A Case Report of Sequential Use of a Yeast-CEA Therapeutic Cancer Vaccine and Anti-PD-L1 Inhibitor in Metastatic Medullary Thyroid Cancer.

Medullary thyroid cancer (MTC) accounts for ~4% of all thyroid malignancies. MTC derives from the neural crest and secretes calcitonin (CTN) and carcinoembryonic antigen (CEA). Unlike differentiated thyroid cancer, MTC does not uptake iodine and I-131 RAI (radioactive iodine) treatment is ineffective. Patients with metastatic disease are candidates for FDA-approved agents with either vandetanib or cabozantinib; however, adverse effects limit their use. There are ongoing trials exploring the role of less toxic immunotherapies in patients with MTC. We present a 61-year-old male with the diagnosis of MTC and persistent local recurrence despite multiple surgeries. He was started on sunitinib, but ultimately its use was limited by toxicity. He then presented to the National Cancer Institute (NCI) and was enrolled on a clinical trial with heat-killed yeast-CEA vaccine (NCT01856920) and his calcitonin doubling time improved in 3 months. He then came off vaccine for elective surgery. After surgery, his calcitonin was rising and he enrolled on a phase I trial of avelumab, a programmed death-ligand 1 (PD-L1) inhibitor (NCT01772004). Thereafter, his calcitonin decreased > 40% on 5 consecutive evaluations. His tumor was subsequently found to express PD-L1. CEA-specific T cells were increased following vaccination, and a number of potential immune-enhancing changes were noted in the peripheral immunome over the course of sequential immunotherapy treatment. Although calcitonin declines do not always directly correlate with clinical responses, this response is noteworthy and highlights the potential for immunotherapy or sequential immunotherapy in metastatic or unresectable MTC.

Rendimiento diagnóstico de la punción mediante ultrasonografía endoscópica de las lesiones quísticas del páncreas / Diagnostic yield of endoscopic ultrasound with fine-needle aspiration in pancreatic cystic lesions

Introducción: A pesar de los avances en las técnicas de imagen, en muchos casos son insuficientes para establecer el diagnóstico de las lesiones quísticas pancreáticas (LQP). Son escasas las publicaciones en nuestro medio que evalúan la combinación de varios métodos obtenidos mediante la punción aspirativa con aguja fina con ultrasonografía endoscópica (USE-PAAF). El objetivo del estudio fue evaluar la utilidad global de la USE-PAAF en el diagnóstico de las LQP. Material y métodos: Estudio retrospectivo a partir de una base de datos actualizada prospectivamente de una cohorte de pacientes remitidos para USE-PAAF por LQP. Se estudió la sensibilidad, la especificidad, el rendimiento diagnóstico del antígeno carcinoembrionario (CEA), la citología y la viscosidad para detectar lesiones mucinosas. Resultados: Desde noviembre de 2013 a abril del 2018 se realizaron 122 USE por LQP. Se realizó USE-PAAF en 94/122 (77%) y se intervinieron 21/122 (17,2%) pacientes. Se incluyeron 33/122 pacientes que tuvieron confirmación diagnóstica mediante histología, imagen (quiste seroso con patrón típico) o evolución clínica. El estudio de la curva ROC determinó el punto de corte ≥419ng/ml para diferenciar lesión quística mucinosa/no mucinosa. El rendimiento diagnóstico del CEA fue del 87,5% (21/24), de la citología del 81,8% (27/33) y de la viscosidad del 84,4% (27/32). Los 3 parámetros en combinación obtuvieron el mejor resultado (30/33, 90,9%). Conclusión: La combinación del análisis del CEA, la citología y la viscosidad del líquido pancreático obtenido mediante USE-PAAF aumenta el rendimiento en el diagnóstico de las lesiones quísticas pancreáticas mucinosas, siendo superior al 90%

