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1.
Int J Hyperthermia ; 40(1): 2248424, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37611915

RESUMO

INTRODUCTION: Neoadjuvant chemotherapy and radiotherapy for the management of soft tissue sarcomas (STS) are still preferably delivered sequentially, with or without concurrent hyperthermia. Concurrent delivery of chemo-, radio- and thermotherapy may produce synergistic effects and reduce chemotherapy-free intervals. The few available studies suggest that concurrent chemoradiation (CRT) has a greater local effect. Data on the efficacy and toxicity of adding hyperthermia to CRT (CRTH) are sparse. MATERIALS AND METHODS: A cohort of 101 patients with STS of the extremities and trunk who received CRT (n = 33) or CRTH (n = 68) before resection of macroscopic tumor (CRT: n = 19, CRTH: n = 49) or re-resection following a non-oncological resection, so called 'whoops procedure', (CRT: n = 14, CRTH: n = 19) were included in this retrospective study. CRT consisted of two cycles of doxorubicine (50 mg/m2 on d2) plus ifosfamide (1500 mg/m2 on d1-5, q28) plus radiation doses of up to 60 Gy. Hyperthermia was delivered in two sessions per week. RESULTS: All patients received the minimum dose of 50 Gy. Median doses of ifosfamide and doxorubicin were comparable between CRT (75%/95%) and CRTH (78%/97%). The median number of hyperthermia sessions was seven. There were no differences in acute toxicities. Major wound complications occurred in 15% (CRT) vs. 25% (CRTH) (p = 0.19). In patients with macroscopic disease, the addition of hyperthermia resulted in a tendency toward improved remission: regression ≥90% occurred in 21/48 (CRTH) vs. 4/18 (CRT) patients (p = 0.197). With a median postoperative follow-up of 72 months, 6-year local control and overall survival rates for CRTH vs. CRT alone were 85 vs. 78% (p = 0.938) and 79 vs. 71% (p = 0.215). CONCLUSIONS: Both CRT and CRTH are well tolerated with an expected rate of wound complications. The results suggest that adding hyperthermia may improve tumor response.


Assuntos
Hipertermia Induzida , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Terapia Neoadjuvante , Ifosfamida , Estudos Retrospectivos , Sarcoma/terapia , Neoplasias de Tecidos Moles/terapia , Hipertermia , Quimiorradioterapia , Doxorrubicina/uso terapêutico
2.
Am J Pathol ; 191(4): 602-617, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33497701

RESUMO

Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6-STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing-based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4-STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6-STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co-transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6-dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT6/genética , Tumores Fibrosos Solitários/genética , Éxons/genética , Feminino , Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/metabolismo , Tumores Fibrosos Solitários/patologia
3.
Am J Pathol ; 191(7): 1314-1324, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33887215

RESUMO

Solitary fibrous tumors (SFTs) harbor activating NAB2-STAT6 gene fusions. Different variants of the NAB2-STAT6 gene fusion have been associated with distinct clinicopathologic features. Lipomatous SFTs are a morphologic variant of SFTs, characterized by a fat-forming tumor component. Our aim was to evaluate NAB2-STAT6 fusion variants and to further study the molecular genetic features in a cohort of lipomatous SFTs. A hybrid-capture-based next-generation sequencing panel was employed to detect NAB2-STAT6 gene fusions at the RNA level. In addition, the RNA expression levels of 507 genes were evaluated using this panel, and were compared with a control cohort of nonlipomatous SFTs. Notably, 5 of 11 (45%) of lipomatous SFTs in the current series harbored the uncommon NAB2 exon 4-STAT6 exon 4 gene fusion variant, which is observed in only 0.9% to 1.4% of nonlipomatous SFTs. Furthermore, lipomatous SFTs displayed significant differences in gene expression compared with their nonlipomatous counterparts, including up-regulation of the gene peroxisome proliferator activated receptor-γ (PPARG). Peroxisome proliferator activated receptor-γ is a nuclear receptor regulating adipocyte differentiation, providing a possible explanation for the fat-forming component in lipomatous SFTs. In summary, the current study provides a possible molecular genetic basis for the distinct morphologic features of lipomatous SFTs.


