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1.
Anticancer Res ; 40(4): 2199-2208, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234915

RESUMO

BACKGROUND/AIM: To date, there is no clear understanding whether preoperative long-course chemoradiotherapy combined with surgery for rectal cancer is detrimental to anorectal function. The purpose of this study was to clarify the influence of preoperative chemoradiotherapy and surgery for middle and lower rectal cancer on postoperative anorectal function. PATIENTS AND METHODS: Data of 113 patients with middle or lower rectal cancer treated with preoperative chemoradiotherapy plus surgery or surgery alone between January 2013 and December 2016 were analyzed. A total of 84 and 29 patients underwent low anterior resection and intersphincteric resection, respectively. In patients with T3 or deeper and with any N stage cancer below peritoneal reflection, surgery plus lateral lymph node dissection or preoperative radiation (total: 50.4 Gy/28 fractions) to the pelvis with chemoradiotherapy plus surgery was treated. Anorectal function was assessed prior to treatment and 6 and 12 months postoperatively. Specifically, maximum resting pressure and maximum squeezing pressures were measured. The Wexner score was recorded prior to treatment and 12 months postoperatively. RESULTS: maximum resting pressure and maximum squeezing pressure decreased post-surgery in both groups. Maximum resting pressure and maximum squeezing pressure at 12 months and the Wexner score at 12 months post-surgery were comparable among patients treated with chemoradiotherapy plus surgery and those treated with surgery alone. CONCLUSION: Preoperative chemoradiotherapy did not clearly impair postoperative anorectal function in patients who underwent low anterior resection and intersphincteric resection.


Assuntos
Canal Anal/fisiopatologia , Neoplasias Retais/cirurgia , Neoplasias Retais/terapia , Reto/fisiopatologia , Idoso , Canal Anal/patologia , Canal Anal/cirurgia , Quimiorradioterapia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Período Pré-Operatório , Reto/patologia , Reto/cirurgia
2.
Anticancer Res ; 40(3): 1625-1629, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132066

RESUMO

Pulmonary sarcomatoid carcinoma is a rare variant of non-small cell lung cancer. Here, we report on the case of a 67-year-old male with a diagnosis of biopsy-proven moderately differentiated squamous cell carcinoma of the left lower lobe of the lung. The tumor cells on biopsy had epithelioid morphology with strong immunoreactivity for CK7 and p40. The mass was surgically removed one year later due to its poor response to stereotactic radiotherapy and chemotherapy. The lobectomy specimen revealed pleomorphic mitotically active spindle cell neoplasm with scattered foci of epithelial component. The tumor cells showed diffuse immunopositivity for vimentin, as well as focal immunoreactivity for CK7, p40 and S100 in the epithelial component. To the best of our knowledge, this is the first documented case of histopathologic sarcomatoid transformation of lung squamous cell carcinoma after neoadjuvant therapy. The clinical course, diagnosis and a review of literature are presented.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante/métodos , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/patologia , Masculino
3.
Magy Seb ; 73(1): 29-36, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32172578

RESUMO

Introduction: The raison d'etre of laparoscopic surgery of colonic tumours is supported by many I/a level evidence. There are a lot of excellent early and late results regarding sigmoid and upper third rectum tumours in favour of laparoscopic surgery. There are not many literature proposals like this regarding chemo-irradiated tumours. Material and method: One hundred ninety-six patients received neoadjuvant treatment due to lower and middle third rectum tumours in the Borsod-Abaúj-Zemplén County Hospital between the 1st of January 2006 and the 31st of December 2011. Twelve patients out the 196 were not followed up, so we analysed 184 patients' data. We performed laparoscopic surgery on 67 patients. Conversion happened on 15 patients out of the 67 cases. Open surgery was performed on 117 patients. We strived for the ligation of the inferior mesenteric artery at the origin, the sparing of the autonomic nerves and the precise implementation of TME. The splenic flexure has been taken down during the operations that involved resection. Results: The Dukes stages as well as the, ASA stages were similar in both groups. There was no significant difference in the patients' BMI either. The length of the removed specimens and the tumour size were similar too. The defining factors of recurrence are the involvement of the circumferential resection margin (CRM) and the complete execution of the TME. These were appropriate in our laparoscopic cases, and we did not find a significant difference in between the groups (Chi-square test, p = 0.94). The operation time was similar in the laparoscopic, converted and open surgeries, and there was no significant difference either. The shortest postoperative care time was in the laparoscopic group, but the Mann-Whitney test did not reveal a significant difference. Similarly to literature data, we experienced much less wound-related complications like infections and fever in the laparoscopic group. There was a significant difference in terms of transfusion demand comparing the laparoscopic and open operation groups, to the detriment of the open surgery group (Chi-square test, p = 0.04). We did not find a significant difference in recurrence or survival during follow-up of the patients. Conclusion: In addition to the short-term advantages of laparoscopic surgery, it is a safe procedure for the chemo-irradiated rectum tumours even from an oncological point of view. Both open and laparoscopic surgery requires high-level competency and qualification and these must be performed in centres.


