RESUMO
BACKGROUND: Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available. METHODS: The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based, sequence of three treatment lines in patients with RAS/BRAFV600E wild type (WT) mCRC, as determined by local laboratory. Before first-line therapy, CGP is performed with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively. RESULTS: For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF≥10%) was detected among 140/205 (68.3%) patients. 1013 genomic variants were identified. F1L CDx found KRAS, NRAS or BRAFV600E alterations in 19 patients, whose tumors were classified as RAS/BRAFV600E WT by local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. Concordance of 61.4% between the two tests was observed. Concordance increased to 72.7% for F1L CDx with TF ≥10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor (EGFR) resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including 6 cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). CONCLUSION: Baseline liquid biopsy-based CGP is feasible, it has high concordance with tumor tissue-based CGP, it could better recapitulate tumor heterogeneity, and it is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAFV600E WT mCRC patients.
RESUMO
Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.
Assuntos
Antineoplásicos , Neoplasias Colorretais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Mutação , Panitumumabe/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score <3+ and absence of ISH amplification, and IHC "downscoring" from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post-progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over-expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over-expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab-based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti-HER2 second-line strategies in initially HER2-positive disease.
Assuntos
Neoplasias Esofágicas/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Feminino , Humanos , Imuno-Histoquímica , Masculino , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. PATIENTS AND METHODS: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. RESULTS: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. CONCLUSIONS: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/efeitos adversos , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Itália , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Resultado do TratamentoRESUMO
OBJECTIVE: There are no well-defined criteria for assessing the efficacy and quality of wound dressings, and evaluation is often simplistic and based on the subjective opinion of the health-care professional. The aim of this study was to identify specific parameters suitable for measuring dressings' performance, and to recommend laboratory tests able to evaluate these specific criteria in an objective manner. METHOD: After reviewing all tests currently used in Italy and examining the criteria for evaluating the quality of dressings, the authors selected 12 clinically significant parameters. These parameters were measured using standard and non-standard tests, and in some cases, these tests were modified and improved to simulate real-life conditions more accurately. RESULTS: Most of the tests used were able to discriminate well between dressings belonging to different brands, with some tests being more suitable than others for the assessment of specific dressings. CONCLUSION: These results highlighted some issues in the standard testing procedures, such as the need of a suitable fluid that mimics the real exudate, and the importance of standard temperature and humidity conditions during testing. Our study paves the way for a larger project aimed at a systematic evaluation of dressing quality able to assess every wound dressing on the market.
Assuntos
Curativos Hidrocoloides/normas , Cicatrização/fisiologia , Ferimentos e Lesões/terapia , Estudos de Avaliação como Assunto , Humanos , Itália , Padrões de ReferênciaRESUMO
BACKGROUND: Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information. PATIENTS AND METHODS: In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer. RESULTS: Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect. CONCLUSIONS: This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Mutação , Antineoplásicos/uso terapêutico , Sequência de Bases , Camptotecina/uso terapêutico , Cetuximab , Classe I de Fosfatidilinositol 3-Quinases , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Fluoruracila/uso terapêutico , GTP Fosfo-Hidrolases/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucovorina/uso terapêutico , Proteínas de Membrana/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genética , Proteínas ras/genéticaRESUMO
BACKGROUND: To date, few studies of preoperative chemotherapy or chemoradiotherapy (crt) in gastroesophageal junction (gej) cancer have been statistically powered; indeed, gej tumours have thus far been grouped with esophageal or gastric cancer in phase iii trials, thereby generating conflicting results. METHODS: We studied 41 patients affected by locally advanced Siewert type i and ii gej adenocarcinoma who were treated with a neoadjuvant crt regimen [folfox4 (leucovorin-5-fluorouracil-oxaliplatin) for 4 cycles, and concurrent computed tomography-based three-dimensional conformal radiotherapy delivered using 5 daily fractions of 1.8 Gy per week for a total dose of 45 Gy], followed by surgery. Completeness of tumour resection (performed approximately 6 weeks after completion of crt), clinical and pathologic response rates, and safety and outcome of the treatment were the main endpoints of the study. RESULTS: All 41 patients completed preoperative treatment. Combined therapy was well tolerated, with no treatment-related deaths. Dose reduction was necessary in 8 patients (19.5%). After crt, 78% of the patients showed a partial clinical response, 17% were stable, and 5% experienced disease progression. Pathology examination of surgical specimens demonstrated a 10% complete response rate. The median and mean survival times were 26 and 36 months respectively (95% confidence interval: 14 to 37 months and 30 to 41 months respectively). On multivariate analysis, TNM staging and clinical response were demonstrated to be the only independent variables related to long-term survival. CONCLUSIONS: In our experience, preoperative chemoradiotherapy with folfox4 is feasible in locally advanced gej adenocarcinoma, but shows mild efficacy, as suggested by the low rate of pathologic complete response.