Assuntos
Adipócitos/patologia , PPAR gama/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT6/genética , Tumores Fibrosos Solitários/genética , Adulto , Idoso , Diferenciação Celular/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Tumores Fibrosos Solitários/patologia , Regulação para Cima
4.
Laryngorhinootologie ; 101(4): 298-303, 2022 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-34583388

RESUMO

Traditionally, the multimodal therapy concept for differentiated thyroid carcinomas consists of thyroidectomy with neck dissection (for cN + neck) and adjuvant radioiodine ablation with subsequent risk-adapted TSH suppression. The extent of radioiodine uptake in metastatic thyroid carcinomas plays a significant role is significant in terms of prognosis. Radioiodine refractory lesions are characterized by the lack of radioiodine uptake in combination with the lack of decrease in the tumor marker thyroglobulin as well as signs of progression on imaging. Due to the mostly indolent course over a long period of time, a wait-and-see strategy in combination with local management of distant metastase symptom relief appears to be primarily sufficient. By evidence for change in tumor dynamics, the need for a multi-tyrosine kinase inhibitor (sorafenib, lenvatinib)-based systemic therapy should be thoroughly evaluated. These substances are mostly associated with an unfavorable side-effect profile (diarrhea, rash, arterial hypertension, local wound healing disorders), which leads to a non-negligible rate of treatment-associated morbidity and a high number of treatment interruptions. For this reason, two selective RET inhibitors (selpercatinib, pralsetinib) for differentiated thyroid carcinomas were approved by the FDA in 2020. A new perspective for the future would be the variable re-differentiation strategies, which aim to increase the sensitivity of tumor cells to radioiodine.


Assuntos
Adenocarcinoma , Neoplasias da Glândula Tireoide , Adenocarcinoma/cirurgia , Humanos , Radioisótopos do Iodo/uso terapêutico , Esvaziamento Cervical , Prognóstico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapia , Tireoidectomia
5.
Med Sci Monit ; 24: 4198-4203, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29920509

RESUMO

BACKGROUND In many studies, confocal laser endomicroscopy (CLE) has proven to be a useful tool in pulmonology; nevertheless, the application in this field is still experimental. By contrast, CLE is almost a standard technique in gastroenterology. The aim of the present study was to demonstrate the identification of bronchoalveolar lavage (BAL) components applying CLE, using a dye. MATERIAL AND METHODS In 21 patients with various underlying diseases a bronchoscopy with BAL was performed. As in routine clinical practice common, BAL fluid (BALF) was analyzed in terms of cytologic, virologic, and microbiologic aspects. To one fraction of BALF, we added acriflavine. After centrifugation CLE was applied and the video sequences were analyzed by an experienced investigator. RESULTS Using CLE, BALF components (such as alveolar macrophages or leucocytes) could be easily identified. A further subdivision of leucocytes (neutrophilic, eosinophilic granulocytes, and lymphocytes) was not possible. Analogous to conventional cytology, a precise distinction of lymphocyte subpopulation (cd 4/cd 8 ratio) was not feasible. In terms of quantification, this is still the application field of flow cytometry and immunohistochemistry. CONCLUSIONS Using CLE, alveolar macrophages and leucocytes in stained BALF can be differentiated independent of smoking status. Further studies should be initiated in order to subclassify leucocytes in eosinophilic, neutrophilic granulocytes, and lymphocytes, which is important for routine clinical practice.


Assuntos
Lavagem Broncoalveolar/métodos , Broncoscopia/métodos , Endoscopia/métodos , Acriflavina , Adulto , Idoso , Idoso de 80 Anos ou mais , Lavagem Broncoalveolar/instrumentação , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Microscopia Confocal/métodos , Pessoa de Meia-Idade , Estudos Prospectivos
6.
J Mol Diagn ; 26(5): 387-398, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38395409

