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BACKGROUND: Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. PATIENTS AND METHODS: In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery. RESULTS: The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. CONCLUSIONS: Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.
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Melanoma , Nivolumab , Humanos , Nivolumab/uso terapéutico , Ipilimumab/efectos adversos , Terapia Neoadyuvante , Melanoma/patología , Adyuvantes Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.
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Melanoma , Neoplasias Cutáneas , Humanos , Inmunoterapia , Ipilimumab , Melanoma/tratamiento farmacológico , Terapia Neoadyuvante , Reproducibilidad de los Resultados , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.
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Hemangiopericitoma , Neoplasias Meníngeas , Tumores Fibrosos Solitarios , Adulto , Hemangiopericitoma/radioterapia , Hemangiopericitoma/cirugía , Humanos , Neoplasias Meníngeas/radioterapia , Neoplasias Meníngeas/cirugía , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Tumores Fibrosos Solitarios/radioterapia , Tumores Fibrosos Solitarios/cirugíaRESUMEN
This pilot study explored the value of localized index node removal after neoadjuvant immunotherapy in patients with stage III melanoma, for use as a response indicator to guide the extent of completion lymph node dissection. Promising technology.
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Antineoplásicos Inmunológicos/uso terapéutico , Ipilimumab/uso terapéutico , Escisión del Ganglio Linfático/métodos , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Terapia Neoadyuvante , Nivolumab/uso terapéutico , Femenino , Humanos , Escisión del Ganglio Linfático/instrumentación , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Metástasis Linfática , Magnetismo , Masculino , Melanoma/diagnóstico por imagen , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos Piloto , UltrasonografíaRESUMEN
Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
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Ganglios Linfáticos/patología , Melanoma/terapia , Patología/normas , Neoplasias Cutáneas/terapia , Piel/patología , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Biopsia , Ensayos Clínicos como Asunto , Consenso , Procedimientos Quirúrgicos Dermatologicos/métodos , Dermatología/normas , Humanos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/cirugía , Oncología Médica/normas , Melanoma/patología , Terapia Neoadyuvante/métodos , Guías de Práctica Clínica como Asunto , Pronóstico , Piel/efectos de los fármacos , Neoplasias Cutáneas/patología , Manejo de Especímenes/métodos , Manejo de Especímenes/normas , Resultado del TratamientoRESUMEN
BACKGROUND: Several inflammatory markers have gained interest as prognostic factors for cancer. The aim of this study is to evaluate the inflammatory markers interleukin-6 (IL-6), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as predictive markers for aggressive behavior and early recurrences in primary, localized soft tissue sarcoma (STS). METHODS: 115 STS patients were retrospectively reviewed. IL-6 and CRP blood levels, NLR and PLR were obtained prior to treatment. Early recurrence was defined as disease relapse (local or distant) within the first year after surgery. Cox regression analysis was used to identify prognostic factors for early recurrence. RESULTS: IL-6 elevation was associated with a higher tumor grade, increased size, tumor necrosis and a higher mitotic count. NLR elevation was associated with a higher tumor grade, PLR elevation with a larger tumor size. Early recurrences were found in 24 patients (21 %). Univariable analysis revealed that tumor grade (p = 0.029), tumor size (p = 0.030, >10 cm vs < 5 cm), tumor depth (p = 0.036), necrosis on imaging (p = 0.008), mitotic count (p = 0.045, ≥20 mitoses vs 0-9 mitoses), and IL-6 level (p = 0.044) were associated with early recurrence. The factors age at diagnosis, tumor location, necrosis at pathology, (neo)adjuvant radio- or chemotherapy, resection margin, CRP level, NLR and PLR were not related to early disease recurrence. CONCLUSIONS: Increased inflammatory markers in STS are associated with an aggressive phenotype. STS patients with elevation of IL-6 may be at risk for early disease recurrence.
