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BACKGROUND: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. PATIENTS AND METHODS: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. RESULTS: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. CONCLUSION: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. TRIAL REGISTRATION: Clinical trial registration: NCT02925234. First registration date: 05/10/2016.
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Neoplasias Encefálicas , Inestabilidad de Microsatélites , Humanos , BiomarcadoresRESUMEN
INTRODUCTION: Despite evidence-based guidelines, variation in esophageal cancer care exists in daily practice. Many oncology networks deployed regional agreements to standardize the patient care pathway and reduce unwarranted clinical variation. The aim of this study was to explore the trends in variation of esophageal cancer care between participating hospitals of the Managed Clinical Network (MCN) in the Netherlands. MATERIALS AND METHODS: Patients with esophageal cancer diagnosed from 2012 to 2016 were selected from the Netherlands Cancer Registry. Variation on treatment strategies, lead time to start of treatment, and 2-year survival, were calculated and compared between five clusters of hospitals within the network. RESULTS: A total of 1763 patients, diagnosed in 17 hospitals, were included. 71% of all patients received treatment with a curative intent, which ranged from 69% to 77% between the clusters of hospitals in 2015-2016. Although variation in treatment modalities between the clusters was observed in 2012-2014, no significant variation existed in 2015-2016, except for patients receiving no treatment at all. The 2-year overall survival of patients receiving treatment with a curative intent did not vary significantly between the clusters of hospitals (range: 56%-63%). Nevertheless, the median lead time before patients started treatment with a curative intent varied between clusters of hospitals in 2015-2016 (range: 34-47 days; p < 0.001). CONCLUSION: Limited variation in esophageal cancer treatment between clusters of hospitals in the MCN existed. This study shows that oncology networks can promote standardization of cancer care and reduce variation between hospitals through insight into variation.
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Neoplasias Esofágicas , Humanos , Resultado del Tratamiento , Terapia Combinada , Hospitales , Países Bajos/epidemiologíaRESUMEN
BACKGROUND: Currently, metastatic hormone-sensitive prostate cancer (mHSPC) patients are often treated with docetaxel chemotherapy at the initiation of hormonal therapy. This treatment is based on the results of two pivotal trials. However, trial populations are not a representative of real-world patient populations. OBJECTIVE: We aimed to analyze whether survival rates in our daily practice cohort is comparable with those in clinical trials and to characterize the tolerability of docetaxel chemotherapy in daily practice. DESIGN SETTING AND PARTICIPANTS: In this retrospective cohort analysis, we studied 159 mHSPC patients treated with early docetaxel from April 2014 up to June 2020 in a top clinical hospital in The Netherlands. Patients were selected using hospital pharmacy records. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared the results of our cohort with the results of the cohorts of the two pivotal trials. We aimed to analyze the survival rates in our cohort and characterize the tolerability of docetaxel chemotherapy in daily practice. RESULTS AND LIMITATIONS: Despite the relatively high number of comorbidities in our daily practice cohort, overall survival of our cohort showed great similarity with that of the two pivotal trials: 60.2 mo compared with 57.6 and 59.1 mo. Furthermore, early docetaxel was well tolerated in daily practice. Nearly 90% of the patients completed the full six cycles, and polyneuropathy led to relatively few dose reductions (6.9%). CONCLUSIONS: Early docetaxel is well tolerated in daily practice. Our daily practice cohort showed great similarity in overall survival to the clinical trials. Our results might be of interest in the developing landscape of mHSPC treatment. PATIENT SUMMARY: We studied docetaxel chemotherapy for metastatic prostate cancer in daily practice. These patients have the same survival as selected patients participating in clinical trials. Docetaxel was well tolerated in daily practice.
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In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance.
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Neoplasias Colorrectales/genética , Genoma Humano/genética , Genómica/métodos , Secuenciación Completa del Genoma/métodos , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia/métodos , Estudios de Cohortes , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival. METHODS: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001). CONCLUSIONS: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.
