RESUMO
As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
Assuntos
Carcinoma , Neoplasias Gástricas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Gástricas/diagnóstico , Biomarcadores , Esôfago/metabolismoRESUMO
As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
Assuntos
Antígeno B7-H1 , Carcinoma , Humanos , Antígeno B7-H1/metabolismo , Biomarcadores , Esôfago , Junção Esofagogástrica/patologia , Carcinoma/patologia , Biomarcadores Tumorais/metabolismoRESUMO
Background: Bipolar sealing devices are routinely used to seal blood vessels. The aim of the study is to evaluate the feasibility and safety of colonic sealing with the use of the bipolar energy devices in rats as model for experimental appendectomy. Methods: Seventy-five male Wistar rats underwent a cecal resection with four different bipolar sealing devices or a linear stapler. The harvesting procedure was performed immediately or at postoperative day (POD) 7. The sealing front bursting pressure (BP) was measured in both groups. At POD7, the resection line was clinically examined and the hydroxyproline (HDP) levels were determined. Hematoxylin and Eosin (H&E) staining was used for histopathological evaluation of the sealing front as well. Results: There was no mortality and no insufficiency. The BPs between the bipolar sealing devices showed no statistical differences. The early phase of the seal (POD 0) provides a low BP with an 30.8% increase until POD 7. The BPs in the stapler group showed significant better values. The hydroxyproline levels did not differ statistically between the groups. Histopathologically, there were more signs of ischemic necrosis in the stapler group than in the sealing devices groups. Conclusion: The resection and sealing of the cecum as an experimental appendectomy model with the use of bipolar energy devices proved feasible and safe in rats. The different energy devices in this study produce comparable results. To justify clinical practice in humans, several studies on the underlying mechanisms of early stage wound healing are needed.
Assuntos
Apendicectomia/instrumentação , Ceco/cirurgia , Eletrocoagulação/instrumentação , Hemostasia Cirúrgica/instrumentação , Técnicas de Fechamento de Ferimentos/instrumentação , Animais , Apendicectomia/efeitos adversos , Apendicectomia/métodos , Eletrocoagulação/métodos , Estudos de Viabilidade , Hemostasia Cirúrgica/efeitos adversos , Hemostasia Cirúrgica/métodos , Masculino , Modelos Animais , Ratos , Ratos Wistar , Grampeadores Cirúrgicos/efeitos adversos , Técnicas de Fechamento de Ferimentos/efeitos adversosRESUMO
BACKGROUND: Patients with inflammatory bowel diseases, i.â¯e., ulcerative colitis and Crohn's disease (CD), face an increased risk of developing colorectal cancer (CRC). Evidence, mainly from ulcerative colitis, suggests that TP53 mutations represent an initial step in the progression from inflamed colonic epithelium to CRC. OBJECTIVES: In this study, we aimed to analyze the genetic events that define CD-CRCs, in particular the dynamics of their development from histologically undetectable precursor lesions to invasive disease. MATERIALS AND METHODS: We analyzed 73 tissue samples from 28 patients with CD-CRC, including precursor lesions by next generation sequencing (563 gene panel) and array-based comparative genomic hybridization. The results were compared with our own data and the Cancer Genome Atlas data on sporadic CRC. RESULTS: The gain of 5p was significantly more prevalent in CD-CRCs than in sporadic CRCs, despite an overall similar chromosomal aberration pattern. CD-CRCs had a distinct mutation signature with TP53 being the most frequently mutated gene in CD-CRCs. TP53 mutations and copy number alterations were early events in CD progression and could sometimes already be detected in non-dysplastic colonic mucosa, indicating occult tumor evolution. CONCLUSIONS: Molecular profiling of CD-CRCs and precursor lesions revealed an inflammation-associated landscape of genome alterations: gains of 5p and TP53 mutations occurred early in tumor development. Detection of these aberrations in precursor lesions may help predict disease progression and distinguishes CD-associated from sporadic colorectal neoplasia.
