Treatment of metastatic disease in patients with neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GENTs) compromise a heterogeneous group of relatively uncommon neoplasms with a yearly incidence rate of 1.2 to 3.0 per 100,000 population. These tumors share numerous histologic and biologic features, allowing their consideration as a common entity. They are postulated to arise from neuroendocrine cells, but most are not from neural crest origin. Their predominant site of origin is the gastrointestinal tract, where most involve the small intestine and appendix, but are also found in the adrenal medulla, bronchopulmonary system, pancreas, thyroid, parathyroid, and paraganglia cells. A common feature is their often indolent course, but some tumors are poorly differentiated and behave aggressively. This article addresses the surgical management of endocrine malignancies and the treatment of metastatic disease in patients with neuroendocrine tumors.     

Complete response in 5 out of 38 patients with advanced hepatocellular carcinoma treated with stem cell differentiation stage factors: case reports from a single centre

Hepatocellular carcinoma (HCC) represents the third cause of cancer-related death. Because HCC is multi-centric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors (SCDSF) taken from zebra fish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent adult stem cells. In such a trial the patients, with "intermediate" and "advanced" HCC according to BCLC/AASLD guidelines, presented benefit in terms of performance status (PS) and objective tumoral response, with some cases (2.4%) of complete response (CR). The aim of this cohort study is to report the experience of a tertiary referral center on the evidence of cases of CR in patients with "advanced" stage HCC treated with SCDSF as supportive care. CR was regarded as sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of AFP levels. Out of 49 patients consecutively recruited and retrospectively evaluated, 38 had "advanced" stage and 11 "terminal" stage. In 5 patients with "advanced" stage a sustained CR was reported (13.1%). Improvement on PS was obtained in 17 patients (34.6%). No side effects occurred. SCDSF treatment confirmed its efficacy in patients with "advanced" HCC, in terms of PS and tumoral response.     

Potential pitfalls of crossover and thoughts on iniparib in triple-negative breast cancer

As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control arm to "crossover" and receive the experimental therapy after disease progression. Although some researchers worry that allowing such crossover may abolish gains in progression-free survival in the experimental arm, the possibility that crossover might inadvertently benefit the experimental arm has not been addressed. In clinical trials in which the experimental agent has little or no intrinsic activity and is used to modulate an active combination, such crossover might negatively affect the overall survival of the control arm. Because resistance to the active combination--manifested as disease progression--has occurred, the likelihood of benefit from adding the experimental drug is reduced. Consequently, patients who were randomly assigned to the control arm continue to receive the now inactive combination after crossover, whereas patients in the experimental arm who discontinue study participation may seek out potentially effective salvage regimens. This difference in subsequent therapies may confer an advantage to the experimental arm that is manifested as gains beyond those achieved in progression-free survival, gains that occur not because the experimental therapy induced a change in tumor biology that persists beyond treatment discontinuation but because the control arm suffers by continuing to receive a therapy on which their tumor is progressing. Such an outcome may explain the recently reported trial results for iniparib in triple-negative breast cancer. Given that allowing patients in the control arm to receive the experimental agent may confound interpretation of overall survival, such crossover should not be used indiscriminately, especially if the experimental agent has little or no intrinsic activity.     

Correlations between the abnormal development of the skull base and facial skeleton growth in anterior synostotic plagiocephaly: the predictive value of a classification based on CT scan examination

Background

Anterior cranial plagiocephaly, depending on the early hemicoronal suture fusion, is the most relevant form of plagiocephaly in terms of clinical implications. Its estimated incidence ranges between 0.4 and 1 per 1,000 live births. In the present report, we aim at validating the classification of Di Rocco and Velardi, proposing a scheme based on basicranium analysis using CT scans and its predictive value by evaluating the developmental characteristics of a population of adult subjects affected by anterior plagiocephaly who had underwent the surgical correction in the first months of life.