Assuntos
Quimiorradioterapia/métodos , Laparoscopia/métodos , Neoplasias Retais/cirurgia , Reto/cirurgia , Procedimentos Cirúrgicos Eletivos , Humanos , Ligadura , Excisão de Linfonodo/métodos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia , Neoplasias Retais/patologia , Resultado do Tratamento
4.
J Comput Assist Tomogr ; 44(2): 269-274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195807

RESUMO

OBJECTIVE: To prospectively compare the performance of model-based and model-free dynamic contrast-enhanced (DCE) pharmacokinetic parameters in monitoring breast cancers' early response to neoadjuvant chemotherapy (NACT). METHODS: Sixty patients, with 61 pathology-proven breast cancers, were examined using DCE magnetic resonance imaging before, after the first cycle, and after full cycles of NACT. Both model-based (Ktrans and others) and model-free parameters, mainly time-intensity curve (TIC), were measured. According to Miller-Payne grading, patients were divided into response and nonresponse group. Mann-Whitney U test, Fisher exact test, multivariate logistic regression, and receiver operating characteristic curve were used in analysis. RESULTS: After the first cycle, among all the parameters, Ktrans and TIC were strongly associated with tumors' early response. There was no significant difference between the areas under receiver operating characteristic curve of Ktrans and TIC (0.768, 0.852, respectively). CONCLUSIONS: Model-based and model-free DCE parameters, especially Ktrans and TIC, have similar performance in predicting the efficacy of NACT for breast cancers.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Meios de Contraste/farmacocinética , Aumento da Imagem/métodos , Imagem por Ressonância Magnética/métodos , Terapia Neoadjuvante/métodos , Adulto , Mama/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Resultado do Tratamento
5.
Einstein (Sao Paulo) ; 18: eRC4990, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32130329

RESUMO

Transarterial radioembolization (TARE) with yttrium-90 microspheres is a palliative locoregional treatment, minimally invasive for liver tumors. The neoadjuvant aim of this treatment is still controversial, however, selected cases with lesions initially considered unresectable have been enframed as candidates for curative therapy after hepatic transarterial radioembolization. We report three cases in which the hepatic transarterial radioembolization was used as neoadjuvant therapy in an effective way, allowing posterior potentially curative therapies.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Colangiocarcinoma/terapia , Neoplasias Hepáticas/terapia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Resultado do Tratamento , Radioisótopos de Ítrio
6.
Bull Cancer ; 107(4): 438-446, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32057467