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BACKGROUND: Localization of non-palpable melanoma, Merkel cell carcinoma (MCC) and soft tissue sarcoma (STS) lesions can be difficult due to size, location, and obesity of patients or fibrosis due to previous treatments. Magnetic seed localization (MSL) is a common method to localize non-palpable breast lesions, but the feasibility of MSL for non-palpable melanoma, MCC and STS lesions has not yet been described. METHODS: In this retrospective single center cohort study, all consecutive patients between January 2021 and October 2023 who had a resection of a non-palpable melanoma, MCC or STS lesion guided by Sirius Pintuition, a MSL technique, were included. The primary endpoint was successful lesion localization during surgery and the secondary endpoints were seed migration, negative resection margins, and complications. RESULTS: Seventy-nine seeds were placed for 76 lesions, which were resected during 68 surgeries in 61 patients. All lesions (100 %) were localized and resected. Median time of surgery was 44 min. No seed migration was observed. A negative resection margin was achieved for 60 (78.9 %) lesions. Clavien Dindo grade ≥2 complications occurred in 7.4 %. CONCLUSION: Magnetic seed localization with Sirius Pintuition is feasible for both non-palpable melanoma, MCC, and STS lesions.
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BACKGROUND: Little is known about the factors that drive metastasis formation in colorectal cancer (CRC). Here, we set out to identify genes and proteins in patients with colorectal liver metastases that correlate with early disease recurrence. Such factors may predict a propensity for metastasis in earlier stages of CRC. METHODS: Gene expression profiling and proteomics were used to identify differentially expressed genes/proteins in resected liver metastases that recurred within 6 months following liver surgery vs those that did not recur for >24 months. Expression of the identified genes/proteins in stage II (n=243) and III (n=176) tumours was analysed by immunohistochemistry on tissue microarrays. Correlation of protein levels with stage-specific outcome was assessed by uni- and multivariable analyses. RESULTS: Both gene expression profiling and proteomics identified Maspin to be differentially expressed in colorectal liver metastases with early (<6 months) and prolonged (>24 months) time to recurrence. Immunohistochemical analysis of Maspin expression on tumour sections revealed that it was an independent predictor of time to recurrence (log-rank P=0.004) and CRC-specific survival (P=0.000) in stage III CRC. High Maspin expression was also correlated with mucinous differentiation. In stage II CRC patients, high Maspin expression did not correlate with survival but was correlated with a right-sided tumour location. CONCLUSION: High Maspin expression correlates with poor outcome in CRC after spread to the local lymph nodes. Therefore, Maspin may have a stage-specific function possibly related to tumour cell dissemination and/or metastatic outgrowth.
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Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Serpinas/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/genética , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Serpinas/genéticaRESUMEN
Patients with liver metastases from colon carcinoma show highly variable responses to chemotherapy and tumor recurrence is frequently observed. Therapy-resistant cancer stem cells have been implicated in drug resistance and tumor recurrence. However, the factors determining therapy resistance and tumor recurrence are poorly understood. The aim of this study was to gain insight into these mechanisms by comparing the proteomes of patient-derived cancer stem cell cultures and their differentiated isogenic offspring. We established colonosphere cultures derived from resection specimens of liver metastases in patients with colon cancer. These colonospheres, enriched for colon cancer stem cells, were used to establish isogenic cultures of stably differentiated nontumorigenic progeny. Proteomics based on one-dimensional gel electrophoresis coupled to nano liquid chromatography tandem MS was used to identify proteome differences between three of these paired cultures. The resulting data were analyzed using Ingenuity Pathway Software. Out of a total data set of 3048 identified proteins, 32 proteins were at least twofold up-regulated in the colon cancer stem cells when compared with the differentiated cells. Pathway analysis showed that "cell death " regulation is strikingly different between the two cell types. Interestingly, one of the top-up-regulated proteins was BIRC6, which belongs to the class of Inhibitor of Apoptosis Proteins. Knockdown of BIRC6 sensitized colon cancer stem cells against the chemotherapeutic drugs oxaliplatin and cisplatin. This study reveals that differentiation of colon cancer stem cells is accompanied by altered regulation of cell death pathways. We identified BIRC6 as an important mediator of cancer stem cell resistance against cisplatin and oxaliplatin. Targeting BIRC6, or other Inhibitors of Apoptosis Proteins, may help eradicating colon cancer stem cells.
