Association of creatine kinase and skin toxicity in phase I trials of anticancer agents.

BACKGROUND: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. METHODS: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. RESULTS: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l(-1)) compared with G1 (median 81 U l(-1)) and no rash (median 55 U l(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. CONCLUSION: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials.

Creatinine clearance is associated with toxicity from molecularly targeted agents in phase I trials.

OBJECTIVES: This study aimed to evaluate any correlations between baseline creatinine clearance and the development of grade 3/4 toxicities during treatment within oncology phase I trials of molecularly targeted agents where entry criteria mandate a serum creatinine of ≤ 1.5 × the upper limit of normal. METHODS: Documented toxicity and creatinine clearance (calculated by the Cockcroft-Gault formula) from all patients treated with molecularly targeted agents in the context of phase I trials within our centre over a 5-year period were analyzed. RESULTS: Data from 722 patients were analyzed; 116 (16%) developed at least one episode of grade 3/4 toxicity. Patients who developed a late-onset (>1 cycle) grade 3/4 toxicity had a lower creatinine clearance than those who did not (82.69 ml/min vs. 98.97 ml/min; p = < 0.001). CONCLUSION: Creatinine clearance (even when within normal limits) should be studied as a potential factor influencing late toxicities in the clinical trials of molecularly targeted anti-cancer drugs.

Analysis of the concordance in the EGFR pathway status between primary tumors and related metastases of colorectal cancer patients:implications for cancer therapy.

Patients with metastatic Colorectal Cancer (mCRC), in which primary tumors are KRAS mutated, have no response to anti-EGFR therapy. However, less than half of mCRC patients with KRAS wild-type primary tumors respond to anti-EGFR therapy. Other downstream effectors of the EGFR pathway are being analyzed to fine-tune KRAS predictive value. However, as the primary tumor is the tissue of analysis that determines the use of anti-EGFR therapy in advanced disease, a high concordance in the status of these effectors between primary tumors and related metastases is required. We analyzed the concordances of downstream EGFR effectors in tumoral pairs of primaries and related metastases in a series of KRAS wild-type patients. One hundred seventeen tumoral pairs from patients with CRC were tested for KRAS mutational status. The level of concordance in the presence of KRAS mutations was 91% between the primary tumor and related metastases. The 70 pairs with KRAS wild-type primary tumors were further analyzed for BRAF and PIK3CA mutational status and for EGFR, PTEN and pAKT expression, and the number of concordant pairs was 70 (100%), 66 (94%), 43 (61%), 46 (66%) and 36 (54%), respectively. Our findings suggest that the mutational status of KRAS, BRAF and PIK3CA in the primary tumor is an adequate surrogate marker of the status in the metastatic disease. On the other hand, the immunohistochemical analysis of EGFR, PTEN and pAKT showed a much higher degree of discordance between primaries and related metastases.

Prognostic value of carcinoembryonic antigen level in rectal cancer treated with neoadjuvant chemoradiotherapy.

BACKGROUND: The purpose of this study was to identify clinical and pathological parameters to improve prediction of disease-free survival (DFS) and overall survival (OS) in patients treated with neoadjuvant chemoradiotherapy for rectal cancer. METHODS: Between July 1995 and May 2007, 148 patients with primary rectal adenocarcinoma received neoadjuvant chemoradiotherapy followed by mesorectal excision. Preoperative treatment included various protocols, UFT and leucovorin (28%) and oxaliplatin-based chemotherapy (72%). Clinical and pathological variables were evaluated in relation to patient outcomes. RESULTS: Thirteen percent of patients achieved a complete pathologic response. No response or minimal response as defined by Dworak (Tumor Regression Grade 0/1) was observed in 30 patients (20%). At a median follow-up of 37 months, the 3-year DFS and OS were 64% and 83%, respectively. Pre-treatment serum carcinoembryonic antigen (CEA) level

Meningeal relapse by follicular lymphoma as a single mass

Follicular lymphoma is the second most common lymphoma throughout the world. Its course is usually indolent. Affection of Central Nervous System by a follicular lymphoma is usually as primary disease, and secondary affection is usually due to high-grade transformation. In this case-report we describe a young patient who presented a follicular lymphoma which secondary affected the central nervous system without high grade transformation (AU)

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Dolor abdominal y fiebre de dos meses de evolución / Abdominal pain and fever with two months of duration

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Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethyl-hydrazine (DMH).

