumour markers are within the normal range. Pathological evaluation of resected tissue confirms the structures of benign mature teratoma. CASE: Authors report a case of metastatic germ cell testicular cancer treated with 2 lines of chemotherapy and everolimus, that had finally been subjected for the resection of voluminous metastatic masses. We give a brief overview of current records concerning clinical management of GTS, and support the major role of surgical treatment in GTS. RESULTS: Patient with metastatic mixed germ cell tumour of testis underwent a radical orchiectomy and completed the 1st line treatment with BEP (bleomycin, etoposide, cisplatin) regimen. Radiographic restaging showed considerable disease progression to the retroperitoneum and supraclavicular lymph nodes. Second-line treatment with VIP (etoposide, ifosfamide, cisplatin) did not reverse the progression and the patient was consulted at our institute. Following the enrolment to the clinical study with everolimus, the patient exhibited continual metastatic growth in contrast to serum markers decrease. GTS was confirmed after resection of enormous retroperitoneal tumour mass, as well as from the specimen obtained from the subsequent supraclavicular and hepatal metastasectomy. The patient attained complete remission and has been closely observed over the last 31 months since the last surgery. CONCLUSION: GTS is resistant to chemotherapy and radiation and complete surgical resection results in excellent disease control. Clinicians should be aware of this infrequent presentation of testicular tumours, to ensure the timely diagnosis and the appropriate surgical removal without any delay. Despite the great extent and vital vasculature encasement, surgery may be feasible and successful, as we report in our case, consistently with the published data.
Assuntos
Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/cirurgia , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias Retroperitoneais/cirurgia , Teratoma/cirurgia , Neoplasias Testiculares/cirurgia , Adulto , Gerenciamento Clínico , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Neoplasias Embrionárias de Células Germinativas/patologia , Prognóstico , Neoplasias Retroperitoneais/patologia , Teratoma/patologia , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
BACKGROUND: Leptomeningeal metastasis (LM) in breast cancer is associated with a poor prognosis. Although no randomised trial has demonstrated that intrathecal chemotherapy actually prolongs survival, this treatment is considered standard of care in this setting. The prognosis of patients with LM is poor, with a median overall survival time of less than 6 months. METHODS: Herein, we report a case of a young woman with breast cancer who presented with LM at the time of relapse and was subsequently treated with two lines of intrathecal chemotherapy that prolonged survival. RESULTS: A 28-year old woman without a significant past medical history was diagnosed with triple-negative invasive ductal carcinoma. Eight months after adjuvant treatment she developed multiple brain metastases and LM developed subsequently 1 month after finishing whole brain irradiation. Initially, she was treated with a combination of methotrexate, cytarabine and dexamethasone intrathecally but after 3 months she presented with a worsening clinical status and increased numbers of cancer cells in cerebrospinal fluid. Subsequently, she received a combination of thiotepa and methotrexate intrathecally, which resulted in a prolonged response lasting 10 months. The patient died 32 months after initial diagnosis and 18 months from LM infiltration due to disease progression in the liver and lungs as well as LM. CONCLUSION: The prognosis of patients with LM remains poor because of the limited effectiveness of currently available therapies; however, intrathecal chemotherapy could substantially prolong survival in selected patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/patologia , Feminino , Humanos , Injeções Espinhais , Neoplasias Meníngeas/secundário , PrognósticoRESUMO
Testicular germ cell tumors (TGCTs) are highly sensitive to cisplatinbased chemotherapy. Nevertheless, there are metastatic tumors that do not completely respond to frontline chemotherapy. For these tumors, surgical resection of residual masses is necessary to achieve longterm disease control. Resected tissues represent valuable clinical material, which may be used for the engraftment into immunocompromised mice to produce patientderived xenografts (PDXs). They typically maintain similarities to the parental tumors and therefore serve as more realistic preclinical models. Moreover, a correlation between PDX treatment outcomes and clinical response to chemotherapy has been previously described. The aim of the present study was to establish and characterize TGCT patientderived xenografts. These originated from retroperitoneal lymph node metastases infiltrated with TGCTs following previous cisplatinbased chemotherapy, in order to analyze novel treatment options for cisplatinresistant testicular tumors. We generated two testicular patientderived xenograft models in SCID beige male mice. Immunohistochemical analyses demonstrated that histological characteristics of the primary tumor were not retained, and transformation into lymphoma, and eventually plasmocytoma, was observed. A potential explanation for the lymphoma transformation observed in PDXs may include tumorinfiltrating lymphocytes (TILs) in xenografted samples of patients, which are transformed following engraftment into immunodeficient recipient mice. Based on these data, we indicated that lymphomagenesis prevention and terminal differentiation represent new challenges in the establishment of PDX models derived from patients with germ cell tumors.