Introduction: Despite advances in imaging techniques, in many cases they are insufficient to establish the diagnosis of pancreatic cystic lesions (PCL). There are few publications in our setting that evaluate the combination of several methods obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The aim of the study was to evaluate the overall utility of EUS-FNA in the diagnosis of PCL. Material and methods: Retrospective study based on a database updated prospectively of a cohort of patients referred for EUS-FNA due to PCL detected in an imaging test. The sensitivity, specificity and diagnostic yield of carcinoembryonic antigen (CEA), cytology and viscosity were studied to detect mucinous lesions. Results: From November 2013 to April 2018, 122 EUS were performed for PCL. EUS-FNA was performed in 94/122 (77%) and 21/122 (17.2%) patients were operated on. We included 33/122 patients who had diagnostic confirmation by histology, imaging (serous cyst with typical pattern) or clinical evolution. The study of the ROC curve determined the cutoff point ≥419 ng/ml to differentiate mucinous/non-mucinous cystic lesions. The diagnostic yield of CEA was 87.5% (21/24), cytology 81.8% (27/33) and viscosity 84.4% (27/32). The three parameters in combination obtained the best result (30/33, 90.9%). Conclusion: The combination of CEA analysis, cytology and viscosity of pancreatic fluid obtained by EUS-FNA increases the performance in the diagnosis of mucinous pancreatic cystic lesions, with it being greater than 90%

Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial.

Vaccination with priming and expansion of tumour reacting T cells is an important therapeutic option to be used in combination with novel checkpoint inhibitors to increase the specificity of the T cell infiltrate and the efficacy of the treatment. In this phase I/II study, 14 high-risk disease-free ovarian (OC) and breast cancer (BC) patients after completion of standard therapies were vaccinated with MUC1, ErbB2 and carcinoembryonic antigen (CEA) HLA-A2+-restricted peptides and Montanide. Patients were subjected to 6 doses of vaccine every two weeks and a recall dose after 3 months. ECOG grade 2 toxicity was observed at the injection site. Eight out of 14 patients showed specific CD8+ T cells to at least one antigen. None of 4 patients vaccinated for compassionate use showed a CD8 activation. An OC patient who suffered from a lymph nodal recurrence, showed specific anti-ErbB2 CD8+ T cells in the bulky aortic lymph nodes suggesting homing of the activated T cells. Results confirm that peptide vaccination strategy is feasible, safe and well tolerated. In particular OC patients appear to show a higher response rate compared to BC patients. Vaccination generates a long-lasting immune response, which is strongly enhanced by recall administrations. The clinical outcome of patients enrolled in the trial appears favourable, having registered no deceased patients with a minimum follow-up of 8 years. These promising data, in line with the results of similar studies, the high compliance of patients observed and the favourable toxicity profile, support future trials of peptide vaccination in clinically disease-free patients who have completed standard treatments.

Marcadores tumorales / Tumor markers

Los marcadores tumorales son moléculas (generalmente glucoproteínas), que pueden estar elevadas en presencia de un cáncer, bien como reacción del huésped ante el tumor o bien como producto del propio tumor. Estas moléculas, cuya concentración sérica también depende de la variabilidad biológica del paciente, son detectables en diferentes fluidos biológicos. La utilidad de los marcadores tumorales viene determinada por la sensibilidad y especificidad de cada uno de ellos. No existe un marcador tumoral 100 % sensible y específico. Un marcador tumoral con una alta sensibilidad sería aquél que se encuentra elevado en la mayoría de los pacientes que presentan una determinada neoplasia, mientras que la especificidad vendría dada por aquellos pacientes con niveles normales del marcador tumoral que no presentan ningún tipo de neoplasia. Así, los marcadores con altos valores de sensibilidad y especificidad permitirían detectar a los pacientes que padecen cáncer y diferenciarlos de individuos sanos o de pacientes que presenten patologías benignas. Podemos decir que, en general, debido a la falta de una elevada sensibilidad y especificidad diagnósticas, los marcadores tumorales no sirven para la detección temprana de las neoplasias, pero sí ayudan a la confirmación de un diagnóstico ya establecido por métodos más sensibles. La mayoría de ellos tienen además un valor pronóstico en el momento del diagnóstico, ya que su concentración se relaciona con el tamaño tumoral. Su verdadero valor clínico reside, sin embargo, en el seguimiento de los pacientes, tanto para detectar una recidiva temprana, como para evaluar la efectividad del tratamiento instaurado. Nos proponemos en esta revisión hacer un repaso de los marcadores tumorales más utilizados en nuestra práctica clínica y de algunas recomendaciones que se han consensuado sobre la indicación de determinación de los mismos en diversos tumores (AU)