OBJECTIVE: Interleukin 12 (IL-12) is a cytokine that may enhance the proliferation and cytotoxic activity of T lymphocytes and natural killer (NK) cells. A relationship between extensive intratumoral infiltration of NK cells and longer survival rates in colorectal cancer (CRC) patients was previously noted. Preliminary evidence suggests that the combined administration of IL-12 and IL-2 may produce additive immunomodulatory activity. The purpose of this study was to determine whether the systemic administration of IL-12 (+/- IL-2) may induce an immune response against CRC as induced by 1,2-dimethylhydrazine (DMH). METHODS: Sixty-five 6-week-old Wistar rats were treated with weekly subcutaneous injections of DMH for 26 weeks at a dose of 20 mg/kg of body weight. Once tumoral induction was over, the animals were randomly allocated to one of three groups: I, control; II, intraperitoneal injections of IL-12; III, intraperitoneal injections of IL-12 combined with IL-2. At 30 weeks, all surviving animals were sacrificed. We studied the following parameters in each rat--number of tumors, size of tumors, and total tumoral volume. Tumor samples were studied using the monoclonal antibody CD 57 for the detection of NK cells. The extent of NK infiltration was classified as small, less than 50 NK cells/50 high-power field (HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive, more than 150 NK cells/50 HPF. RESULTS: Thirty-five rats died before completion of the carcinogen exposure, and 30 rats were randomized (10 each group). In group II, 2 animals died during treatment. All rats in groups I and III developed tumors, while in group II two rats (25%) were tumor-free. Moreover, only one rat in group II developed multiple neoplasms, in contrast with group I and group III, where six rats (60%) and seven rats (70%), respectively, had more than one tumor. We found statistically significant differences in the mean number of tumors found in group II when compared to group I (p = 0.028) and group III (p = 0.019). Other parameters measured, such as biggest tumor size and total tumoral volume were found to be lower in group II, although no statistical differences were found between groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p = 0.077) and 70% in group III (p = 0.02). CONCLUSION: The administration of DMH to rodents provides a reliable and consistent means of inducing CRC that may be suitable for the evaluation of anti-cancer therapies. Our findings suggest that IL-12 is effective against the development of experimental CRC. Its antineoplastic effect could be attributed to the stimulus of this cytokine on the intratumoral infiltration of NK cells.

Estudio de la respuesta antitumoral de la interleucina- 12 en cáncer de colon inducido mediante 1, 2-dimetilhidracina (DMH) / Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1, 2 dimethyl-hydrazine (DMH)