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Adenocarcinoma/secundario , Diferenciación Celular , Neoplasias del Colon/patología , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Hepáticas/secundario , Células Madre Neoplásicas/metabolismo , Adenocarcinoma/metabolismo , Antineoplásicos/farmacología , Cisplatino/farmacología , Neoplasias del Colon/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Neoplasias Hepáticas/metabolismo , Anotación de Secuencia Molecular , Terapia Molecular Dirigida , Células Madre Neoplásicas/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Mapas de Interacción de Proteínas , Proteómica , Piridinas/farmacología , Esferoides Celulares , Espectrometría de Masas en Tándem , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
INTRODUCTION: The development of desmoid fibromatosis (DF) is associated with pregnancy. The current treatment consensus recommends active surveillance (AS). However, data in pregnancy-associated DF is scarce and it is uncertain whether AS is the best management strategy for this DF-subgroup. The aim of this study was to describe demographic, tumor, obstetric, treatment characteristics and treatment outcome in pregnancy-associated DF. METHODS: Female DF patients who were 18-50 years old at time of diagnosis (2000-2020) and had a history (≤5 years) of pregnancy at time of diagnosis were included. RESULTS: Overall, 62 patients were included. The most common locations were abdominal wall (74%), pelvis (10%) and extremities (10%). Mutational analysis was conducted in 31 patients of which 94% had CTNNB1-mutations. Ten patients (16%) were diagnosed during pregnancy, while the remainder were diagnosed after pregnancy with a median time from delivery to diagnosis of 19 months (1-60). The frontline management was AS in 38 patients (61%) of whom 12 (33%) developed progressive disease and surgery in 23 patients (37%). In total, 30 patients underwent surgery and five had local recurrence (17%). Positive resection margins were no prognostic factor. Nine patients received systemic treatment in second- or third-line. CONCLUSIONS: Pregnancy-associated DF generally has an indolent behavior, where our results underscore the difficulty of establishing a clear definition of this entity. This study shows that AS should be the frontline management strategy for pregnancy-associated DF. When active treatment is indicated, surgery is a good option with low recurrence rates, even with positive (R1) resection margins.
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Fibromatosis Agresiva , Embarazo , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Fibromatosis Agresiva/genética , Fibromatosis Agresiva/terapia , Estudios Retrospectivos , Márgenes de Escisión , Recurrencia Local de Neoplasia/cirugía , Resultado del TratamientoRESUMEN
INTRODUCTION: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfusion (ILP). In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies. METHODS: All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years. RESULTS: Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group. CONCLUSION: We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Radioterapia Adyuvante , Melfalán , Quimioterapia del Cáncer por Perfusión Regional/efectos adversos , Factor de Necrosis Tumoral alfa , Sarcoma/cirugía , Neoplasias de los Tejidos Blandos/cirugía , Extremidades/patología , Recuperación del Miembro , Perfusión , Recurrencia Local de Neoplasia/cirugíaRESUMEN
BACKGROUND: The pro-inflammatory cytokine interleukin-6 (IL-6) plays a role in cancer development and progression, but research into the predictive value of IL-6 on postoperative outcome in soft tissue sarcoma (STS) is scarce. The purpose of this study is to investigate the predictive value of serum IL-6 level for the achievement of assumed (post)operative outcome after STS surgery, the so-called textbook outcome. METHODS: Preoperative IL-6 serum levels were collected in all patients with a STS at first presentation between February 2020 and November 2021. Textbook outcome was defined as a R0 resection, no complications, no blood transfusions, no reoperation within the postoperative period, no prolonged hospital stay, no hospital readmission within 90-days, and no mortality within 90-days. Factors associated with textbook outcome were determined by multivariable analysis. RESULTS: Among 118 patients with primary, non-metastatic STS, 35.6% achieved a textbook outcome. Univariate analysis showed that smaller tumor size (p = 0.026), lower tumor grade (p = 0.006), normal hemoglobin (Hb, p = 0.044), normal white blood cell (WBC) count (p = 0.018), normal C-reactive protein (CRP) serum level (p = 0.002) and normal IL-6 serum level (p = 1.5 × 10-5) were associated with achieving textbook outcome after surgery. Multivariable analysis showed that elevated IL-6 serum level (p = 0.012) was significantly associated with not achieving a textbook outcome. CONCLUSIONS: Increased IL-6 serum level is predictive for not achieving a textbook outcome after surgery for primary, non-metastatic STS.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Interleucina-6 , Pronóstico , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , CitocinasRESUMEN