Tumor markers are molecules (usually glycoproteins), the levels of which may be elevated in the presence of a cancer, either as a host's reaction to the tumor or as a product of the tumor itself. These molecules, whose serum concentration also depends on the biological variability of the patient, are detectable in different biological fluids. The usefulness of tumor markers is determined by the sensitivity and specificity of each of them. There is no tumor marker which is 100% sensitive and specific. A tumor marker with a high sensitivity would be the one that is elevated in the majority of patients who present certain neoplasm, whereas specificity would be determined by those patients with normal levels of the tumor marker who do not present any type of neoplasm. Thus, markers with high levels of sensitivity and specificity would allow for the detection of patients with cancer, and for their differentiation from healthy individuals or from patients with benign pathologies. We can say that, in general, due to the lack of high diagnostic sensitivity and specificity, tumor markers are not helpful for an early detection of neoplasms, but they do help to confirm a diagnosis already established by more sensitive methods. Most markers also have a prognostic value at the time of diagnosis, since their concentration is related to tumor size. However, their true clinical value lies in patient monitoring, both for detecting early recurrence and for evaluating the effectiveness of the established treatment. Our aim is to review the tumor markers most commonly used in our clinical practice, as well as some agreed recommendations on the indication of their determination in various tumors (AU)

Detection of bone metastases in breast cancer patients in the PET/CT era: do we still need the bone scan? / La detección de metástasis óseas en pacientes con cáncer de mama en la era de PET/TAC: ¿necesitamos todavía la gammagrafía ósea?

Aim. To examine the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of bone metastasis in breast cancer patients and assess whether whole body bone scan (BS) with 99mTc-methylene diphosphonate provides any additional information. Material and Methods. Study group comprised 150 patients, mean age 52 years (range 27-85) with breast cancer, suspected of having bone metastases. All patients had undergone both FDG-PET/CT and BS with or without single photon emission tomography/computed tomography (SPECT/CT) within a period of 6 weeks. The final diagnosis of bone metastasis was established by histopathological findings, additional imaging, or clinical follow-up longer than 10 months. Cancer antigen 15-3 (CA15-3) and carcinoembryogenic antigen (CEA) were measured in all patients. Results. Histologically 83%, 7% and 10% had infiltrating ductal, lobular and mixed carcinoma respectively. Confirmed bone metastases were present in 86 patients (57.3%) and absent in 64 (42.7%). Mean CA15-3 and CEA values in patients with bone metastases were 74.6 ng/mL and 60.4 U/mL respectively, compared to 21.3 ng/mL and 3.2 U/mL without metastases (p < 0.001). The sensitivity of FDG-PET/CT for the detection of bone metastases was 97.6% compared to 89.5% with SPECT/CT. In 57 patients, FDG-PET/CT correctly identified additional pulmonary, hepatic, nodal and other soft tissue metastases, not detected by BS. Conclusion. Our findings suggest that FDG-PET/CT is superior to BS with or without SPECT/CT (AU)