Objetivo: la interleucina (IL-12) es una citocina que estimulala proliferación y la actividad citotóxica de los linfocito T y las célulasnatural killer (NK). En trabajos previos se ha observado unarelación entre la infiltración intratumoral de células NK y una mayorsupervivencia en carcinomas colorrectales (CCR). Existen evidenciasde un efecto aditivo en la actividad inmunomoduladora dela asociación de IL-12 con IL-2. Así, nos hemos propuesto el estudiode la capacidad de respuesta inmune antitumoral, tras la administraciónsistémica de IL-12 sola o combinada con IL-2, en unmodelo experimental de CCR inducidos mediante la administraciónde 1,2-dimetilhidracina (DMH).Método: sesenta y cinco ratas Wistar de 6 semanas a las quese administró en inyección subcutánea una dosis semanal deDMH a razón de 20 mg/kg de peso durante 26 semanas. Finalizadoel periodo de inducción, los animales se distribuyeron aleatoriamenteen tres grupos. I: grupo control. Grupo II, se administróIL-12 recombinante murina. Grupo III: se administró IL-12, combinadacon IL-2. Las ratas se sacrificaron en la semana 30, estudiándoselos siguientes parámetros: número y localización de tumores,tamaño y carga tumoral. Se realizó inmunotinción paracélulas NK con anticuerpo monoclonal CD 57. Se establecierontres grupos según la cuantía del infiltrado: leve, menos 50 células/50 campos de gran aumento (CGA), moderado, entre 50 y150/células/50 CGA y elevado, más de 150 células/50 CGA.Resultados: durante la inducción tumoral fallecieron 35 ratas.Las 30 restantes fueron distribuidas aleatoriamente en 3 gruposde 10. Durante las 2 semanas de tratamiento fallecieron 2 ratas,del grupo II. Todas las ratas de los grupos I y III desarrollaronCCR. En el grupo II, dos animales (25%) no desarrollaron tumor.Sólo una rata del grupo II desarrolló neoplasias múltiples en contrastecon el grupo I en el que esto ocurrió en 6 ratas (60%) y siete(70%) en el grupo III. Se hallaron diferencias estadísticamentesignificativas en el número de tumores desarrollados entre el grupoII respecto al I (p = 0,028) y al grupo III (p = 0,019). El mayortamaño tumoral o el volumen tumoral total fueron menores en elgrupo II pero no se obtuvieron diferencias estadísticamente significativascon los restantes grupos. Un 10% de las ratas del grupo Ipresentó moderada o extensa infiltración, frente al 60% del grupoII (p = 0,077) y al 70% del grupo III (p = 0,02). Entre los grupos IIy III no se encontró ninguna diferencia estadística (p = 1).Conclusión: El modelo usado de inducción tumoral es un modeloútil para el estudio de la eficacia de distintos tratamientos antitumorales.Pensamos que la IL-12 tiene un efecto antineoplásicofrente al desarrollo de tumores experimentales, lo que puede seratribuido, al menos en parte, al estímulo ejercido por esta citocinasobre los infiltrados intratumorales de células NK

Objective: interlukin 12 (IL-12) is a cytokine that may enhancethe proliferation and cytotoxic activity of T lymphocytesand natural killer (NK) cells. A relationship between extensive intratumoralinfiltration of NK cells and longer survival rates in colorectalcancer (CRC) patients was previously noted. Preliminaryevidence suggests that the combined administration of IL-12 andIL-2 may produce additive immunomodulatory activity. The purposeof this study was to determine whether the systemic administrationof IL-12 (+/- IL-2) may induce an immune responseagainst CRC as induced by 1,2-dimethylhydrazine (DMH).Methods: sixty-five 6-week-old Wistar rats were treated withweekly subcutaneous injections of DMH for 26 weeks at a dose of20 mg/kg of body weight. Once tumoral induction was over, theanimals were randomly allocated to one of three groups: I, control;II, intraperitoneal injections of IL-12; III, intraperitoneal injectionsof IL-12 combined with IL-2. At 30 weeks, all surviving animalswere sacrificed. We studied the following parameters in eachrat – number of tumors, size of tumors, and total tumoral volume.Tumor samples were studied using the monoclonal antibodyCD 57 for the detection of NK cells. The extent of NK infiltrationwas classified as small, less than 50 NK cells/50 high-power field(HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive,more than 150 NK cells/50 HPF.Results: thirty-five rats died before completion of the carcinogenexposure, and 30 rats were randomized (10 each group). Ingroup II, 2 animals died during treatment. All rats in groups I andIII developed tumors, while in group II two rats (25%) were tumorfree.Moreover, only one rat in group II developed multiple neoplasms,in contrast with group I and group III, where six rats(60%) and seven rats (70%), respectively, had more than one tumor.We found statistically significant differences in the meannumber of tumors found in group II when compared to group I(p=0.028) and group III (p = 0.019). Other parameters measured,such as biggest tumor size and total tumoral volume were found tobe lower in group II, although no statistical differences were foundbetween groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p =0.077) and 70% in group III (p = 0.02).Conclusion: The administration of DMH to rodents provides areliable and consistent means of inducing CRC that may be suitablefor the evaluation of anti-cancer therapies. Our findings suggest thatIL-12 is effective against the development of experimental CRC. Itsantineoplastic effect could be attributed to the stimulus of this cytokineon the intratumoral infiltration of NK cells