BACKGROUND: Prior to the advent of effective systemic therapy for melanoma, isolated limb perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma (ITM). However, many patients who are now treated by ILP will have received prior immunotherapy. We sought to compare response rates to ILP in patients who had previously received immunotherapy compared to immunotherapy naive patients. MATERIALS AND METHODS: All patients who underwent ILP for ITM between January 2015 and July 2020 for melanoma were identified retrospectively from two tertiary institutions. Surgical morbidity and oncologic outcomes were compared between immunotherapy naive and immunotherapy pre-treated patients. RESULTS: 97 perfusions were performed for melanoma. Of those, 18 patients had undergone prior immunotherapy. There were no differences in clinicopathological characteristics or perioperative outcomes between cohorts. Surgical morbidity and local toxicity were similar between both cohorts. Patients who underwent immunotherapy prior to ILP had significantly decreased complete response (CR) rates compared with immunotherapy-naïve (6% vs 47%, p = 0.0018) and a significantly decreased overall survival (OS) and distant progression free survival (DPFS) (p = 0.0031 and p = 0.0006 respectively). There was no difference in overall response (OR), partial response (PR), stable disease (SD), progressive disease (PD) and local progression free survival (LPFS) between cohorts. CONCLUSION: Oncological outcomes and complete response rates are worse in patients who have received immunotherapy prior to ILP compared with immunotherapy naïve patients. Despite this, ILP is still a valuable second line treatment for local control in patients who have multiple, bulky and/or recurrent ITM post immunotherapy.
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Melanoma , Neoplasias Primarias Secundarias , Neoplasias Cutáneas , Quimioterapia del Cáncer por Perfusión Regional/efectos adversos , Extremidades/patología , Humanos , Inmunoterapia , Melanoma/tratamiento farmacológico , Melanoma/patología , Melfalán , Perfusión , Estudios Retrospectivos , Neoplasias Cutáneas/patología , Factor de Necrosis Tumoral alfaRESUMEN
OBJECTIVE: In the Netherlands, the surgical mask is part of the standard surgical attire even for the non-sterile personnel in the operation theatre. Solid evidence on the effect on postoperative infection rates is missing. Due to a national scarcity in surgical masks during the first wave of the COVID-19 crisis the usage of these masks was decreased. In our tertiary referral centre for Surgical Oncology, this led to the decision that, for a period of ten weeks, the surgical masks were only being used by the sterile surgical team and not by non-sterile operation theatre personnel. This retrospective study evaluates the influence of this intervention in terms of postoperative wound infection rates. DESIGN: Retrospective cohort study. METHOD: Consecutive patients undergoing surgery during the first COVID-19 wave (2-3-2020 until 11-05-2020) were compared with patients undergoing surgery in the same period a year earlier. Patients undergoing surgery for soft-tissue malignancies were included. Intra-abdominal surgery was excluded. Primary outcome measurement was wound infection rate within 30 days following surgery. Secondary, a cost reduction analysis was made. RESULTS: In the COVID-19 wave, a total of 219 patients underwent surgery for soft-tissue malignancies, compared to 241 a year earlier. The incidence of postoperative wound infection was 58/460 (12.6%) for the total cohort. There was no difference in infection rate between the COVID-19 period and the same period in 2019; 25/219 (11,4%; 95% CI: 7,8-16,4)) vs. 33/241 (13,7%; 95% CI: 9,8-18,6), p = 0,46) respectively. During the COVID-19 wave, a total of 6.400 of surgical masks were used by the personnel in the operation theatre complex, compared to a total of 11.000 in the same period in 2019. This resulted in a reduction of 42% in usage of surgical masks. CONCLUSION: Based on this mono-centric, explorative retrospective cohort study, it seems that omitting the surgical mask for the non-sterile operation theatre personnel does not influence the postoperative wound infection rate. Despite the fact that our sample size is small, the impressive reduction in usage of 42% demands further research initiatives on a larger scale.