RESUMO

Small blue round cell sarcomas (SBRCSs) are a heterogeneous group of tumors with overlapping morphologic features but markedly varying prognosis. They are characterized by distinct chromosomal alterations, particularly rearrangements leading to gene fusions, whose detection currently represents the most reliable diagnostic marker. Ewing sarcomas are the most common SBRCSs, defined by gene fusions involving EWSR1 and transcription factors of the ETS family, and the most frequent non-EWSR1-rearranged SBRCSs harbor a CIC rearrangement. Unfortunately, currently the identification of CIC::DUX4 translocation events, the most common CIC rearrangement, is challenging. Here, we present a machine-learning approach to support SBRCS diagnosis that relies on gene expression profiles measured via targeted sequencing. The analyses on a curated cohort of 69 soft-tissue tumors showed markedly distinct expression patterns for SBRCS subgroups. A random forest classifier trained on Ewing sarcoma and CIC-rearranged cases predicted probabilities of being CIC-rearranged >0.9 for CIC-rearranged-like sarcomas and <0.6 for other SBRCSs. Testing on a retrospective cohort of 1335 routine diagnostic cases identified 15 candidate CIC-rearranged tumors with a probability >0.75, all of which were supported by expert histopathologic reassessment. Furthermore, the multigene random forest classifier appeared advantageous over using high ETV4 expression alone, previously proposed as a surrogate to identify CIC rearrangement. Taken together, the expression-based classifier can offer valuable support for SBRCS pathologic diagnosis.


Assuntos
Sarcoma de Células Pequenas , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Estudos Retrospectivos , Sarcoma de Células Pequenas/diagnóstico , Sarcoma de Células Pequenas/genética , Sarcoma de Células Pequenas/patologia , Fatores de Transcrição/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Análise de Sequência de RNA , Proteínas de Fusão Oncogênica/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise
7.
Eur J Cancer ; 207: 114144, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38852290

RESUMO

PURPOSE: Providing patient access to precision oncology (PO) is a major challenge of clinical oncologists. Here, we provide an easily transferable model from strategic management science to assess the outreach of a cancer center. METHODS: As members of the German WERA alliance, the cancer centers in Würzburg, Erlangen, Regensburg and Augsburg merged care data regarding their geographical impact. Specifically, we examined the provenance of patients from WERA´s molecular tumor boards (MTBs) between 2020 and 2022 (n = 2243). As second dimension, we added the provenance of patients receiving general cancer care by WERA. Clustering our catchment area along these two dimensions set up a four-quadrant matrix consisting of postal code areas with referrals towards WERA. These areas were re-identified on a map of the Federal State of Bavaria. RESULTS: The WERA matrix overlooked an active screening area of 821 postal code areas - representing about 50 % of Bavaria´s spatial expansion and more than six million inhabitants. The WERA matrix identified regions successfully connected to our outreach structures in terms of subsidiarity - with general cancer care mainly performed locally but PO performed in collaboration with WERA. We also detected postal code areas with a potential PO backlog - characterized by high levels of cancer care performed by WERA and low levels or no MTB representation. CONCLUSIONS: The WERA matrix provided a transparent portfolio of postal code areas, which helped assessing the geographical impact of our PO program. We believe that its intuitive principle can easily be transferred to other cancer centers.

8.
Int J Colorectal Dis ; 28(8): 1057-64, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23404343

RESUMO

PURPOSE: This study aims to report our multicenter experience with diagnosis, management, and prognosis of anorectal gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS: We retrospectively reviewed cases treated and/or followed up at our institutions in the period 2000-2011. RESULTS: Fifteen patients were identified (eight men and seven women; mean age, 55 years). Presenting symptoms were rectal/perirectal (eight), rectovaginal space (four), or retrovesical/prostatic (three) mass. Primary surgical treatment was local excision (six), deep anterior resection (eight), and palliative diagnostic excision (one). Tumor mean size was 4.8 cm. All but two cases were high risk (Miettinen and Lasota, Semin Diagn Pathol 23:70-83, 2006). R0 resection was achieved in 46% of cases: one of six local excisions vs. five of seven deep anterior resection (16 vs. 71%, respectively). All three cases who received total mesorectal excision had R0. Non-R0 status was mainly due to opening of tumor capsule at surgery (Rx). Seven of 14 patients (50%) developed ≥1 pelvic local recurrences at a mean period of 48.4 months (mean follow-up, 61.6 months). Only two patients developed distant metastasis (adrenal, liver, and peritoneal). Recurrences developed after Rx (three), R1 (two), and unknown R-status (two). Successful mutational analysis in 13 patients revealed KIT mutations in all (10 exon 11, 2 exon 9, and 1 exon 13). CONCLUSION: Our results confirm the high local recurrence rate of anorectal GISTs (50%) which correlates with the common practice of suboptimal oncological primary tumor resection (Rx or R1 = 7/13). This uncommon subset of GISTs needs more standardized oncological surgical approach to minimize the propensity for local disease recurrence.