RESUMO
Sorafenib is considered the standard systemic therapy for hepatocellular carcinoma (HCC), in patients with well-preserved liver function (Child-Pugh A class) and advanced-stage HCC (BCLC-C) or in patients with HCC progressing after locoregional therapies, with a high grade of recommendation. The approval of sorafenib for this indication was grounded on the efficacy and the safety results reported by two international randomized, controlled trials, the SHARP and the Asia-Pacific studies. In addition, the efficacy and the safety of sorafenib in clinical practice are addressed by several field-practice experiences, including the multinational GIDEON study and the SOFIA study. Finally, further research on sorafenib is ongoing to optimize the use of this molecule. This review aims to provide an overview of the most relevant clinical data on the efficacy and the safety of sorafenib in patients with HCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Alvo Molecular , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pesquisa Translacional Biomédica , Animais , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Medicina Baseada em Evidências , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Sorafenibe , Fatores de Tempo , Resultado do TratamentoRESUMO
Increased insulin-like growth factor (igf) signalling has been observed in breast cancer, including endocrine-responsive cancers, and has been linked to disease progression and recurrence. In particular, igf-1 has the ability to induce and promote lymphangiogenesis through the induction of vascular endothelial growth factor C (vegfc). In the present study, we analyzed serum and tumour samples from 60 patients with endocrine-positive breast cancer to determine the expression and the possible relationship of circulating igf-1, igf binding protein 3 (igfbp3), and vegfc with the presence of lymphatic metastasis and other immunohistochemical parameters. The analysis revealed a clear and significant correlation between high basal levels of igf-1, igfbp3, and vegfc and lymph node metastasis in endocrine-responsive breast cancer. In addition, expression of those molecules was significantly higher in breast cancer patients than in healthy control subjects. Those findings may enable more accurate prediction of prognosis in patients with breast cancer.
RESUMO
This pooled analysis was performed using individual patient data from three phase II trials that included on the whole 113 esophageal cancer treated preoperatively with chemoradiotherapy (CRT), in order to analyze the efficacy and survival outcomes according to the achievement of the pathologic complete response (pCR). Thirty-nine patients were treated with 5-fluorouracil/cisplatin and RT (40 Gy), 33 patients received paclitaxel/cisplatin weekly during weeks 1-6 with and RT (46 Gy), 41 patients were treated with induction bio-chemotherapy with cetuximab and FOLFOX-4 followed by concomitant cetuximab and RT of 50.4 Gy. One hundred and two out of 113 resected patients were included in the survival analysis. The median overall survival (OS) time for the whole population was 21.5 months. The 12, 24, and 36 months OS rates were 85.4, 45.2, and 33%, respectively. The difference in survival probability between patients with pCR and patients with partial response or stable disease after treatment was significant (P= 0.0002, hazard ratios = 0.21, 95% CI 0.18-0.60). On multivariate analysis, the pathologic response and histology were the only covariates independently associated with OS (P= 0.0157 and P= 0.0212, respectively). In our series, complete responder patients had a significant longer survival probability after treatment when compared to patients with partial response or stable disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Cisplatino/uso terapêutico , Neoplasias Esofágicas/terapia , Fluoruracila/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Esofágicas/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The presence of KRASG12C mutation in metastatic colorectal cancer (mCRC) correlates with poor outcome. Although different selective inhibitors are under clinical development, the optimal treatment remains uncertain. Thus, we conducted a retrospective analysis in a large cohort of patients with KRASG12C mCRC treated in 12 Italian oncology units. PATIENTS AND METHODS: Patients with unresectable mCRC harboring KRASG12C mutation receiving a first-line chemotherapy doublet or triplet between 2011 and 2021 were included in the study. Evaluation of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) analysis was carried out. RESULTS: A total of 256/6952 (3.7%) patients with mCRC displayed KRASG12C mutation; of