Assuntos
Neoplasias Colorretais , Doença de Crohn , Proteína Supressora de Tumor p53/genética , Braço , Carcinogênese , Cromossomos Humanos Par 5 , Neoplasias Colorretais/genética , Hibridização Genômica Comparativa , Dosagem de Genes , Humanos , Mutação , Proteína Supressora de Tumor p53/metabolismoRESUMO
TGF-ß signaling in liver cells has variant roles in the dynamics of liver diseases, including hepatocellular carcinoma (HCC). We previously found a correlation of high levels of the important endogenous negative TGF-ß signaling regulator SMAD7 with better clinical outcome in HCC patients. However, the underlying tumor-suppressive molecular mechanisms are still unclear. Here, we show that conditional (TTR-Cre) hepatocyte-specific SMAD7 knockout (KO) mice develop more tumors than wild-type and corresponding SMAD7 transgenic mice 9 months after diethylnitrosamine (DEN) challenge, verifying SMAD7 as a tumor suppressor in HCC. In line with our findings in patients, Smad7 levels in both tumor tissue as well as surrounding tissue show a significant inverse correlation with tumor numbers. SMAD7 KO mice presented with increased pSMAD2/3 levels and decreased apoptosis in the tumor tissue. Higher tumor incidence was accompanied by reduced P21 and upregulated c-MYC expression in the tumors. Activation of signal transducer and activator of transcription factor 3 signaling was found in Smad7-deficient mouse tumors and in patients with low tumoral SMAD7 expression as compared with surrounding tissue. Together, our results provide new mechanistic insights into the tumor-suppressive functions of SMAD7 in hepatocarcinogenesis.
RESUMO
Valid HER2 testing is essential for optimal therapy of patients with HER2 positive gastric cancer and the correct use of first-line treatment. While each breast cancer is routinely being tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is often only done upon request by the therapist. An interdisciplinary German expert group took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this manuscript reflect the consensus of all participants and correspond to their opinions and long-term experience.
Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas de Diagnóstico do Sistema Digestório/normas , Oncologia/normas , Guias de Prática Clínica como Assunto , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Medicina Baseada em Evidências , Alemanha , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.
Assuntos
Adenocarcinoma/genética , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Algoritmos , Biópsia , Regulação Neoplásica da Expressão Gênica/genética , Fidelidade a Diretrizes , Humanos , Comunicação Interdisciplinar , Colaboração Intersetorial , Prognóstico , Reprodutibilidade dos Testes , Estômago/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapiaRESUMO
Purpose. The addition of cetuximab to radiochemotherapy (RCT) failed to improve complete response rates in locally advanced rectal cancer (LARC). We report the long-term results in patients treated within two sequential clinical trials. Methods. Patients receiving neoadjuvant RCT using capecitabine and irinotecan (CapIri) within a phase I/II trial or CapIri + cetuximab within a phase II trial were evaluated for analysis of disease-free survival (DFS) and overall survival (OS). KRAS exon 2 mutational status had been analyzed in patients receiving cetuximab. Results. 37 patients from the CapIri trial and 49 patients from the CapIri-cetuximab treatment group were evaluable. Median follow-up time was 75.2 months. The 5-year DFS rate was 82% (CapIri) and 79% (CapIri-cetuximab) (P = 0.62). The median OS was 127.4 months. 5-year OS was 73% for both groups (CapIri and CapIri-cetuximab) (P = 0.61). No significant difference in DFS (P = 0.86) or OS (P = 0.39) was noticed between patients receiving CapIri and those receiving CapIri-cetuximab with KRAS wild-type tumors. Conclusions. As the addition of cetuximab did not improve neither DFS nor OS it should not play a role in the perioperative treatment of patients with LARC, not even of patients with (K)RAS WT tumors.
RESUMO
Two cases of symptomatic proctitis with rectal tumors suspicious for malignancy are presented. A florid regenerative proctitis was shown in the histological examination. In both cases a sexually transmitted infection (STI) was causing the symptoms. In rare cases STIs present as pseudo tumors mimicking malignancy in clinical examination and endoscopic/radiological analysis. A close collaboration between gastroenterologist and pathologist is necessary for a correct diagnosis and to prevent unnecessary surgical treatment.