Assuntos
Neoplasias do Ânus/patologia , Neoplasias do Ânus/terapia , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/terapia , Recidiva Local de Neoplasia/terapia , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Neoplasias do Ânus/diagnóstico por imagem , Neoplasias do Ânus/genética , Sequência de Bases , Benzamidas/uso terapêutico , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Radiografia , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/genética , Padrões de Referência , Estudos Retrospectivos , Resultado do Tratamento
9.
Support Care Cancer ; 21(6): 1743-50, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23344656

RESUMO

BACKGROUND: Early integration of palliative care into cancer disease management is beneficial for patients with advanced tumors. However, little is known about the association of palliative care interventions with symptom burden and treatment aggressiveness at the end of life (EoL). METHODS: To assess determinants of symptom burden and treatment intensity at the EoL, a retrospective chart review was conducted in university cancer clinic outpatients who died between July 2009 and June 2011. The objective was the correlation of place of death, palliative care utilization, prior EoL discussion, and social background (determinant variables) with symptom burden and treatment intensity (outcome variables). RESULTS: Ninety-six patients (61 men and 35 women) died; the mean age at death was 62.4 years (range 24-83). Mean duration of treatment was 17.9 months (range 1-129). Data on the last 14 days (3) of life were available for 62 (44) patients. Forty-seven patients received aggressive EoL care which was strongly associated with hospital death (p = 0.000, χ2 test). The 15 patients having used palliative care services or dying in a palliative care unit (PCU) had fewer symptoms (p = 0.006, t test) and interventions (p = 0.000, t test) at the EoL. Having addressed EoL issues was correlated with fewer procedures during the last 3 days (p = 0.035, t test). CONCLUSIONS: Most cancer patients receive aggressive EoL care interfering with quality of life. Despite limitations by small sample size and missing data, the results suggest that palliative care utilization is associated with reduced symptom burden and intensity of treatment at the EoL. Timely discussion of EoL issues may reduce the number of unnecessary interventions and facilitate referral to the PCU.


Assuntos
Avaliação das Necessidades , Neoplasias/terapia , Avaliação de Processos e Resultados em Cuidados de Saúde , Cuidados Paliativos/métodos , Assistência Terminal/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Procedimentos Clínicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Oncologia , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Cuidados Paliativos/estatística & dados numéricos , Qualidade de Vida , Estudos Retrospectivos , Assistência Terminal/estatística & dados numéricos , Adulto Jovem
10.
Cancers (Basel) ; 15(24)2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38136436

RESUMO

Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making.

11.
Virchows Arch ; 480(5): 1115-1120, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34389899

RESUMO

Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts and hemosiderotic fibrolipomatous tumor (HFLT) are two rare low-grade locally recurring neoplasms with predilection for the foot/ankle. Recent studies support a close link between the two entities, and origin of PHAT from HFLT and occurrence of hybrid HFLT/PHAT have been documented. Both lesions often harbor TGFBR3 or MGEA5 rearrangements. Rare sarcomas originating from HFLT/PHAT have been reported, typically resembling myxofibrosarcoma or myxoinflammatory fibroblastic sarcoma. We describe a novel SMARCA4-deficient undifferentiated sarcoma with rhabdoid features originating from hybrid HFLT/PHAT in the foot of a 54-year-old male. The tumor pursued a highly aggressive course with rapid regrowth after resection and multiple metastases resulting in patient's death within 5 months, despite systemic chemotherapy. Immunohistochemistry revealed SMARCA4 loss in the undifferentiated sarcoma, but not in the HFLT/PHAT. Molecular testing confirmed TGFBR3/MGEA5 rearrangements. This report expands the phenotypes of sarcomas developing from pre-existing PHAT/HFLT.


Assuntos
Fibrossarcoma , Lipoma , Neoplasias Hepáticas , Sarcoma , Neoplasias de Tecidos Moles , DNA Helicases , Fibrossarcoma/patologia , Humanos , Lipoma/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteínas Nucleares/genética , Sarcoma/genética , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética
12.
J Clin Med ; 11(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35956173