these, 111 met the inclusion criteria. The ORR of first-line therapy was 38.7% (43/111). Median PFS (mPFS) was 9 months [95% confidence interval (CI) 7.5-10.5 months]. After progression, only 62% and 36% of the patients are fit to receive second or third lines of treatment, with limited clinical benefit. Median OS (mOS) was 21 months (95% CI 17.4-24.6 months). In patients receiving first-line triplet chemotherapy, ORR was 56.3% (9/16), mPFS was 13 months (95% CI 10.3-15.7 months) and mOS was 32 months (95% CI 7.7-56.3 months). For irinotecan-based doublets, ORR was 34.5 (10/29), mPFS was 9 months (95% CI 6.4-11.6 months) and mOS was 22 months (95% CI 16.0-28.0 months). With oxaliplatin-based doublets ORR was 36.4% (24/62), mPFS was 7 months (95% CI 4.6-9.4 months) and mOS was 18 months (95% CI, 13.6-22.4 months). CONCLUSION: Patients with KRASG12C-mutant mCRC had a disappointing response to standard treatments. Within the limitations of a retrospective study, these results suggest that first-line chemotherapy intensification with FOLFOXIRI is a valid option in fit patients.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Estudos Retrospectivos , Fluoruracila/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do Tratamento , Neoplasias do Colo/tratamento farmacológicoRESUMO
BACKGROUND: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. METHODS: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). RESULTS: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. CONCLUSIONS: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/terapia , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Biomarcadores Tumorais/sangue , Cetuximab , Terapia Combinada , Citocinas/sangue , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/patologia , Esofagectomia , Feminino , Fluoruracila/administração & dosagem , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Radioterapia AdjuvanteRESUMO
OBJECTIVE: This study evaluated single intra-articular injections of Hymovis MO.RE., a hyaluronic acid hexadecyl derivative (HYADD4-G), to manage post-traumatic or degenerative knee or ankle chondropathy in professional soccer players. PATIENTS AND METHODS: Twenty-five players affected by knee (n = 12) or ankle (n = 13) chondropathy were prospectively enrolled and treated by two single Hymovis MO.RE. (32 mg/4 ml) injections at the beginning of the football season (V0, baseline) and at mid-season (V1, 19-20 weeks thereafter), and were followed-up until the end of the season (V2, after further 19-20 weeks). Knee cases were evaluated using the 2000 IKDC knee subjective examination form and the modified Lysholm scoring system. Ankle cases were evaluated using the American Orthopaedic Foot Ankle Society (AOFAS) ankle-hindfoot score. Patients were also evaluated using a VAS Likert scale and a four-category scale recording both the patient's and the doctor's assessment on joint mobility in degrees and overall treatment efficacy. Adverse events, patient withdrawals and local reaction to injections were also assessed. RESULTS: In knee patients, the 2000 IKDC subjective score improved from 46.8 ± 11.4 at V0 to 83.1 ± 12.5 at V2. Their modified Lysholm score improved from 58.8 ± 8.9 at V0 to 90.6 ± 8.3 at V2. In the ankle patients, the AOFAS score improved from 52.2 ± 5.6 at V0 to 96.4 ± 4.5 at V2. VAS Likert values and subjective evaluations improved at V1 and were maintained at V2. No side effects were recorded. CONCLUSIONS: A single Hymovis MO.RE. (32 mg/4 ml) intra-articular injection, repeated after 19-20 weeks, may be a viable option to improve symptoms and function in professional soccer players suffering from knee and ankle chondropathy.
Assuntos
Articulação do Tornozelo/efeitos dos fármacos , Doenças das Cartilagens/tratamento farmacológico , Ácido Hialurônico/administração & dosagem , Articulação do Joelho/efeitos dos fármacos , Articulação do Tornozelo/fisiopatologia , Atletas , Doenças das Cartilagens/fisiopatologia , Estudos de Coortes , Seguimentos , Humanos , Ácido Hialurônico/efeitos adversos , Injeções Intra-Articulares , Articulação do Joelho/fisiopatologia , Estudos Prospectivos , Amplitude de Movimento Articular , Futebol , Resultado do TratamentoRESUMO
OBJECTIVE: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. MATERIALS AND METHODS: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann-Whitney test for continuous variables, as appropriate. RESULTS: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old, 9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations. CONCLUSION: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage, due to the therapeutic implications and cancer risk prevention in patients' relatives.