Assuntos
Neoplasias Retais/etiologia , Neoplasias Retais/patologia , Doenças Bacterianas Sexualmente Transmissíveis/complicações , Doenças Bacterianas Sexualmente Transmissíveis/patologia , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas , Neoplasias Retais/terapia , Doenças Bacterianas Sexualmente Transmissíveis/terapiaRESUMO
The introduction of total genome sequencing led to the confirmation that tumors show substantial genetic heterogeneity. This phenomenon, which describes the presence of different genetic cell clones within a tumor also complicates the diagnostics of HER2. This article gives a review of new knowledge on polysomy 17 and genetic tumor heterogeneity in connection with HER2 determination of breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cromossomos Humanos Par 17/genética , Regulação Neoplásica da Expressão Gênica/genética , Heterogeneidade Genética , Hibridização In Situ , Polirribossomos/genética , Receptor ErbB-2/genética , Aneuploidia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , TrastuzumabRESUMO
EGCG is a flavonoid that exhibited therapeutic activity in cancer. In this study three glioblastoma cell lines (U87, A172 and U251) were treated with EGCG, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Treatment with subtoxic doses of EGCG in combination with TRAIL induces rapid apoptosis in TRAIL-resistant glioma cells, suggesting that this combined treatment may offer an attractive strategy for treating gliomas. EGCG treatment down-regulated phosphoprotein-enriched in astrocytes (PEA15) through an Akt (PKB)-dependent mechanism. In addition, over-expression of PEA15 attenuated cytotoxicity induced by the combination of EGCG and TRAIL. In summary, PEA15 is a key regulator in TRAIL-EGCG-mediated cell death in malignant glioma.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Catequina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteínas Reguladoras de Apoptose , Caspase 7/metabolismo , Catequina/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Glioma/patologia , Humanos , Proteínas Inibidoras de Apoptose , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , SurvivinaRESUMO
Celecoxib is a cyclooxygenase 2-selective nonsteroidal anti-inflammatory drug (NSAID) that exhibited therapeutic activity in cancer. In this study three malignant glioma, U87-MG, U251 and A172, were treated with celecoxib, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the combination of both. Single treatment with celecoxib (25-100muM) for 24h resulted in a concentration-dependant decrease of cellular viability in U87-MG, U251 and A172. Combining subtoxic concentrations of celecoxib with TRAIL strongly increased cell death in human malignant glioma cells. After 8h treatment with celecoxib we found down-regulation of the inhibitor of apoptosis protein survivin that was mediated by proteasomal degradation. In addition, over-expression of survivin not only attenuated celecoxib-induced cytotoxicity but also cytotoxicity induced by the combination of celecoxib and TRAIL. Taken together, in malignant glioma survivin is a key regulator in celecoxib- and TRAIL-celecoxib-mediated cell death.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Glioblastoma/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas de Neoplasias/metabolismo , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Apoptose/fisiologia , Celecoxib , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/fisiopatologia , Humanos , Proteínas Inibidoras de Apoptose , Transdução de Sinais/efeitos dos fármacos , SurvivinaRESUMO
Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare, painless lymphoproliferative disorder of unknown origin with a usually benign course. About 40% of the patients show an extranodal involvement with skin being the most common site in 27% of these patients. We describe a patient with widespread disease involving the respiratory tract, kidneys and skin. Histopathology revealed the characteristic features of SHML with emperipolesis and immunohistochemical positivity of histiocytes for S100 and macrophage-associated antigens.
Assuntos
Corticosteroides/uso terapêutico , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIMS: To investigate the correlation between centrally assessed human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) results and response to treatment of patients with metastatic breast cancer enrolled in a first-line, phase II, open-label, 3-weekly trastuzumab (Herceptin) monotherapy trial (WO16229). METHODS: Samples from participants in the WO16229 trial were collected and tumour HER2 status determined by IHC and FISH. HER2 test results were interpreted according to manufacturers' test kit protocols. Responders were defined as patients showing either partial or complete responses. RESULTS: Response data were available for 103/105 patients; centrally confirmed HER2 status was available for 95 patients. Intra-laboratory concordance for central IHC and FISH results was 93%. Complete responses were seen in two patients; their samples were IHC 3+ and FISH positive. Partial responses were seen in 17 patients; all were IHC 3+ and 14 were FISH positive. IHC and FISH showed 100% and 84.2% sensitivity, respectively, in determining response to trastuzumab. Polysomy was observed in 27% of patients; six responded to trastuzumab treatment. All six responders showed HER2 overexpression (IHC 3+) and HER2 gene amplification; two were FISH negative due to chromosome 17 polysomy. CONCLUSIONS: HER2 determination by IHC and FISH correlates with clinical response data in the WO16229 trial with high concordance of IHC and FISH results. Polysomy is the major cause of response in FISH-negative cases; polysomic cases should be retested by strictly standardised IHC.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cromossomos Humanos Par 17/genética , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Poliploidia , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Trastuzumab , Resultado do TratamentoRESUMO
Intracranial vascular malformations are rare but tend to appear more frequently than usual in patients with type I neurofibromatosis (NFI). Aneurysms of the basilar artery have been described four times so far. We report two cases of 51- and 62-year-old patients with type I neurofibromatosis who showed long fusiform dilation of the basilar artery. Clinically both patients presented with locked-in syndrome and died 15 and 11 days after admission. The diagnosis was confirmed by autopsy. These are the first published cases of locked-in syndrome following thrombosis of a megadolichobasilar artery in association with neurofibromatosis I. Our results show that cerebral vascular malformations are found more frequently than random chance would predict in patients with NF I.