RESUMO

Oral antitumor therapeutics (OAT) bear a high risk for medication errors, e.g., due to drug-drug or drug-food interactions or incorrect drug intake. Advanced age, organ insufficiencies, and polymedication are putting uro-oncological patients at an even larger risk. This analysis sets out to (1) investigate the frequency and relevance of medication errors in patients with prostate cancer or renal cell carcinoma treated with OAT and (2) compile recommendations for clinical practice. This post-hoc subgroup analysis used data collected in the randomized AMBORA trial (2017-2020; DRKS00013271). Clinical pharmacologists/pharmacists conducted advanced medication reviews over 12 weeks after initiation of a new oral regimen and assessed the complete medication process for drug-related problems. Medication errors related to either the OAT, prescribed or prescription-free concomitant medication, or food were classified regarding cause and severity. We identified 67 medication errors in 38 patients within the complete medication within 12 weeks. Thereof, 55% were detected at therapy initiation, 27% were caused by the patients, and 25% were drug-drug or drug-food interactions. Problem-prone issues are summarized in a 'medication safety table' to provide recommendations for clinical practice in uro-oncology. Tailored strategies including intensified care by clinical pharmacologists/pharmacists should be implemented in clinical practice to improve medication safety.

13.
Leukemia ; 36(10): 2468-2478, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35974101

RESUMO

The prospective multicentre Phase II PTLD-2 trial (NCT02042391) tested modified risk-stratification in adult SOT recipients with CD20-positive PTLD based on principles established in the PTLD-1 trials: sequential treatment and risk-stratification. After rituximab monotherapy induction, patients in complete remission as well as those in partial remission with IPI < 3 at diagnosis (low-risk) continued with rituximab monotherapy and thus chemotherapy free. Most others (high-risk) received R-CHOP-21. Thoracic SOT recipients who progressed (very-high-risk) received alternating R-CHOP-21 and modified R-DHAOx. The primary endpoint was event-free survival (EFS) in the low-risk group. The PTLD-1 trials provided historical controls. Rituximab was applied subcutaneously. Of 60 patients enrolled, 21 were low-risk, 28 high-risk and 9 very-high-risk. Overall response was 45/48 (94%, 95% CI 83-98). 2-year Kaplan-Meier estimates of time to progression and overall survival were 78% (95% CI 65-90) and 68% (95% CI 55-80) - similar to the PTLD-1 trials. Treatment-related mortality was 4/59 (7%, 95% CI 2-17). In the low-risk group, 2-year EFS was 66% (95% CI 45-86) versus 52% in the historical comparator that received CHOP (p = 0.432). 2-year OS in the low-risk group was 100%. Results with R-CHOP-21 in high-risk patients confirmed previous results. Immunochemotherapy intensification in very-high-risk patients was disappointing.


Assuntos
Transtornos Linfoproliferativos , Transplante de Órgãos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Transplante de Órgãos/efeitos adversos , Estudos Prospectivos , Rituximab
14.
Cancers (Basel) ; 14(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36291825

RESUMO

(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots-regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.

15.
Virchows Arch ; 479(6): 1095-1099, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33891143

RESUMO

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) is an exceedingly rare low-grade thyroid malignancy of unknown histogenesis. NUT carcinoma is another rare, highly aggressive neoplasm with predilection for the midline, defined by recurrent NUTM1 fusions. The bromodomain family genes (BRD4 or BRD3) and rarely NSD3, ZNF532, or others are known fusion partners. We describe an extraordinary case of a 42-year-old female with a thyroid SMECE treated by thyroidectomy and neck dissection. She presented 6 months later with extensive midline recurrence encasing/compressing the trachea. Biopsy revealed poorly differentiated carcinoma with abrupt squamous differentiation, suggestive of NUT carcinoma. Immunohistochemistry confirmed expression of monoclonal NUT antibody. Targeted RNA sequencing revealed the NSD3-NUTM1 fusion in the NUT carcinoma, but not in the SMECE. This unique case highlights unusual sequential origin of two exceptionally rare entities at same anatomic site and underlines the necessity of sampling unexpectedly aggressive recurrences of otherwise indolent malignancies.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Mucoepidermoide/cirurgia , Eosinofilia/cirurgia , Fusão Gênica , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Proteínas de Neoplasias/genética , Segunda Neoplasia Primária/genética , Proteínas Nucleares/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto , Carcinoma Mucoepidermoide/patologia , Diagnóstico Diferencial , Eosinofilia/patologia , Feminino , Humanos , Esvaziamento Cervical , Recidiva Local de Neoplasia , Segunda Neoplasia Primária/patologia , Valor Preditivo dos Testes , Esclerose , Neoplasias da Glândula Tireoide/patologia , Resultado do Tratamento
16.
J Clin Oncol ; 39(18): 1983-1994, 2021 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-33822650

RESUMO

PURPOSE: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking. METHODS: Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug-related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience. RESULTS: Two hundred two patients were included. Antitumor drug-related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group. CONCLUSION: Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects.