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COVID-19 , Máscaras , Humanos , Estudios Retrospectivos , SARS-CoV-2 , Infección de la Herida Quirúrgica/epidemiología , Infección de la Herida Quirúrgica/prevención & controlRESUMEN
BACKGROUND: Stage IIB/IIC (8th AJCC) melanoma patients are known to have high-risk primary tumors, however they follow the same routine to sentinel lymph node biopsy (SLNB) as more low risk tumors. Guidelines are not conclusive regarding the use of preoperative imaging for these patients. The aim of this pilot study was to assess the value of ultrasound (US) and 18F-FDG PET/CT prior to lymphoscintigraphy (LSG) and SLNB for stage IIB/C melanoma patients. METHODS: From 2019-04 till 2020-01, all stage IIB/C melanoma patients underwent US of the regional lymph nodes and whole body 18F-FDG PET/CT before their planned LSG and SLNB. Suspected metastases were confirmed with fine needle aspiration (FNA), prior to surgery. RESULTS: In total 23 patients were screened: six had metastases detected by imaging, two by US, one by 18F-FDG PET/CT and three were detected by both imaging modalities. All metastases were nodal and therefore treatment was altered to lymph node dissection and all but one also received adjuvant therapy. Eight (47%) of the 17 patients without macroscopic disease, still had a positive SN. Sensitivity, specificity and false negative rate for US and 18F-FDG PET/CT were 36%, 89%, 64% and 29%, 100% and 71%, respectively. CONCLUSION: Preoperative negative imaging does not exclude the presence of SN metastases, therefore SLNB cannot be foregone. However, US detected metastases in 22% of patients, altering their treatment, which suggests it is effective in the work-up of stage IIB/C melanoma. Staging with 18F-FDG PET/CT is not of added value prior to LSG and SLNB and should therefore not be used.
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Metástasis Linfática/diagnóstico por imagen , Melanoma/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Cutáneas/diagnóstico por imagen , Ultrasonografía , Imagen de Cuerpo Entero , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja Fina , Femenino , Fluorodesoxiglucosa F18 , Humanos , Metástasis Linfática/patología , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Proyectos Piloto , Estudios Prospectivos , Radiofármacos , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive tumour. Adequate margins have a positive impact on recurrence rates. The aim of this study is to assess how adequate margins are achieved and secondly which additional treatment modalities might be necessary to achieve adequate margins. MATERIAL & METHODS: Patients with DFSP treated between 1991 and 2016 at three tertiary centres were included. Patient- and tumour characteristics were obtained from a prospectively held database and patient files. RESULTS: A total of 279 patients with a median age of 39 (Interquartile range [IQ], 31-50) years and a median follow-up of 50 (IQ, 18-96) months were included. When DFSP was preoperatively confirmed by biopsy and resected with an oncological operation in a tertiary centre, in 86% was had clear pathological margins after one excision. Wider resection margins were significantly correlated with more reconstructions (p = 0.002). A substantial discrepancy between the primary surgical macroscopic and the pathological margins was found with a median difference of 22 (range, 10-46) mm (Fig. 1). There was no significant influence of the width of the pathological clear margins (if > 1 mm) and the recurrence rate (p = 0.710). CONCLUSION: The wider the resection margins, the more likely it is to obtain clear pathological margins, but the more likely patients will need any form of reconstruction after resection. The aim of the primary excision should be wide surgical resection, where the width of the margin should be balanced against the need for reconstructions and surgical morbidity.