Objetivo. Para examinar el valor de la 18F-fluorodeoxiglucosa Tomografía por Emisión de Positrones y de la Tomografía Axial Computerizada (FDG-PET/TAC) para la detección de metástasis óseas en pacientes con cáncer de mama y evaluar si el rastreo gammagráfico óseo (GO) con 99mTc-difosfonato de metileno proporciona cualquier información adicional. Material y métodos. El grupo de estudio estuvo integrado por 150 pacientes, media de edad 52 años (rango 27-85) con cáncer de mama y sospecha de metástasis óseas. Todas las pacientes tenían FDG-PET/TAC y GO con o sin SPECT/TAC en un plazo de 6 semanas. El diagnóstico final de metástasis óseas fue establecido por los resultados histopatológicos, los estudios adicionales de imagen o el seguimiento clínico superior a 10 meses. En todas las pacientes se determinaron los niveles séricos de CA 15-3 y antígeno carcinoembrionario (CEA). Resultados. Histológicamente, 83%, 7% y 10% tenían carcinoma ductal infiltrante, lobular y mixto respectivamente. Las metástasis óseas confirmadas estuvieron presentes en 86 pacientes (57.3%) y ausentes en 64 (42.7%). Los valores medios de CA15-3 y CEA en pacientes con metástasis óseas fueron 74.6 ng/mL y 60.4 U/mL, respectivamente, en comparación con 21,3 ng/mL y 3,2 U/mL sin metástasis (p <0,001). La sensibilidad de la FDG-PET/TAC para la detección de metástasis óseas fue del 97,6% en comparación con el 89,5%, para la SPECT/TAC. En 57 pacientes, la FDG-PET/TAC identificó correctamente metástasis adicionales pulmonares, hepáticas, ganglios linfáticos y partes blandas, no detectadas por GO. Conclusión. Nuestros resultados sugieren que la FDG-PET/TAC es superior a GO con o sin SPECT/TAC (AU)

Efficient induction of anti-tumor immunity by a TAT-CEA fusion protein vaccine with poly(I:C) in a murine colorectal tumor model.

Protein vaccines may be a useful strategy for cancer immunotherapy because recombinant tumor antigen proteins can be produced on a large scale at relatively low cost and have been shown to be safe for clinical application. However, protein vaccines have historically exhibited poor immunogenicity; thus, an improved strategy is needed for successful induction of immune responses. TAT peptide is a protein transduction domain composed of an 11-amino acid peptide (TAT(47-57): YGRKKRRQRRR). The positive charge of this peptide allows protein antigen fused with it to improve cell penetration. Poly(I:C) is a synthetic double-stranded RNA that is negatively charged and favors interaction with the cationic TAT peptide. Poly(I:C) has been reported on adjuvant role in tumor vaccine through promotion of immune responses. Therefore, we demonstrated that vaccine with a mixture of TAT-CEA fusion protein and poly(I:C) can induce anti-tumor immunity in a murine colorectal tumor model. Splenocytes from mice vaccinated with a mixture of TAT-CEA fusion protein and poly(I:C) effectively induced CEA-specific IFN-γ-producing T cells and showed cytotoxic activity specific for MC-38-cea2 tumor cells expressing CEA. Vaccine with a mixture of TAT-CEA fusion protein and poly(I:C) delayed tumor growth in MC-38-cea-2 tumor-bearing mice. Depletion of CD8(+) T cells and NK cells reversed the inhibition of tumor growth in an MC-38-cea2-bearing mice, indicating that CD8(+) T cells and NK cells are responsible for anti-tumor immunity by vaccine with a mixture of TAT-CEA fusion protein and poly(I:C). Taken together, these results suggest that poly(I:C) could be used as a potent adjuvant to induce the anti-tumor immunity of a TAT-CEA fusion protein vaccine in a murine colorectal tumor model.

A Phase I safety study of plasmid DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients.

A plasmid DNA vaccine, encoding a truncated form of human CEA fused to a T-helper epitope (CEA66 DNA) was delivered three times intradermally at 2 mg or intramuscularly at 8 mg by Biojector® to patients with colorectal cancer. Prior to the first vaccination, all patients received cyclophosphamide (300 mg/m²) intravenously. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered subcutaneously with each vaccination. All patients completed the vaccine schedule. There were no grade 3 or 4 adverse events (AE). The most frequently reported AE grades 1 and 2 were injection site reactions, fatigue, headache, arthralgia, chest tightness and myalgia. Vaccination with CEA66 DNA in combination with GM-CSF was well tolerated and no signs of autoimmunity have been detected.

Induction of type 1 cytokines during neem leaf glycoprotein assisted carcinoembryonic antigen vaccination is associated with nitric oxide production.