Assuntos
Transformação Celular Neoplásica/patologia , Linfócitos do Interstício Tumoral/transplante , Linfoma/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Adulto , Animais , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Humanos , Linfonodos/citologia , Linfonodos/patologia , Metástase Linfática , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Testiculares/terapia , Testículo/patologia , Testículo/cirurgiaRESUMO
BACKGROUND: Epithelioid angiomyolipoma (EAML) of the kidney, in contrast to classic benign renal angiomyolipoma, is a rare mesenchymal neoplasm with malignant potential. Represent-ing a member of the perivascular epithelioid cells (PEComa) tumor family aris-ing from the perivascular epithelioid cells, its accurate dia-gnosis and therapeutic approach remains challenging. METHODS: We report a case of a patient with malignant EAML, initially treated as renal cell carcinoma (RCC) at our institution. In this paper, we briefly summarize current status of clinical and histopathological knowledge of renal PEComas with metastatic potential and reconsider the dia-gnostic and therapeutic approach in this particular case to highlight the risk of mis-dia-g----nosis, malignant potential of renal PEComas and to demonstrate an unexpected treatment response. RESULTS: The patient in our case was dia-gnosed with chromophobe RCC with sarcomatoid features. She underwent a radical nephrectomy and epinephrectomy with a satisfactory postoperative history. Local recurrence urged chemother-apy commencement with sunitinib in the first line, and shortly afterwards, the patient was enrolled in a clinical trial with everolimus, with an extraordinary favorable treatment response for 30 months. Follow-ing the extirpation of single abdominal nodularity after 36 months of treatment with mTOR inhibitor, and proceed-ing the everolimus administration, the dis-ease slowly progressed to the right liver lobe, result-ing in right hemihepatectomy in another 24 months. The immunoprofile of liver metastases with positive stain-ing of melanoma markers and smooth muscle markers induced the revaluation of the primary tumor and abdominal nodularity specimen to an invasive EAML of the kidney. Further dis-ease progression was unavoidable despite several chemother-apy regimens, and the patient died 104 months after primary dia-gnosis. CONCLUSIONS: Renal tumors with adverse radiographic and histopathological features should become candidates for immunohistochemical stain-ing as its omission frequently leads to a misdia-gnosis, as showed in our case report. Atypical treatment response might suggest a possibility of a diagnostic mistake and should lead to reevaluation of the diagnostic and treatment process in the particular patient. Key words: renal PEComa -â epithelioid angiomyolipoma -â dia-gnosis -â everolimus.
Assuntos
Angiomiolipoma/diagnóstico , Neoplasias Renais/diagnóstico , Adulto , Angiomiolipoma/patologia , Angiomiolipoma/terapia , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/terapia , Erros de Diagnóstico , Everolimo/uso terapêutico , Evolução Fatal , Feminino , Humanos , Rim/patologia , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Cuidados para Prolongar a Vida , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Nefrectomia , Sunitinibe/uso terapêuticoRESUMO
Endogenous and exogenous factors can severely affect the integrity of genetic information by inducing DNA damage and impairing genome stability. The protection of genome integrity is ensured by the so-called "DNA damage response" (DDR), a set of evolutionary-conserved events that, triggered upon DNA damage detection, arrests the cell cycle, and attempts DNA repair. Here, we review the role of the DDR proteins as post-transcriptional regulators of gene expression, in addition to their roles in DNA damage recognition, signaling, and repair. At the same time, we discuss recent insights into how pre-mRNA splicing factors go beyond their splicing activities and play direct functions in detecting, signaling, and repairing DNA damage. The importance of extensive two-way crosstalk and interaction between the RNA processing and the DDR stems from growing evidence that the defects of their communication lead to genomic instability.