RESUMO

INTRODUCTION: Perioperative chemotherapy is the standard strategy for localized gastric cancers. Nevertheless, this strategy seems to be inefficient, if not deleterious, for patients with tumors harboring microsatellite instability (MSI) and/or mismatch repair deficiency (dMMR), a tumor phenotype predictive for the efficacy of immune checkpoint inhibitors (ICKi). AIM: The GERCOR NEONIPIGA single-arm phase II study (NCT04006262; EUDRACT 2018-004712-22) aims at evaluating the efficacy of a peri-operative strategy with nivolumab and ipilimumab in neoadjuvant setting, then nivolumab alone after surgery for patients with resectable MSI/dMMR gastric cancer. MATERIAL AND METHODS: Main inclusion criteria are: gastric and oesogastric junction adenocarcinoma (GOA), T2-T4, all N stage and M0, MSI/dMMR. Patients will be treated with nivolumab 240mg Q2W, 6 infusions, and ipilimumab 1mg/kg Q6W, 2 infusions in neoadjuvant setting. Following surgery, patients with TRG 1-2-3 (Mandard tumor regression grade), acceptable tolerance of neoadjuvant treatment and postoperative ECOG performance status 0-1, will be treated with adjuvant nivolumab 480mg Q4W, 9 infusions. RESULTS: The primary endpoint is pathological complete response rate (pCR-R). Based on a Fleming design, with α=5% and ß=20%, 27 patients have to be evaluated (H0=5%; H1=20%). Secondary endpoints include disease-free survival, overall survival and safety. CONCLUSION: This study is planned to include 32 patients to evaluate the pCR-R with the combination of nivolumab and ipilimumab in neoadjuvant setting for MSI/dMMR localized GOA. The MSI/MMR status should be systematically assessed on diagnostic biopsies of all GOA. If it meets its primary endpoint, the GERCOR NEONIPIGA study might mark a turning point in the management of localized MSI/dMMR GOA patients.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ipilimumab/uso terapêutico , Nivolumabe/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Quimioterapia Adjuvante , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Humanos , Instabilidade de Microssatélites , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/métodos , Seleção de Pacientes , Assistência Perioperatória , Fenótipo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do Tratamento
7.
Anticancer Res ; 40(2): 1175-1181, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014971

RESUMO

BACKGROUND/AIM: This study aimed to evaluate the association of sarcopenia and Clinical Outcomes with esophageal cancer under neoadjuvant chemoradiotherapy (CRT). PATIENTS AND METHODS: A retrospective study assessing patients with esophageal cancer who underwent CRT between 2001 and 2014 was conducted in the medical center. Hospital patients' records on sarcopenia and treatment outcomes were statistically analyzed. RESULTS: The sarcopenia group had significantly lower body mass index than the non-sarcopenia group. CRT-related severe adverse events with mucositis, fever, and neutropenic fever were greater in the sarcopenia group. Overall survival and disease-free survival were significantly better in the non-sarcopenia group. Sarcopenic patients who received nutritional support with enteral access had less severe mucositis. There was no difference in mortality of sarcopenia patients with nutritional support via enteral access or without. Moreover, sarcopenia and advanced tumor stage were independent factors for mortality outcome. CONCLUSION: Sarcopenia before CRT may be associated with increased toxicities and worse overall survival/ disease-free survival in esophageal cancer patients.


Assuntos
Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/mortalidade , Sarcopenia/etiologia , Sarcopenia/mortalidade , Idoso , Composição Corporal , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Sarcopenia/diagnóstico , Análise de Sobrevida , Resultado do Tratamento
8.
Isr Med Assoc J ; 22(2): 75-78, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32043322

RESUMO

BACKGROUND: The treatment of elderly patients with advanced stage ovarian carcinoma is challenging due to a high morbidity. OBJECTIVES: To evaluate the clinical course and outcome of elderly patients with advanced stage ovarian carcinoma receiving neoadjuvant chemotherapy (NACT). METHODS: A retrospective study of all patients with stage IIIC and IV ovarian carcinoma receiving NACT in one medical center (between 2005 and 2017). The study group criteria age was above 70 years. The control group criteria was younger than 70 years old at diagnosis. Demographics and treatment outcomes were compared between groups. Primary outcomes were progression-free survival (PFS) and overall survival (OS). RESULTS: Overall, 105 patients met the inclusion criteria, 71 patients (67.6%) were younger than 70 years and 34 patients (32.4%) older. Rates of interval cytoreduction were significantly higher in younger patients (76.1% vs. 50.0%, P = 0.01). Of those who underwent interval cytoreduction, no difference was found in rates of optimal debulking between groups (83.35% vs. 100%, P = 0.10). Using a Kaplan-Meier survival analysis, no significant differences were observed between groups in PFS or OS, P > 0.05. Among the elderly group alone, patients who underwent interval cytoreduction had significantly longer PFS than those without surgical intervention (0.4 ± 1.7 vs. 19.3 ± 19.4 months, P = 0.001). CONCLUSIONS: Elderly patients with ovarian carcinoma who received NACT undergo less interval cytoreduction than younger patients, with no difference in PFS and OS. However, among the elderly, interval cytoreduction is associated with significantly higher PFS.