Assuntos
Aneurisma Intracraniano/diagnóstico , Neurofibromatose 1/diagnóstico , Insuficiência Vertebrobasilar/diagnóstico , Artéria Basilar/patologia , Infartos do Tronco Encefálico/diagnóstico , Infartos do Tronco Encefálico/genética , Angiografia Cerebral , Aberrações Cromossômicas , Evolução Fatal , Humanos , Aneurisma Intracraniano/genética , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neurofibromatose 1/genética , Exame Neurológico , Ponte/patologia , Tomografia Computadorizada por Raios X , Insuficiência Vertebrobasilar/genéticaRESUMO
Her-2 status determination is an essential prerequisite before considering patient eligibility for treatment with trastuzumab. Currently the most common techniques to assess Her-2 status in routine practice are immunohistochemistry (IHC) and dual color FISH for receptor expression and gene amplification analysis, respectively. Despite both methods are well-established in breast cancer there are a variety of yet unsolved questions: 1. Do we really need IHC since interlab variation is still quite high (up to 30%)? 2. Are FISH and CISH equivalent techniques? 3. Are there any precautions to be taken if Her-2 is tested in non-breast cancer samples? 4. What is the value of Her-2 status in blood serum (ELISA)? 5. Do we get better response prediction if new Her2 antibodies, other techniques such as quantitative (q) RT-PCR or multiparameter assays according to downstream signalling pathways are applied? 6. Is Her-2 status still predictive when other therapeutic antibodies than trastuzumab (e. g. pertuzumab) or kinase inhibitors (e. g. lapatinib) are used? These questions will be discussed under the review of the recent literature and under own experiences obtained either by centralized Her-2 assessment in a variety of breast and non-breast cancer therapy studies and within international ring studies between reference labs from Australia (M. Bilous), Canada (W. Hanna), France (F. Penault-Llorcoa), Great Britain (M. Dowsett), Japan (R. Y. Osamura), and Netherlands (M. v. d. Vijver) in which we participated.
Assuntos
Neoplasias da Mama/patologia , Receptor ErbB-2/análise , Algoritmos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase , Receptor ErbB-2/genética , TrastuzumabRESUMO
AIMS: Cytotoxic luteinizing hormone releasing hormone (LHRH) analogues AN-152 and AN-207 consist of [D-Lys6] LHRH linked to doxorubicin or its hyperactive derivate AN-201 and bind with high affinity to LHRH receptors. We evaluated the use of AN-207 and AN-201 in a nude mice model. In order to provide a rationale for the possible use of cytotoxic LHRH analogues in different malignancies we investigated the expression of LHRH-R in human renal cell carcinoma (RCC), melanoma and non Hodgkin's Lymphoma (NHL). METHODS: The expression of LHRH-R was examined in surgically removed human specimens of primary tumours and metastases from 37 RCC, 19 melanomas and 17 NHLs. In addition, human tumour cell lines expressing LHRH receptors were transplanted into nude mice and anti-tumour efficacy and systemic toxicity of AN-207 and its cytotoxic radical AN-201 were compared in various experiments. RESULTS: Positive staining for LHRH receptors was found in all of the RCC (37/37) and the melanoma specimens (19/19) as well as in 100% (10/10) of the NHLs. In in vivo experiments AN-207 significantly inhibited tumour growth while the cytotoxic radical alone was ineffective. Furthermore, side effects were reduced with targeted therapy. CONCLUSIONS: LHRH receptor expression was found to be very high in melanomas, RCCs and NHLs. Therefore targeted therapy with cytotoxic LHRH analogues may be a promising, novel therapy for advanced stages of these tumours. A first clinical trial with AN-152 was initiated recently in breast cancer patients.
Assuntos
Neoplasias Renais/patologia , Linfoma não Hodgkin/patologia , Melanoma/patologia , Animais , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Doxorrubicina/uso terapêutico , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Metástase Neoplásica , Receptores LHRH/análise , Receptores LHRH/antagonistas & inibidoresRESUMO
We report on the analysis of a murine anaplastic lymphoid cell line TS1G6, established recently by interleukin (IL)-9 transfection. TS1G6 revealed a highly characteristic pattern of large anaplastic cells with mononuclear, binuclear, or multinuclear cells resembling Hodgkin (H) or Sternberg-Reed (SR) cells. This cell line is tumorigenous after injection of as few as 10(4) lymphoma cells into nude or immunocompetent C57Bl/6 mice and leads to death from progressive disease of all treated animals within a few weeks. The histological analysis of these tumors revealed a diffuse large cell malignant lymphoma that is morphologically almost identical to human anaplastic large cell lymphoma (ALCL). The lymphoma cells did not show overexpression of the anaplastic lymphoma kinase (ALK) gene, which is found in about 50% of the cases of human ALCL. Thus, this model may be an animal model for an important subset of human ALCL. The cytokine profile, which is of the T helper 2 type, showed strong parallels to the human lymphoma counterpart. Mice suffering from such lymphomas could not be cured with a regimen using high dose cyclophosphamide similar to many ALCL patients. Such an animal model for ALCL has not yet been recognized, but may provide the basis for investigating new antitumor immunotherapies in a fully immunocompetent host.