Involvement of the nitric oxide (NO) release in CEAM phi NLGP (carcinoembryonic antigen pulsed macrophages with neem leaf glycoprotein) vaccination and its relationship with vaccine induced type 1 immune response were aimed to study in the present communication. Vaccination with CEAM phi NLGP resulted in macrophage activation as evidenced by its increased number and expression of CD69 marker. Activated macrophages demonstrated upregulation in synthesis of IL-12 and downregulation in IL-10, along with excess IFN gamma production in splenic cells, as evidenced from mRNA analysis. Induction of such type 1 immunity was further confirmed by expression of type 1 specific transcription factor, T-bet and enhancement of intracellular glutathione content. Such vaccination also induced greater nitric oxide (NO) production from macrophages. Dependence of induced type 1 immune response on the NO release and vice versa was studied by in vitro neutralization of IFN gamma/IL-12 and in vivo inhibition of NO production by methylene blue. Obtained results clearly demonstrated the interdependence of two anti-tumor immune functions, namely, NO production and generation of type 1 immune response. Understanding of the mechanism of this NO related immune modulation would have great impact in proposing CEAM phi NLGP vaccine in clinic for the treatment of CEA+ tumors.

Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I(131) KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma.

BACKGROUND: Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I(131) in pancreatic cancer (ISRCTN 16857581). METHODS: Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death. RESULTS: Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33%) patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3).The overall response rate was 6% (1/18). Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months), with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79). One patient was still alive at the time of this analysis. CONCLUSION: Dose limiting toxicity for KAb201 with I(131) by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm.

Co-administration of carcinoembryonic antigen and HIV TAT fusion protein with CpG-oligodeoxynucleotide induces potent antitumor immunity.

Although dendritic cells (DC) have been well demonstrated as a strong cellular adjuvant for a tumor vaccine, there are several limitations for clinical application. A protein-based vaccine using a potent adjuvant is an appealing approach for tumor antigen-specific immunotherapy because of their simplicity, safety, efficacy and capacity for repeated administration. CpG-oligodeoxynucleotides (ODN) have been used as adjuvants to stimulate innate and adaptive immune responses for cancer treatment. The authors evaluated the adjuvant effects of CpG-ODN in a vaccine incorporating recombinant fusion protein of the HIV TAT PTD domain and carcinoembryonic antigen (TAT-CEA). Mice vaccinated with TAT-CEA and CpG-ODN (TAT-CEA + CpG) showed enhanced CEA-specific immunity, including cytotoxic T-lymphocytes (CTL) activity and interferon (IFN)-gamma secreting T cells compared with CEA and CpG-ODN (CEA + CpG) or TAT-CEA vaccination alone. Vaccination with TAT-CEA + CpG elicited Th1-based responses, as indicated by the higher ratio of immunoglobulin (Ig)G2a antibody/IgG1 antibodies specific for CEA. The survival rate was significantly increased after vaccination with TAT-CEA + CpG in a tumor model using MC38/CEA2. Furthermore, the TAT-CEA +/- CpG vaccine groups showed similar antitumor immunity to the CEA peptide-pulsed DC (CEA peptide/DC) vaccine groups. These data suggest that coadministration of TAT fusion protein with CpG-ODN may serve as a potential formulation for enhancing antitumor activity.

Multiple costimulatory modalities enhance CTL avidity.

Recent studies in both animal models and clinical trials have demonstrated that the avidity of T cells is a major determinant of antitumor and antiviral immunity. In this study, we evaluated several different vaccine strategies for their ability to enhance both the quantity and avidity of CTL responses. CD8(+) T cell quantity was measured by tetramer binding precursor frequency, and avidity was measured by both tetramer dissociation and quantitative cytolytic function. We have evaluated a peptide, a viral vector expressing the Ag transgene alone, with one costimulatory molecule (B7-1), and with three costimulatory molecules (B7-1, ICAM-1, and LFA-3), with anti-CTLA-4 mAb, with GM-CSF, and combinations of the above. We have evaluated these strategies in both a foreign Ag model using beta-galactosidase as immunogen, and in a "self" Ag model, using carcinoembryonic Ag as immunogen in carcinoembryonic Ag transgenic mice. The combined use of several of these strategies was shown to enhance not only the quantity, but, to a greater magnitude, the avidity of T cells generated; a combination strategy is also shown to enhance antitumor effects. The results reported in this study thus demonstrate multiple strategies that can be used in both antitumor and antiviral vaccine settings to generate higher avidity host T cell responses.