Assuntos
Carcinoma Epitelial do Ovário , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos de Citorredução/estatística & dados numéricos , Neoplasias Ovarianas , Fatores Etários , Idoso , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/terapia , Intervalo Livre de Doença , Feminino , Humanos , Israel/epidemiologia , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
9.
Science ; 367(6477)2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32001626

RESUMO

Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti-PD-1 or anti-PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti-PD-1 and anti-PD-L1 efficacy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Imunoterapia/métodos , Terapia Neoadjuvante/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Linfócitos T/imunologia
10.
Anticancer Res ; 40(2): 915-921, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014935

RESUMO

BACKGROUND/AIM: This study aimed was to clarify the impact of pegfilgrastim (PEG) 3.6 mg primary prophylaxis of febrile neutropenia (FN) on the average relative dose intensity (ARDI) of neoadjuvant/adjuvant FEC-100 for breast cancer. MATERIALS AND METHODS: This retrospective, single-centre cohort study including 296 patients who received FEC-100 compared PEG and non-PEG groups. The PEG group received PEG 3.6 mg as a single subcutaneous injection in each study cycle. The primary endpoint was the ARDI of FEC-100. The secondary endpoints were patient percentage of ARDI≥85%, factors associated with ARDI≥85%, and reasons for reduced ARDI. RESULTS: The PEG group showed significantly higher mean ARDI (95.6% versus 90.7%, p<0.001) and patient percentage of ARDI≥85% (93.0% versus 79.9%, p=0.001). PEG was significantly associated with ARDI≥85% (p=0.009). Neutropenia and FN, the main reasons for reduced ARDI, were significantly lower in the PEG group (p<0.05). CONCLUSION: Primary PEG 3.6 mg prophylaxis increased the ARDI of FEC-100.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Filgrastim/uso terapêutico , Terapia Neoadjuvante/métodos , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Estudos de Coortes , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Epirubicina/farmacologia , Epirubicina/uso terapêutico , Feminino , Filgrastim/farmacologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/farmacologia , Estudos Retrospectivos
11.
J Comput Assist Tomogr ; 44(2): 275-283, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32004189

RESUMO

OBJECTIVE: The objective of this study was to develop a nomogrom for prediction of pathological complete response (PCR) to neoadjuvant chemotherapy in breast cancer patients. METHODS: Ninety-one patients were analyzed. A total of 396 radiomics features were extracted from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and apparent diffusion coefficient (ADC) maps. The least absolute shrinkage and selection operator was selected for data dimension reduction to build a radiomics signature. Finally, the nomogram was built to predict PCR. RESULTS: The radiomics signature of the model that combined DCE-MRI and ADC maps showed a higher performance (area under the receiver operating characteristic curve [AUC], 0.848) than the models with DCE-MRI (AUC, 0.750) or ADC maps (AUC, 0.785) alone in the training set. The proposed model, which included combined radiomics signature, estrogen receptor, and progesterone receptor, yielded a maximum AUC of 0.837 in the testing set. CONCLUSIONS: The combined radiomics features from DCE-MRI and ADC data may serve as potential predictor markers for predicting PCR. The nomogram could be used as a quantitative tool to predict PCR.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia , Meios de Contraste , Aumento da Imagem/métodos , Imagem por Ressonância Magnética/métodos , Terapia Neoadjuvante/métodos , Nomogramas , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade
13.
PLoS One ; 15(1): e0227738, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945122