Materials and methods

The group of patients here considered was retrieved from among all patients operated upon for craniostenosis in the pediatric neurosurgery unit of Policlinico Gemelli in Rome between January 1, 1980 and December 31, 1989. The study group consisted of 13 patients, seven females and six males, affected by anterior synostotic plagiocephaly ranging in age between 20 and 32?years (mean 25.54?years). We also formed a group of unaffected patients in order to control for normal variability in the population. The subjects of the study group were evaluated using CT scan exams and cephalometric analyses were performed using three-dimensional reconstruction.

Discussion and conclusion

In this study, we were able to associate a facial phenotype to confirm the predictive value of the classification proposed. It is highly probable that the different outcomes depend on the different degrees of involvement in the synostotic process by the various skull base sutures which were essentially unaffected by the surgical procedures.     

Prognostic value of symptom burden for overall survival in patients receiving chemotherapy for advanced nonsmall cell lung cancer

BACKGROUND:

Patient–reported outcomes have shown independent prognostic value for patients with nonsmall cell lung cancer (NSCLC). However, translating patient‐reported outcomes into useful prognostic information for individual patients has been problematic.

METHODS:

A total of 94 patients with advanced NSCLC and an Eastern Cooperative Oncology Group performance status (PS) of 0 to 2 who qualified for chemotherapy rated symptom severity using the M. D. Anderson Symptom Inventory before and after their first chemotherapy cycle. Prognostic values of baseline symptoms and changes in symptom severity were examined by Cox proportional hazards models.

RESULTS:

In multivariate analysis, controlled for demographic and other factors, baseline coughing rated ≥4 independently predicted significantly higher risk for shorter survival (hazards ratio [HR], 8.69; P < .0001). Patients with coughing ≥4 and a PS of 2 were more likely to have shorter survival (HR, 20.6; P < .0001) than patients with coughing <4 and a PS of 0 to 1. A 1–point or greater increase in severity of fatigue (P < .05), shortness of breath, or poor appetite (P < .01) from baseline to the end of the first chemotherapy cycle was also found to be independently associated with higher risk for poor survival.

CONCLUSIONS:

An increased risk for shorter survival was indicated by moderate to severe coughing at baseline or by increased fatigue or shortness of breath during the first chemotherapy cycle in patients with advanced NSCLC. Although cross–validation is needed, these data suggest that an individual patient's symptom severity scores, quickly obtainable in the clinic, might contribute clinically useful information for treatment planning for that patient. Cancer 2010. © 2010 American Cancer Society.     

Assessing vaccine potency using TCRmimic antibodies

Dendritic cells (DCs) are highly specialized antigen-presenting cells of the immune system that are efficient at presenting peptide-antigen for the activation of T cells and are often the cell type of choice for vaccine targeting by virtue of high expression levels of MHC and costimulatory molecules. Since the level of peptide-MHC complex significantly influences stimulation of T cells, a proof-of-concept potency assay was developed to directly examine the presentation and density of MHC class I peptides derived from the processing of a model tumor antigen, (hCGbeta), on the surface of DCs. In this study we first generated antibodies (TCR mimics or TCRm) to two peptide-HLA-A*0201 epitopes derived from hCGbeta designated as TMT (40-48) and GVL (47-55). Characterization of each TCRm by ELISA and flow cytometric analysis, demonstrated specific binding to soluble recombinant HLA-A2 protein and HLA-A2.1+ T2 cells loaded with relevant peptide. TCRm reactive against the TMT and GVL epitopes blocked granzyme-B production by peptide-specific cytotoxic T lymphocytes (CTL) lines further supporting their recognition specificity. For the assessment of antigen presentation function, human immature monocyte-derived DCs (iDCs) were treated with the mannose receptor targeting vaccine, B11-hCGbeta and matured with Poly I:C. The TMT and GVL epitope reactive CTL lines responded to vaccine-treated but not vehicle-treated mature DCs (mDCs) with TMT and GVL TCRm specifically blocking IFN-gamma production. The TCRm were then used to directly confirm specific peptide-MHC complexes on mDCs. TCRm staining of vaccine-treated mDCs showed detection of the TMT and GVL peptide-HLA-A2 complexes. These findings demonstrate that TCRms may be important tools for determining the potency of DC-based vaccines.