Assuntos
Antineoplásicos/administração & dosagem , Drogas em Investigação/administração & dosagem , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Drogas em Investigação/efeitos adversos , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Estudos Prospectivos
17.
Oncol Res Treat ; 41(7-8): 430-436, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902787

RESUMO

BACKGROUND: Childhood cancer survivors are at risk for therapy-related sequelae and, therefore, require long-term follow-up. At 2 university hospitals in Germany collaborative multidisciplinary late effects clinics were installed to provide specialized care and to evaluate the current health status of these patients in a clinical setting. Patients andMethods: Every patient who visited the late effects clinics at the university hospital in Lübeck and Erlangen over a period of 3 years and met the inclusion criteria was included in the study. Patients' characteristics as well as cancer diagnosis, treatment related factors and the prevalence of chronic health conditions were assessed. RESULTS: 220 patients attended the late effects clinics during the observation period. The median follow-up period was 16 years (range 5-45 years). In total over 64% of the patients were affected by at least 1 chronic health condition, including endocrine disruptions in 19.1% of the patients. Moreover, secondary neoplasms occurred in 9.1% of the study participants. CONCLUSION: German childhood cancer survivors are affected by multiple therapy-related sequelae. A comprehensive network of late effects clinics should be established to ensure specialized and risk-adapted care for every childhood cancer survivor in Germany.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Comunicação Interdisciplinar , Neoplasias/terapia , Equipe de Assistência ao Paciente , Adolescente , Adulto , Quimiorradioterapia , Criança , Pré-Escolar , Feminino , Seguimentos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Adulto Jovem
18.
Oncol Lett ; 14(1): 1089-1096, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28693278

RESUMO

Although the available treatment options have expanded, the survival of patients with metastatic renal cell carcinoma (RCC) remains poor. As patients with RCC lack responsiveness to chemotherapy or radiation, therapeutic options predominantly include surgical interventions and immunomodulatory approaches, including the administration of tyrosine kinase inhibitors (TKIs) such as sunitinib. Natural killer (NK) cells have been reported to be key players in TKI-mediated off-target effects on the immune system. However, only limited information is available regarding the possible impact of sunitinib on the function of NK cells of individual patients. The present study reports on the immunomonitoring results of three patients with metastatic RCC who underwent sunitinib treatment. These results were compared with age-matched, healthy controls in terms of the immune status of T, B and NK cells, focusing on functional in vitro analyses of NK cells. In all three patients, NK cell number, subset distribution and function, as measured by cluster of differentiation 107a degranulation, did not exhibit any significant alterations as a result of sunitinib treatment. These results indicate that sunitinib does not negatively affect NK cell function, which supports the pursuit of therapeutic modalities that combine immunomodulation and NK cell-stimulating approaches.

19.
Cancer Res ; 64(8): 2865-73, 2004 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15087405

RESUMO

Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.


Assuntos
Tolerância Imunológica/imunologia , Melanoma/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Antígenos de Neoplasias , Relação Dose-Resposta Imunológica , Epitopos de Linfócito T/imunologia , Feminino , Antígeno HLA-A2/imunologia , Humanos , Interleucina-2/imunologia , Interleucina-2/farmacologia , Interleucina-7/imunologia , Interleucina-7/farmacologia , Linfonodos/imunologia , Linfonodos/patologia , Metástase Linfática , Antígeno MART-1 , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia
20.
Cancer Res ; 64(17): 6319-26, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15342421

RESUMO

Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8+ T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A26-35 peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.


Assuntos
Cisteína Endopeptidases/deficiência , Cisteína Endopeptidases/imunologia , Melanoma/imunologia , Complexos Multienzimáticos/imunologia , Proteínas de Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos de Neoplasias , Cisteína Endopeptidases/genética , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Humanos , Linfonodos/imunologia , Linfonodos/patologia , Antígeno MART-1 , Masculino , Pessoa de Meia-Idade , Complexos Multienzimáticos/deficiência , Complexos Multienzimáticos/genética , Mutação , Complexo de Endopeptidases do Proteassoma
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