RESUMO

OBJECTIVES: Incidence of oral cavity squamous cell carcinomas is rising worldwide, and population characterization is important to follow for future trends. The aim of this retrospective study was to present a large cohort of primary oral cavity squamous cell carcinoma from all four health regions of Norway, with descriptive clinicopathological characteristics and five-year survival outcomes. MATERIALS AND METHODS: Patients diagnosed with primary treatment-naïve oral cavity squamous cell carcinomas at all four university hospitals in Norway between 2005-2009 were retrospectively included in this study. Clinicopathological data from the electronic health records were compared to survival data. RESULTS: A total of 535 patients with primary treatment-naïve oral cavity squamous cell carcinomas were identified. The median survival follow-up time was 48 months (range 0-125 months) after treatment. The median five-year overall survival was found to be 47%. Median five-year disease-specific survival was 52%, ranging from 80% for stage I to 33% for stage IV patients. For patients given treatment with curative intent, the overall survival was found to be 56% and disease-specific survival 62%. Median age at diagnosis was 67 years (range 24-101 years), 64 years for men and 72 years for women. The male: female ratio was 1.2. No gender difference was found in neither tumor status (p = 0.180) nor node status (p = 0.266), but both factors influenced significantly on survival (p<0.001 for both). CONCLUSIONS: We present a large cohort of primary treatment-naïve oral cavity squamous cell carcinomas in Norway. Five-year disease-specific survival was 52%, and patients eligible for curative treatment had a five-year disease-specific survival up to 62%.


Assuntos
Metástase Linfática/patologia , Neoplasias Bucais/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante/métodos , Feminino , Seguimentos , Humanos , Metástase Linfática/terapia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/patologia , Neoplasias Bucais/terapia , Esvaziamento Cervical , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Noruega/epidemiologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
J Urol ; 203(4): 734-742, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31928408

RESUMO

PURPOSE: We determined whether prostate specific antigen criteria after focal high intensity focused ultrasound to treat prostate cancer could diagnose treatment failure. MATERIALS AND METHODS: A total of 598 patients in a prospectively maintained national database underwent focal high intensity focused ultrasound with a Sonablate® 500 device from March 2007 to November 2016. Followup consisted of 3-month clinic visits and prostate specific antigen testing in year 1 with prostate specific antigen measurement every 6 to 12 months and multiparametric magnetic resonance imaging with biopsy for magnetic resonance imaging suspicious for recurrence. Treatment failure was considered any secondary treatment, tumor recurrence with Gleason 3 + 4 or greater disease on prostate biopsy without further treatment or metastasis and/or prostate cancer related mortality. To diagnose failure we evaluated a series of nadir + x thresholds with x values of 0.1 to 2.0 ng/ml. RESULTS: Median patient age was 65 years (IQR 60-71) and the median Gleason score was 7 (range 6-9). Gleason 3 + 4 or greater disease was present in 80% of cases. Tumors were radiologically staged as T1c-T2c in 522 of the 596 patients (88%) and as T3a/b in 74 (12.4%). Baseline median prostate specific antigen was 7.80 ng/ml (IQR 5.96-10.45) in failed cases and 6.77 ng/ml (IQR 2.65-9.71) in cases without failure. Optimal performance according to the Youden index to indicate the most appropriate nadir + x at all analyzed time points at 3-month intervals showed that nadir + 1.0 ng/ml would have 27.3% to 100% sensitivity and 39.4% to 85.6% specificity depending on the time of evaluation in the first 3 years. Nadir + 1.5 ng/ml showed 18.2% to 100% sensitivity and 60.6% to 91.8% specificity with nadir + 2.0 ng/ml leading to similar sensitivity and specificity ranges. Nadir + 1.0 ng/ml at 12 months and nadir + 1.5 ng/ml at 24 and 36 months had 100% sensitivity and 96.1% to 100% negative predictive value. CONCLUSIONS: Following focal high intensity focused ultrasound a prostate specific antigen nadir of 1.0 ng/ml at 12 months and 1.5 ng/ml at 24 to 36 months might be used to triage men requiring magnetic resonance imaging and biopsy. These data need prospective validation.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Calicreínas/sangue , Recidiva Local de Neoplasia/diagnóstico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/terapia , Ultrassom Focalizado Transretal de Alta Intensidade , Idoso , Estudos de Viabilidade , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética Multiparamétrica , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Próstata/diagnóstico por imagem , Próstata/patologia , Próstata/efeitos da radiação , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Sensibilidade e Especificidade , Falha de Tratamento
15.
Nat Commun ; 11(1): 385, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959756

RESUMO

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Mama/patologia , Receptor ErbB-2/metabolismo , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Biópsia , Mama/efeitos dos fármacos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Terapia Neoadjuvante/métodos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento
16.
Cancer Immunol Immunother ; 69(3): 355-364, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31893287