Assuntos
Dano ao DNA , Instabilidade Genômica , Proteínas/metabolismo , Processamento Pós-Transcricional do RNA , Reparo do DNA , Precursores de RNA/metabolismo , Fatores de Processamento de RNA , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
Ameloblastoma represents the most common epithelial odontogenic tumor. Because of the proximity of the maxillary tumors to the orbit and skull base, it should be managed as radically as possible. Maxillectomy, mainly via the transfacial or transoral approach, represents the most common type of surgical procedure. Drawback of these approaches is limited control of the superiomedial extent of the tumour in the paranasal area. We report the use of a combined endoscopic endonasal and transoral approach to manage maxillary plexiform ameloblastoma in a 48-year-old male patient. A combined endoscopic endonasal and transoral approach enabled the radical removal of tumour with a 1.5cm margin of radiographically intact bone with good control from both intrasinusal and intraoral aspects. Adequate visualization of the extent of the lesion (e.g. orbit, infratemporal fossa, anterior cranial base) had been achieved. Non-complicated healing was achieved. This technique of partial maxillectomy led to very good aesthetic and functional results. No recurrence had been noted during review appointments. The combination of endoscopic endonasal and transoral approach for a partial maxillectomy allows sufficient reduction of the defect, thus eliminating the necessity for reconstruction and reducing the morbidity associated with it.
Assuntos
Ameloblastoma , Seios Paranasais , Estética Dentária , Humanos , Masculino , Maxila , Pessoa de Meia-Idade , Recidiva Local de NeoplasiaRESUMO
Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Oncologia/métodos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Adolescente , Adulto , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Intervalo Livre de Progressão , Estudos Retrospectivos , Adulto JovemRESUMO
CONTEXT: Testicular germ-cell tumors (GCT) are highly curable. A multidisciplinary approach, including cisplatin-based chemotherapy has resulted in cure in the majority of patients with GCT. Thus, the life expectancy of survivors will extend to many decades post-diagnosis. Late treatment toxicities associated with cisplatin-based chemotherapy may impact their future health. OBJECTIVE: To systematically evaluate evidence regarding the long-term toxicity of cisplatin in GCT survivors. EVIDENCE ACQUISITION: We carried out a critical review of PubMed/Medline in February 2017 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Identified reports were reviewed according to the Consolidated Standards of Reporting Trials (CONSORT) criteria. Eighty-three publications were selected for inclusion in this analysis. EVIDENCE SYNTHESIS: Included reports evaluated long-term toxicities of cisplatin-based chemotherapy in GCT survivors. Studies reporting neuro- and ototoxicity, secondary malignancies, cardiovascular, renal and pulmonary toxicities, hypogonadism and infertility were found. Seven studies (8%) reported genetic underpinnings of long-term toxicities and 3 (4%) and 14 (19%) studies correlated long-term toxicities with circulating platinum levels and cumulative dose of cisplatin, respectively. Significant risks for long-term toxicities associated with cisplatin and platinum-based regimens were reported. The cumulative dose of cisplatin and circulating platinum were reported as risk factors. Several single-nucleotide polymorphisms identified patients susceptible to cisplatin compared with wild-type individuals. CONCLUSIONS: GCT survivors cured with cisplatin-based chemotherapy are at risk for long-term side-effects. Detection of single-nucleotide polymorphisms could be a valuable tool for predicting long-term toxicities. PATIENT SUMMARY: Herein, this article summarizes the available evidence of long-term toxicity of cisplatin-based chemotherapy in GCT survivors and provide insights from Indiana University.