Assuntos
Adenocarcinoma , Proteína BRCA1 , Proteína BRCA2 , Neoplasias Pancreáticas , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Mutação em Linhagem Germinativa , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genéticaRESUMO
STUDY DESIGN: Description of a technique and prospective follow-up study. OBJECTIVES: The aim of this study was to present our experience in the surgical treatment of ischial pressure sores, especially recurrence. SETTING: The Department of Plastic and Reconstructive Surgery and Spinal Injuries Unit, CTO Hospital, Rome, Italy. METHODS: From 1995 to 1997, the authors used in 12 consecutive paraplegic patients, who had a grade III or IV decubitus ulcer in the ischial area only, two different and independent flaps coupled together in a 'criss-cross' musculocutaneous flap: a split-muscle gluteus maximus flap and a rhomboid fasciocutaneous local flap. The average follow-up period was 3 years and 9 months. Details of the operative procedure are presented to prove that this criss-cross closure of the ischial pressure sore beneficial for patients with spinal cord injury. RESULTS: All flaps survived; recurrence of the decubitus ulcer occurred in one patient (8%). Pressure-sore-free survival after surgery was 20 months in the patient with recurrence and an average of 26 months in patients without recurrence. CONCLUSION: The results obtained confirm this procedure to be safe and useful. We believe this technique to be a valuable alternative for the reconstruction of primary or recurrent ischial pressure ulcers.
Assuntos
Procedimentos de Cirurgia Plástica/instrumentação , Procedimentos de Cirurgia Plástica/métodos , Úlcera por Pressão/etiologia , Traumatismos da Medula Espinal/cirurgia , Retalhos Cirúrgicos/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Coxa da Perna , Adulto JovemRESUMO
Penile cancer (PC) is a typical tumor of non-industrialized countries. The incidence is 20-30 times higher in Africa and South America, considering the elevated prevalence of sexually transmitted diseases. Histologically, PC includes squamous cell carcinoma (SCPC), the most frequent, and nonsquamous carcinoma (NSCPC). Early diagnosis is the goal, whereas later diagnosis relates to poor functional outcomes and worse prognosis. The 5-year survival rate is 85% for patients with histologically regional negative lymph nodes, compared to 29%-40% for those with histologically regional positive lymph nodes. To date no new drugs are approved, and there are few new data about molecular mechanisms underlying tumorigenesis. The SCPC remains a rare tumor and the current therapeutic algorithm is based principally on retrospective analysis and less on prospective trials. In this review article, biomarkers of prognosis and efficacy of current treatments are summarized with a focus on those that have the potential to affect treatment decision-making in SCPC.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/diagnóstico , Tomada de Decisão Clínica , Neoplasias Penianas/diagnóstico , Humanos , Masculino , PrognósticoRESUMO
The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Cetuximab , Neoplasias Colorretais/imunologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Panitumumabe , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
The recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the armamentarium of treatment options for patients with colorectal cancer (CRC). In particular, the epidermal growth factor receptor (EGFR), a tyrosine kinase growth factor receptor involved in CRC development and progression, is exploited by the newest monoclonal antibody that is available for use in CRC patients. Cetuximab, the first chimeric monoclonal antibody, which has been generated against the EGFR, is currently registered in USA, Europe and worldwide, in combination with irinotecan in the treatment of metastatic CRC patients who have progressed on irinotecan containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Furthermore, a series of phase III clinical trials are currently evaluating the combination of cetuximab with standard chemotherapy regimens in the first-line treatment chemotherapy-naïve patients with metastatic CRC.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Receptores ErbB/imunologia , Animais , Anticorpos Monoclonais Humanizados , Cetuximab , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.
Assuntos
Neoplasias da Mama/sangue , Proteína Supressora de Tumor p53/biossíntese , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/patologia , Neovascularização Patológica/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
Two inhibitors of phosphatidylinositol 3-kinase (PI3K) pathway taselisib, targeting the mutant PI3K-subunit-alpha (PI3KA) and ipatasertib, AKT-inhibitor, are currently under clinical investigation in breast cancer (BC) patients. We have previously demonstrated the anti-tumor efficacy of these anti-PI3K/AKT-inibitors in combination with anti-microtubule drugs in human BC cell lines, through a complete cytoskeleton disorganization. In this work, we generated ex-vivo three-dimensional (3D) cultures from human BC as a model to test drug efficacy and to identify new molecular biomarkers for selection of BC patients suitable for anti-PI3K/AKT-inibitors treatment. We have established 3D cultures from 25/27 human BC samples, in which the ability of growth in vitro replicates the clinical and biological aggressiveness of the original tumors. According to the results of next generation sequencing analysis, a direct correlation was found between PI3KA mutations and the sensitivity in 3D models in vitro to taselisib and ipatasertib alone and combined with anti-microtubule agents. Moreover, mutations in HER and MAPK families related genes, including EGFR, KRAS and BRAF, were found in resistant samples, suggesting their potential role as negative predictive factors of response to these agents. Thus, we demonstrated that ex vivo 3D cultures from human BC patients allow a rapid and efficient drug screening for chemotherapies and targeted agents in genetically selected patients and represent an innovative model to identify new biomarkers of drug resistance.