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Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama Masculina/mortalidad , Quimiocina CXCL12/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Microambiente Tumoral , Anciano , Neoplasias de la Mama Masculina/metabolismo , Neoplasias de la Mama Masculina/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Transducción de Señal , Tasa de SupervivenciaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Síndrome Mano-Pie/epidemiología , Ácido Oxónico/administración & dosificación , Tegafur/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Capecitabina/efectos adversos , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Esquema de Medicación , Combinación de Medicamentos , Estudios de Seguimiento , Síndrome Mano-Pie/etiología , Humanos , Incidencia , Estimación de Kaplan-Meier , Ácido Oxónico/efectos adversos , Supervivencia sin Progresión , Tegafur/efectos adversosRESUMEN
OBJECTIVE: Certain polymorphisms of the DPYD gene encoding for the dihydropyrimidine dehydrogenase (DPD) enzyme are associated with fluoropyrimidine-induced toxicity. Dose reductions of the fluoropyrimidine prodrug capecitabine are recommended for patients carrying these DPYD variants to prevent toxicities. Capecitabine dose escalation after an initial genotype-guided dose reduction is advocated when treatment is well tolerated. However, practical guidelines on how to implement these dose escalations are lacking. We implemented a protocol for tolerance-guided capecitabine dosing in DPYD variant carriers and aimed to explore its effect on toxicity of treatment. PATIENTS AND METHODS: Patients receiving capecitabine-based chemotherapy for different types of solid tumors were identified retrospectively. Capecitabine doses were reduced in case of a DPYD variant (DPYD*2A, c.2846A>T, DPYD*13, or c.1236G>A) and subsequently adjusted on the basis of tolerance. Outcome was evaluated by clinical chart review and dosing characteristics from the hospital pharmacy. Results were compared with a cohort of capecitabine-treated DPYD wild-type patients. RESULTS: Of 185 patients eligible for analysis, 11 patients were heterozygous for a DPYD variant. A median dose escalation of 8.5% was achieved using the prespecified protocol. One DPYD variant carrier experienced a grade 3 toxicity after a dose escalation. Overall, DPYD variant carriers did not experience more, or more severe toxicities than DPYD wild-type patients. The total prevalence of severe toxicities in the wild-type group was 43.1% and is comparable with the literature. CONCLUSION: Tolerance-based capecitabine dose escalation did not lead to more toxicity in DPYD variant carriers compared with wild-type patients. Our results can guide future prospective research.
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Capecitabina/administración & dosificación , Dihidrouracilo Deshidrogenasa (NADP)/genética , Heterocigoto , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Guías de Práctica Clínica como Asunto/normas , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/patología , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Although targeting human epidermal growth factor receptor 2 (HER2) is a meaningful treatment in HER2-positive breast cancer, ultimately resistance develops. Androgen receptor (AR) expression and immune cell infiltration are thought to be involved in trastuzumab response and may, therefore, be of interest as additional targets for therapy in HER2-positive breast cancer. AIM: To improve insights into the presence among AR expression, immune cell infiltration and HER2, we analysed HER2-positive breast tumours. METHODS: Primary tumours of 221 patients treated with trastuzumab for metastatic disease were selected. HER2 status was centrally confirmed. AR, T-cells (CD3 and CD8), programmed cell death protein 1 (PD-1) and PD-1 ligand 1 immunohistochemical staining and M2 tumour-associated macrophages (TAMs; CD68 and CD163) immunofluorescence were performed. Tumour-infiltrating lymphocytes were evaluated by haematoxylin and eosin staining. RESULTS: Sufficient tumour material was available for 150 patients. Oestrogen receptor was expressed in 51.3% of the tumours and AR in 81.3% of the tumours. AR expression was inversely correlated with M2 TAM (Pearson's r = -0.361, P < 0.001), CD3+ (r = -0.199, P < 0.030) and CD8+ (r = -0.212, P < 0.021) T-cell infiltration. Clustering analysis showed high immune cell infiltration in AR low-expressing tumours, and low immune cell infiltration in AR-high expressing tumours. CONCLUSION: AR expression inversely correlates with immune cell infiltration in HER2-positive breast cancer.
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Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Receptores Androgénicos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The addition of trastuzumab to chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) prolongs overall survival (OS) in clinical trials. However, treatment patterns and survival in daily practice are unknown. This study aims to compare trastuzumab use and outcome in HER2-positive MBC patients in a population-based cohort with clinical trial cohorts, with a special focus on elderly patients. MBC patients treated with trastuzumab-based chemotherapy in north-east Netherlands between 2005 and 2009 were identified from 23 hospital pharmacies and the Netherlands Cancer Registry. Baseline, treatment, and survival characteristics (Kaplan-Meier analysis) were compared with those found in clinical trials and differences in patients aged less than 65 versus 65 years or more were studied. Of 225 HER2-positive MBC patients (median: 54.8 years), 130 were treated with first-line trastuzumab. In first-line treatment, the median treatment duration was 9 months and the median OS was 30.7 months, which is comparable with the OS of 31.2 months found in a clinical trial with comparable baseline characteristics. In 25 patients aged 65 years or more compared with those aged less than 65 years treated with first-line trastuzumab, patients with a history of early breast cancer had less often been treated with adjuvant chemotherapy (36 vs. 71%; P=0.001). Other baseline characteristics and OS were similar. Patient, treatment, and survival characteristics in a HER2-positive MBC population-based cohort share considerable similarities to those found in clinical trials. The influence of age on trastuzumab treatment was not detected.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
It is increasingly acknowledged that breast cancer can be an immunogenic disease. Immunogenicity appears to differ between subtypes. For instance, in triple negative breast cancer (TNBC) and HER2-positive breast cancer tumor infiltrating lymphocytes (TILs) are prognostic and predictive for response to chemotherapy containing anthracyclines, but in other subtypes they are not. Preclinical evidence suggests important immune based mechanisms of conventional chemotherapeutics, in particular anthracyclines. Early clinical studies with monoclonal antibodies targeting programmed death protein 1, programmed death-ligand 1 and cytotoxic T-lymphocyte-associated antigen 4 have shown anti-tumor efficacy. Tumor vaccines designed to increase the body's own anti-tumor immunity have shown an increased anti-tumor immunity, however clinical efficacy has not yet been demonstrated. Novel strategies will likely follow. In light of the increased interest in immune modulation, this review focuses on predictive immune-based biomarkers, immune-mediated effects from conventional therapies, as well as recent results and ongoing studies concerning immunotherapies in breast cancer.