Tumor immunity and prolonged survival following combined adenovirus-HSP72 and CEA-plasmid vaccination.

We have studied the effects of recombinant adenoviruses as immune adjuvants for DNA vaccination. In a mouse model, using the weak immunogen carcinoembryonic antigen (CEA), anti-CEA IgG production was significantly higher and occurred earlier when immunization included a recombinant adenovirus together with CEA-plasmid DNA. Combined immunization with a recombinant adenovirus expressing the immunomodulatory molecule heat shock protein 72 (ADHSP72) and CEA-plasmid DNA resulted in CEA-specific T-cell activation capable of protecting mice from tumor formation with CEA expressing cells. Additionally, animals with CEA expressing tumors showed diminished tumor growth and prolonged survival when immunized with ADHSP72 and CEA-plasmid DNA compared to controls. Recombinant adenoviruses expressing immunomodulatory molecules such as HSP72 may be useful adjuvants for DNA vaccination.

In vivo manipulation of dendritic cells overcomes tolerance to unmodified tumor-associated self antigens and induces potent antitumor immunity.

Most tumor-associated Ags are self proteins that fail to elicit a T cell response as a consequence of immune tolerance. Dendritic cells (DCs) generated ex vivo have been used to break tolerance against such self Ags; however, in vitro manipulation of DCs is cumbersome and difficult to control, resulting in vaccines of variable potency. To address this problem we developed a method for loading and activating DCs, in situ, by first directing sufficient numbers of DCs to peripheral tissues using Flt3 ligand and then delivering a tumor-associated Ag and oligonucleotide containing unmethylated CG motifs to these tissues. In this study, we show in three different tumor models that this method can overcome tolerance and induce effective antitumor immunity. Vaccination resulted in the generation of CD8(+) T and NK cell effectors that mediated durable tumor responses without attacking normal tissues. These findings demonstrate that unmodified tumor-associated self Ags can be targeted to DCs in vivo to induce potent systemic antitumor immunity.

Tumor-directed lymphocyte-activating cytokines: refolding-based preparation of recombinant human interleukin-12 and an antibody variable domain-fused protein by additive-introduced stepwise dialysis.

Integration of lymphocyte-activating cytokines (e.g., interleukin-12: IL-12) to tumor cells offers promise for cancer immunotherapy, but the preparation of such heterodimeric proteins by refolding is difficult because of subunit instability. We achieved the refolding of Escherichia coli-expressed human IL-12 by a stepwise dialysis method, preventing the formation of insoluble aggregates by adding a redox reagent and an aggregation suppressor. We also constructed a tumor-specific IL-12 protein, each subunit of which was fused with one chain of variable domain fragment (Fv) of anticarcinoembryonic antigen (CEA) antibody T84.66 (aCEA-IL12). Fusion of IL-12 with Fv greatly increased the yield of functional heterodimer. Several assays have indicated that the Fv domain and IL-12 domain of the fused protein had cognate biological activities, and it enhanced the cytotoxicity of T-LAK cells for the cancer cell line.

Marcadores tumorales serológicos en cirugía hepatobiliopancreática / Serological tumor markers in hepatobiliopancreatic surgery

Los marcadores tumorales son, en general, proteínas que se asocian a enfermedades malignas. Pueden detectarse en sangre periférica y son útiles para el cribado, el diagnóstico, la estadificación, el pronóstico y el seguimiento de estas enfermedades.También pueden servir para detectar la presencia de metástasis ocultas, monitorizar la respuesta al tratamiento y descubrir recurrencias.En el presente artículo se exponen los principales marcadores tumorales serológicos usados en cirugía hepatobiliopancreática. La alfafetoproteína es el marcador más útil en el hepatocarcinoma, especialmente para el diagnóstico y la detección de las recurrencias tras el tratamiento. El antígeno carcinoembrionario será util en los casos de metástasis hepáticas de cáncer colorrectal. El CA 19.9 puede ayudar en el diagnóstico diferencial de las tumoraciones pancreáticas. El antígeno carcinoembrionario, el CA 19.9 y el CA 125 pueden ser útiles en casos de tumores de las vías biliares (AU)