RESUMO

OBJECTIVE: High rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity. METHODS: We analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 weeks of induction chemotherapy and 5 weeks of sequential chemoradiotherapy, both neoadjuvant modalities containing oxaliplatin. The patients had the residual tumor resected and were followed for long-term outcome. RESULTS: Patients who met the main study end point-freedom from distant recurrence-showed a significant rise in HMGB1 during the induction chemotherapy and consolidation over the chemoradiotherapy. The higher the ICD increase, the lower was the metastatic failure risk (hazard ratio 0.26, 95% confidence interval 0.11-0.62, P = 0.002). However, patients who received the full-planned oxaliplatin dose of the chemoradiotherapy regimen had poorer metastasis-free survival (P = 0.020) than those who had the oxaliplatin dose reduced to avert breach of the radiation delivery, which is critical to maintain efficient tumor cell kill and in the present case, probably also protected the ongoing radiation-dependent ICD response from systemic oxaliplatin toxicity. CONCLUSION: The findings indicated that full-dose induction oxaliplatin followed by an adapted oxaliplatin dose that was compliant with full-intensity radiation caused induction and maintenance of ICD and as a result, durable disease-free outcome for a patient population prone to metastatic progression.


Assuntos
Terapia Neoadjuvante/métodos , Oxaliplatina/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Retais/patologia , Fatores de Risco , Resultado do Tratamento
17.
Int J Cancer ; 146(7): 1851-1861, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603993

RESUMO

The goal of our study was to demonstrate the spectrum of genomic alterations present in the residual disease of patients with advanced high-grade serous ovarian cancer (HGSOC) after neoadjuvant chemotherapy (NAC), including matched pretreatment biopsies. During the study period between 2006 and 2017, we collected pre-NAC and post-NAC tumor tissue samples from patients with advanced HGSOC. We performed combined next-generation sequencing and immunohistochemistry to identify actionable targets and pathway activation in post-NAC residual tumors. We also examined whether post-NAC profiling of residual HGSOC identified targetable molecular lesions in the chemotherapy-resistant component of tumors. Among 102 post-NAC samples, 41 (40%) of patients had mutations in homologous recombination repair (HRR) genes (HRR deficiency). Patients with HRR mutations had higher tumor mutation burdens (p < 0.001) and higher alterations in the PI3K-AKT-mTOR pathway (p = 0.004) than patients without these HRR mutations. Nevertheless, we found no significant differences in progression-free survival (p = 0.662) and overall survival (OS; p = 0.828) between the two groups. Most patients (91%) had alterations in at least one of the targetable pathways, and those patients with cell cycle (p = 0.004) and PI3K-AKT-mTOR signaling (p = 0.005) pathway alterations had poorer OS (Bonferroni-corrected threshold = 0.0083, 0.05/6). We showed the genomic landscape of tumor cells remaining in advanced HGSOC after NAC. Once validated, these data can help inform biomarker-driven adjuvant studies in targeting residual tumors to improve the outcomes of patients with advanced HGSOC after NAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cistadenocarcinoma Seroso/genética , Neoplasias Ovarianas/genética , Ovário/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Ciclo Celular/genética , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/terapia , Procedimentos Cirúrgicos de Citorredução/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genômica , Humanos , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Terapia Neoadjuvante/métodos , Neoplasia Residual , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Ovariectomia/métodos , Ovário/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo
18.
Cancer Sci ; 111(1): 23-35, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31660687

RESUMO

Chemoradiotherapy (CRT) is the standard neoadjuvant therapy for locally advanced rectal cancer (RC). However, neoadjuvant chemotherapy (NAC) also shows favorable outcomes. Although the immunological environment of RC has been thoroughly discussed, the effect of NAC on it is less clear. Here, we investigated the immunological microenvironment, including T cell infiltration, activation, and topological distribution, of resected RC tissue after neoadjuvant therapies and evaluated the correlation between T cell subsets and patient prognosis. Rectal cancer patients (n = 188) were enrolled and categorized into 3 groups, namely CRT (n = 41), NAC (n = 46), and control (surgery alone; n = 101) groups. Characterization of residual carcinoma cells and T cell subsets in resected tissues was performed using multiplex fluorescence immunohistochemistry. The densities of total and activated (Ki67high ) T cells in tissues after NAC, but not CRT, were higher than in control. In both CRT and NAC groups, patients presenting with higher treatment effects showed aggressive infiltration of T cell subsets into carcinomas. Multivariate analyses of pathological and immunological features and prognosis revealed that carcinoma Ki67high CD4+ T cells after CRT and stromal Ki67high CD8+ T cells after NAC are important prognostic factors, respectively. Our results suggest that evaluation of T cell activation with Ki67 expression and its tumor localization can be used to determine the prognosis of advanced RC after neoadjuvant therapies.