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Dermatofibrosarcoma/cirugía , Procedimientos Quirúrgicos Dermatologicos/métodos , Márgenes de Escisión , Neoplasias Cutáneas/cirugía , Adulto , Dermatofibrosarcoma/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Neoplasias Cutáneas/diagnósticoRESUMEN
BACKGROUND: Health-related quality of life (HRQoL) data of sarcoma survivors are scarce and the impact of age remains unclear. The aims of this population-based study were to (i) compare HRQoL scores amongst three age-groups [adolescents and young adults (AYA, aged 18-39 years), older adults (OA, aged 40-69 years) and elderly (aged ≥70 years)]; (ii) compare HRQoL of each sarcoma survivor age group with an age- and sex-matched normative population sample; (iii) determine factors associated with low HRQoL per age group. METHODS: Dutch sarcoma survivors, who were 2-10 years after diagnosis, were invited to complete the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions questionnaire on HRQoL. RESULTS: In total, 1099 survivors (58% response rate) completed the questionnaire: 186 AYAs, 748 OAs and 165 elderly. The median time since diagnosis for all patients was 5.2 years. Bone sarcomas were seen in 41% of AYAs, 22% of OAs and in 16% of elderly survivors (P < 0.01). AYA and OA survivors reported statistically significant and clinically meaningful worse physical, role, cognitive, emotional and social functioning compared with a matched norm population, which was not the case for elderly survivors. AYAs reported significantly worse scores on emotional and cognitive functioning compared with OA and elderly survivors. Malignant peripheral nerve sheath tumour, osteosarcoma and chordoma were the subtypes of which survivors reported the lowest HRQoL scores in comparison with the norm. For all age groups, chemotherapy, having a bone sarcoma and having comorbidities were most frequently associated with low scores on HRQoL subscales, whereas a shorter time since diagnosis was not. CONCLUSION: In this nationwide sarcoma survivorship study, the disease and its treatment had relatively more impact on the HRQoL of AYA and OA survivors than on elderly survivors. These results emphasise the need for personalised follow-up care that not only includes risk-adjusted care related to disease relapse, but also age-adjusted care.
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Neoplasias Óseas , Osteosarcoma , Adolescente , Adulto , Anciano , Neoplasias Óseas/epidemiología , Neoplasias Óseas/terapia , Humanos , Calidad de Vida , Encuestas y Cuestionarios , Sobrevivientes , Adulto JovenRESUMEN
Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ipilimumab/administración & dosificación , Melanoma/tratamiento farmacológico , Nivolumab/administración & dosificación , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunoterapia/efectos adversos , Interferón gamma/genética , Ipilimumab/efectos adversos , Masculino , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Mutación/genética , Terapia Neoadyuvante/efectos adversos , Estadificación de Neoplasias , Nivolumab/efectos adversos , RecurrenciaRESUMEN
BACKGROUND: Oxaliplatin and 5-fluorouracil (5-FU) currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumour responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that oncogenic KRAS in colorectal tumour cells sensitises these cells to chemotherapy. METHODS: FACS analysis was used to determine cell-cycle distribution and the percentage of apoptotic and mitotic cells. A multiplexed RT-PCR assay was used to identify KRAS-controlled apoptosis regulators after exposure to 5-FU or oxaliplatin. Lentiviral expression of short-hairpin RNAs was used to suppress p53 or Noxa. RESULTS: Oncogenic KRAS sensitised colorectal tumour cells to oxaliplatin and 5-FU in a p53-dependent manner and promoted p53 phosphorylation at Ser37 and Ser392, without affecting p53 stabilisation, p21 induction, or cell-cycle arrest. Chemotherapy-induced expression of the p53 target gene Noxa was selectively enhanced by oncogenic KRAS. Suppression of Noxa did not affect p21 induction or cell-cycle arrest, but reduced KRAS/p53-dependent apoptosis after exposure to chemotherapy in vitro and in tumour xenografts. Noxa suppression did not affect tumour growth per se, but strongly reduced the response of these tumours to chemotherapy. CONCLUSION: Oncogenic KRAS determines the cellular response to p53 activation by oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa.
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Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo/administración & dosificación , Genes p53 , Genes ras , Compuestos Organoplatinos/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Animales , Apoptosis , Ciclo Celular/efectos de los fármacos , Células HCT116 , Humanos , Masculino , Ratones , Oxaliplatino , Fosforilación , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.