Valor da dosagem do antígeno carcinoembrionário, da fosfatase alcalina e da gama-glutamil transpeptidase no seguimento de pacientes com câncer de cólon e de reto / Value of the dosage of the carcinoembryonic antigen, alkaline phosphatase and gamma-glutamyl transpeptidase in the pursuing of patients with cancer of colon and rectum

Os marcadores biológicos representam os exames de primeira linha na investigação das recidivas neoplásicas. No câncer colorretal, a relação custo-benefício da realização simultânea das dosagens séricas de CEA, fosfatase alcalina (FA) e gama-glutamil-transpeptidase (GT) e a validade de se continuar dosando CEA, quando o exame inicial é normal,não estão claras na literatura. Com o objetivo de estudar o comportamento desses marcadores na evolução dos tumores colorretais, foram estudados 100 pacientes,acompanhados no PO por tempo médio de 30 meses,no período de janeiro de 1991 a fevereiro de 1999 (8 anos). Cinqüenta e três eram do sexo masculino e quarenta e sete do feminino,com idade média de 60 anos. Todos os pacientes foram submetidos a tratamento cirúrgico,sendo que 12 já apresentavam metástases e 17 apresentaram recidiva durante o seguimento. Os resultados mostraram sensibilidade e especificidade de CEA, FA e GT em detectar metástases na operação de, respectivamente, 75por cento; 64por cento; 25por cento; 93por cento; 36por cento; 86por cento e em recidivas de 93por cento; 98por cento; 36por cento; 76por cento; 42por cento; 80por cento, respectivamente. O CEA quase sempre se elevou meses antes que FA e -GT, exceto em um paciente com metástases e noutro com recidiva. Dos pacientes que apresentaram metástases ou recidivas 45,9por cento tinham CEA inicial aumentado e somente 19,2por cento tinham CEA normal. Todos os pacientes que apresentaram CEA normal no Pré-OP,tiveram elevação desse marcador quando se diagnosticou a recidiva,exceto no paciente nº12. Concluiu-se que não há benefício na dosagem da FA e da dGT para diagnóstico de metástases hepáticas e que o CEA deve fazer parte do rastreamento de metástases, mesmo quando o seu valor inicial for normal.

Rejection of syngeneic colon carcinoma by CTLs expressing single-chain antibody receptors codelivering CD28 costimulation.

A new strategy to improve the therapeutic utility of redirected T cells for cancer involves the development of novel Ag-specific chimeric receptors capable of stimulating optimal and sustained T cell antitumor activity in vivo. Given that T cells require both primary and costimulatory signals for optimal activation and that many tumors do not express critical costimulatory ligands, modified single-chain Ab receptors have been engineered to codeliver CD28 costimulation. In this study, we have compared the antitumor potency of primary T lymphocytes expressing carcinoembryonic Ag (CEA)-reactive chimeric receptors that incorporate either TCR-zeta or CD28/TCR-zeta signaling. Although both receptor-transduced T cell effector populations demonstrated cytolysis of CEA(+) tumors in vitro, T cells expressing the single-chain variable fragment of Ig (scFv)-CD28-zeta chimera had a far greater capacity to control the growth of CEA(+) xenogeneic and syngeneic colon carcinomas in vivo. The observed enhanced antitumor activity of T cells expressing the scFv-CD28-zeta receptor was critically dependent on perforin and the production of IFN-gamma. Overall, this study has illustrated the ability of a chimeric scFv receptor capable of harnessing the signaling machinery of both TCR-zeta and CD28 to augment T cell immunity against tumors that have lost expression of both MHC/peptide and costimulatory ligands in vivo.