Assuntos
Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno Ki-67/metabolismo , Neoplasias Retais/imunologia , Neoplasias Retais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Quimiorradioterapia/métodos , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Prognóstico , Neoplasias Retais/tratamento farmacológico , Microambiente Tumoral/imunologia
19.
Am J Pathol ; 190(2): 442-452, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31843500

RESUMO

Pathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P < 0.001), with a median time to recurrence of 41.2 versus 5.5 months in nonresponders. DNA damage repair alterations were noticed in 38.1% (n = 8), confirming a positive correlation with high tumor mutational burden (P = 0.007). Chromosomal 7p12 amplification, including the genes HUS1, EGFR, ABCA13, and IKZF1, predicted nonresponse in patients with a sensitivity, a negative predictive value, and a specificity of 71.4%, 87.5%, and 100%, respectively. Total count of CD3+ T cells/mm2 tumor was a significant predictor of NAC response. In conclusion, 7p12 amplification may predict nonresponse to NAC and worse survival in MIBC. Multicenter, prospective trials with sufficient statistical power may further fortify these findings.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 7/genética , Amplificação de Genes , Neoplasias Musculares/patologia , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/patologia , Neoplasias da Bexiga Urinária/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aberrações Cromossômicas , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Musculares/tratamento farmacológico , Neoplasias Musculares/genética , Invasividade Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
20.
Int J Radiat Oncol Biol Phys ; 106(1): 124-133, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31494181

RESUMO

PURPOSE: Preoperative therapy in borderline resectable pancreatic cancer (BRPC) is intended to increase R0 resection rates. An optimal approach in BRPC is yet to be defined. METHODS AND MATERIALS: Patients with BRPC, confirmed adenocarcinoma, performance status ≤1, and adequate organ function enrolled in a single-institution, phase 2 trial. Patients received FOLFIRINOX × 6 cycles, then radiation therapy (50 Gy in 25 fractions) concurrent with fixed-dose rate gemcitabine (1 g/m2 over 100 minutes) followed by 2 additional gemcitabine infusions. Computed tomography scans were performed at 2-month intervals during treatment. Patients without distant disease were offered surgical exploration. The primary objective was R0 resection rate with an alternate hypothesis of 55%. Secondary objectives included median progression-free survival (PFS), median overall survival (OS), response rate, and safety. The trial registration number is NCT01661088. RESULTS: Twenty-five patients with median age of 60 years (range, 47-77 years) enrolled from November 2011 through January 2017. Twenty-one (84%) completed FOLFIRINOX and 19 (76%) completed all protocol therapy. Treatment-related grade 3 to 4 toxicities included neutropenia (40%), nausea and vomiting (28%), diarrhea (16%), and fatigue (12%). Eighteen patients (72%) underwent laparotomy, 13 (52%) were resected (all R0). The median PFS and OS in 25 patients were 13.1 months (95% confidence interval [CI], 7.3-24.7) and 24.4 months (95% CI, 12.6-40.0), respectively. For resected patients, median PFS was 21.6 months (95% CI, 8.2-37.1) and OS was 37.1 months (95% CI, 15.4-not reached). CONCLUSIONS: Neoadjuvant therapy with FOLFIRINOX, followed by intensity modulated radiation therapy concurrent with fixed-dose-rate gemcitabine in BRPC is feasible and tolerated. Although the alternate hypothesis was not met, the OS of the resected cohort was favorable.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/terapia , Radioterapia de Intensidade Modulada/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno CA-19-9/metabolismo , Quimiorradioterapia/métodos , Desoxicitidina/administração & dosagem , Fracionamento da Dose de Radiação , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Neutropenia/induzido quimicamente , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada/efeitos adversos
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