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Neoplasias de la Mama/clasificación , Neoplasias de la Mama/terapia , Antraciclinas/uso terapéutico , Anticuerpos Monoclonales/inmunología , Biomarcadores , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Antígeno CTLA-4/inmunología , Vacunas contra el Cáncer/administración & dosificación , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias de la Mama Triple Negativas/terapiaAsunto(s)
Anticuerpos Monoclonales Humanizados , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/química , Neoplasias Colorrectales/diagnóstico por imagen , Imagen Molecular/métodos , Tomografía de Emisión de Positrones , Radioisótopos , Radiofármacos , Receptor ErbB-2/análisis , Circonio , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina , Neoplasias Colorrectales/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Valor Predictivo de las Pruebas , Trastuzumab , Resultado del Tratamiento , Adulto JovenRESUMEN
Three species of the genus Amphiesma Duméril, Bibron & Duméril, 1854 have long been confused in the literature, with each other and with other species of the genus. Amphiesma khasiense (Boulenger, 1890) has been considered to inhabit a large geographical region, extending from north-eastern India, east to Vietnam and southern Thailand. Amphiesma boulengeri (Gressitt, 1937) has been regarded as a species endemic to south-eastern China. Amphiesma inas (Laidlaw, 1901) has been recorded from West Malaysia, Thailand and Indonesia (Sumatra). A multivariate analysis of morphometric and meristic characters shows that these three species can be separated by combinations of characters in the scalation and pattern, the most obvious being the structure of the postocular streak. On the basis of our analysis and after comparison with name-bearing type specimens, Amphiesma khasiense is restricted to north-eastern India, Myanmar, western Yunnan Province of China, northern Laos and northern and western Thailand. Other populations from south-eastern China, Vietnam, other parts of Laos, Cambodia and central Thailand, which have been recorded in the literature as A. khasiense, A.johannis or Amphiesma modestum (Günther, 1875), should be referred to Amphiesma boulengeri. Amphiesma inas (Laidlaw, 1901) is a valid species endemic to mountain ranges of southern Peninsular Thailand and West Malaysia. The mention of Amphiesma inas in Sumatra is erroneous, being based on the second known specimen of Amphiesma kerinciense David & Das, 2003, which is here redescribed. A key to species of the Amphiesma khasiense group and other species sharing a greyish-brown background without conspicuous dark and pale stripes, is provided.
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Colubridae/clasificación , Distribución Animal , Estructuras Animales/anatomía & histología , Estructuras Animales/crecimiento & desarrollo , Animales , Asia , Tamaño Corporal , Colubridae/anatomía & histología , Colubridae/crecimiento & desarrollo , Femenino , Masculino , Tamaño de los ÓrganosRESUMEN
A 36-week-pregnant woman developed a symptomatic hydrocephalus. Chest imaging showed bihilar lymphadenopathy and histological examination of a mediastinal lymph node revealed non-caseating granulomas. After delivery, her neurologic complaints progressed. Placement of a ventriculoperitoneal drain (VPD) did not reduce the symptoms. However, steroids resulted in rapid disappearance of the hydrocephalus. Hydrocephalus is a very rare manifestation of sarcoidosis. The diagnosis relies on the ability of clinicians to recognize this disorder. This case shows how a difference in opinion of the several specialists involved can lead to a delay in diagnosis and treatment.
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Arteritis de Células Gigantes/complicaciones , Arteritis de Células Gigantes/diagnóstico , Necrosis/etiología , Prednisolona/uso terapéutico , Cuero Cabelludo/patología , Anciano , Diagnóstico Diferencial , Femenino , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/patología , Humanos , Necrosis/diagnóstico , Necrosis/tratamiento farmacológico , Necrosis/patología , Arterias Temporales/patología , Cicatrización de HeridasRESUMEN
Compression of the left atrium by extra-cardiac structures is a rare cause of dyspnoea or reduced exercise tolerance and can easily be visualized by transthoracic echocardiography (TTE). An impression of the left atrium visualized by TTE could be the first indication of the presence of a pathological structure dorsal to the left atrium; such a structure can, in time, compress the left atrium. The existence of this phenomenon and its clinical implications will be reviewed. The impressing structures are divided into four anatomic groups: (i) gastrointestinal structures, which are the most common, (ii) mediastinal structures, (iii) aorta and intrapericardial structures, and (iv) pulmonary structures. Explanatory examples of left atrial impression with different causes and various levels of severity are presented.