Chronotolerance of experimental radioimmunotherapy: clearance, toxicity, and maximal tolerated dose of 131I-anti-carcinoembryonic antigen (CEA) IgG as a function of time of day of dosing in a murine model.

The temporal variation in bone marrow proliferation has been used to help define the optimal time of day to dose with approximately 30 chemotherapeutic agents, so that treatment efficacy is maximised and toxicity is minimised. Since myelosuppression is also the dose-limiting toxicity for most forms of radioimmunotherapy, we hypothesised that time of day of administration might also influence tolerance for radioantibody therapy. Bone marrow proliferative activity in BALB/c mice was determined using cell cycle analysis of propidium iodide-stained bone marrow samples collected at 3 h intervals. Myelosuppression was determined at weekly intervals after a therapeutic dose of 131I-NP-4 anti-CEA (carcinoembryonic antigen) intact IgG at either 0900 h (2 h after light onset [HALO]), 1300 h (6 HALO) or 1600 h (9 HALO). The highest bone marrow proliferative activity was noted between 20 HALO (0300 h) and 4 HALO (1100 h), and the lowest activity could be measured at 10-13 HALO (1700-2000 h). Seven days after a maximal tolerated dose (MTD) of radioantibody, granulocyte reduction was 50% at both 2 and 6 HALO and only 32% at 9 HALO (P < 0.003). Fourteen days after radioantibody therapy, an 87% granulocyte suppression was observed in mice treated at 2 HALO and only a 64% granulocyte loss was noted in the 9 HALO treated group (P < 0.001). The 2 HALO group recovered earlier than the 9 HALO group (P < 0.013; 22% loss from the 2 HALO dose and 40% loss from the 9 HALO dose) on day 28 post-radioimmunotherapy. The difference in magnitude of neutropenia, rather than duration, was critical for establishing the MTD. A 30% increase in the MTD was possible if mice were dosed at 9 HALO (320 microCi) versus 2 HALO (240 microCi). These studies suggest that principles of chronobiology may govern the magnitude of toxicity and the highest dose tolerated in radioantibody therapy in the same way that it does for cytotoxic drug therapy.

Phase I trial of a recombinant vaccinia virus encoding carcinoembryonic antigen in metastatic adenocarcinoma: comparison of intradermal versus subcutaneous administration.

The principal objectives of this trial were twofold: (a) to examine the safety and relative efficacy of intradermal needle injection versus s.c. jet administration of a carcinoembryonic antigen (CEA)-encoding recombinant vaccinia virus (rV-CEA) over a limited dose range and (b) to evaluate CEA-specific immune responses or antitumor effects induced by rV-CEA vaccination. Patients were randomly assigned to one of two groups, depending upon the technique of vaccine administration. All 20 patients received two doses of 10(7) or 10(8) pfu of rV-CEA at a 4-week interval. Toxicity was limited to modest local inflammation at the inoculation site as well as low-grade fever and increased fatigue, each affecting fewer than 20% of the patients. No evidence of CEA-specific lymphoproliferation, interleukin 2 release, delayed-type hypersensitivity, or antibody response was observed. Thus, the efficacy comparison between the two administration techniques was based upon the induction of immune responses to the vaccinia virus vector. Both techniques induced vaccinia-specific lymphoproliferation, interleukin 2 release, and antibody responses of comparable magnitude and frequency as well as protected 80% of patients against pustule formation following vaccinia scarification. Thus, there is no compelling reason to recommend one administration technique over the other based upon toxicity or efficacy. We have selected s.c. jet injection for subsequent trials of rV-CEA based on the ability to accommodate larger injection volumes, enhanced standardization between clinicians, and avoidance of needles that could transmit the vaccine or blood-borne pathogens to health care workers. We recommend use of 10(8) pfu doses for subsequent trials of recombinant vaccinia virus vaccines based upon the favorable toxicity profile and more consistent local pustule formation indicative of an adequate inoculation of live virus. No objective clinical responses to the rV-CEA vaccine were observed among this population of patients with widely metastatic adenocarcinoma.