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Contains fulltext : 127308pub.pdf (publisher's version ) (Closed access), KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti-EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti-EGFR treatment in a small proportion of patients.

BACKGROUND AND AIM: To assess the effectiveness of the potential advantages with 3-dimensional-based treatment planning versus 2-dimensional pelvic bone-based treatment planning in patients with rectal cancer, controlled for clinical stage. METHODS AND MATERIALS: Areas at risk from computed tomography in 30 patients were delineated: mesorectum, presacral, internal iliac, obturator and external iliac nodes. Two planning target volumes per patient were created: PTV_T3 (M + PSN + ON + IIN) and PTV_T4 (M + PSN + ON + IIN + EIN). Two- and 3-dimensional treatment plans for each planning target volume were calculated. Three analyses were performed: 1) mean volume receiving doses >95% and >105%; according to the percentage of prescribed dose to cover at least 95% of the planning target volume, the treatment plan was defined as optimal dose >95%, acceptable dose between 95% and 90%, inferior dose <90%; 2) comparison of the percentage of volume covered by the dose for 2- vs 3-dimensional; 3) determination of the doses at which the lack of volume coverage started to decrease significantly. RESULTS: For PTV_T3, the following was seen: 1) 2D vs 3D comparison showed optimal PTV_T3 coverage in 76.7% and 96.7%, respectively; 2) 2D vs 3D TP coverage difference was significant between 29%-95% of the total dose; 3) the lack of volume coverage started at 30% for 2D and 89% for 3D. For PTV_T4, the following was seen: 1) 2D vs 3D comparison showed an optimal PTV_T4 coverage in 33.3% and 86.7%, respectively; 2) 2D vs 3D TP coverage difference was significant between 7%-97% of the total dose; 3) the lack of volume coverage started at 7% for 2D and 87% for 3D. CONCLUSIONS: The 3D treatment planning was superior to 2D treatment planning in covering areas at risk for pelvic recurrence in patients treated for rectal cancer. The areas with suboptimal coverage may lead to an increased risk of recurrence and should be correlated with the patterns of recurrence.

The aim of this study is to propose and validate an original new class of solutions for three-dimensional conformal radiation therapy (3DCRT) treatment planning for non-small cell lung cancer (NSCLC) according to the different patterns of disease presentation (on the basis of tumor location and volume) and to explore beams arrangement (planar or no-planar solutions) to respect dose constraints to the lung parenchyma. Benchmarks matched to validate the new approach are interuser reproducibility and saving on planning time. Tumor location was explored and specific categories created according to the tumor volume and location. Therefore, by applying planar and no-planar 3D plans, we searched for an optimization of the beams arrangement for each category. Dose-volume histograms (DVHs) were analyzed and a plan comparison performed. Results were then validated (class solution planning confirmation) by applying the same strategy to another group of patients. This has been realized at two dose levels (50.4 and 59.4 Gy). Fifty-nine patients were enrolled in this dosimetric study. In the first 27 patients ("exploratory sample") three main planning target volume location categories were identified according to the pattern of the disease presentation: (1) centrally located; (2) peripheral T and mediastinal N (P+N); and (3) superior sulcus. Original class solutions were proposed for each location category. On the next 32 patients ("validation sample"), the treatment planning started directly with the recommended approach. Mean V20Gy value was 18.8% (SD ± 7.25); mean V30Gy:12% (SD ± 4.05); and mean lung dose: 11.6Gy (SD ± 5.77). No differences between the two total dose level groups were observed. These results suggest a simple and reproducible tool for treatment planning in NSCLC, allowing interuser reproducibility and cutting down on planning time. © 2010 American Association of Medical Dosimetrists.

Background: The complexity of modern oncology, based on multi-disciplinary management of cancer patients, results in critical amounts of data, leading to problems in managing and sharing information. Methods: Spider is a multi-user system, based on integrated palm technology, created to facilitate data recording, managing and sharing, through Intra-Internet connection. By palms or PCs, data are collected directly at the place where information is generated. Every health professional can edit, modify and display all of the patient's data according to his/her operational level. A powerful engine enables Spider's users to create series of cancer patients' appointments linked to one another by specified time intervals and save them as "Protocols". Applying a protocol to the patient, the system schedules a wave of appointments and alerts keeping the correlation with time intervals previously specified by specialists. XML technology is integrated with traditional RDBMS technology to build the Electronic Patient File (EPF) updated during each patient's admission or consultation, including any new diagnostic/therapeutic events and collective decisions. The system automatically produces all clinical documents routinely in use (discharge letters, exams' requests, etc.). Results: Spider's different archives include 4387 patients (Prostate, n=849; Lung, n=1596; Rectum, n=1541; Head & Neck, n=291; Cervix, n=110). The EPF includes specific modules: staging, surgery, chemotherapy, hormonotherapy, radiotherapy, toxicity, pathology, follow-up and clinical summary. Spider Hospitalization displays the ward map and important details of patients occupying each single bed. Conclusions: Spider makes data capture easier and accurate. The availability of large amounts of information accelerates outcome analysis and improves cancer research.

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Aim: To evaluate by immumohistochemistry the presence of DR subtype 2 (D2R) in well differentiated NETs of different sites and in normal islet cells. Background: Recent data in vitro and in vivo support that dopaminergic drugs might exert an inhibitory effect on hormone secretion and, possibly, on tumor growth in neuroendocrine tumors (NET)s. Their potential therapeutic role needs the demonstration of dopamine receptors (DR) in tumor cells. Little is known on the expression of DR in NETs. Results: 85% of samples (100% of bronchial carcinoids and 93% of islet cell tumors) showed positivity for D2R; intensity of immunoreaction in NETs was similar or higher than in pituitary (54% and respectively 31% of cases). D2R positivity in more than 70% of tumor cells was observed in 46% of samples. Same intensity of D2R-immunoreactivity was found in pituitary and normal islet cells. No differences in D2R expression were recorded on considering tumor grading, size, proliferative activity, presence of metastases, endocrine activity and gender. A significant difference (62.5% vs 96.4%, p = 0.039) was observed in the prevalence of D2R expression between patients with more aggressive tumors and patients without recurrence/progression of disease during follow-up. Methods: 46 NET samples from 44 patients and normal endocrine pancreatic tissue were studied. D2R-staining was performed on NETs and compared with six non-secreting pituitary adenomas and related to clinical-pathological data. Conclusion: The present data demonstrate a high expression of D2R in NETs; this finding is of clinical relevance in view of the potential role of dopaminergic drugs in inhibiting secretion and/or cell proliferation in NETs. ©2008 Landes Bioscience.

Background: Neoplastic microfoci have frequently been found in the mesorectum, with poor outcome. In this study, incidence and clinical significance of mesorectal microfoci (MMF) were analyzed in patients operated on for rectal cancer following neoadjuvant chemoradiation. Methods: A case series of 68 patients with extraperitoneal rectal cancer treated with neoadjuvant chemoradiation and surgery (including total mesorectal excision) were investigated for presence of neoplastic MMF. Results: MMF were found in 26 cases (38.2%). Increasing incidence of microfoci was statistically related to pathologic involvement of the bowel wall (P = 0.0006), Mandard's tumor regression grading (P = 0.0006), and pathologic neoplastic mesorectal involvement (P < 0.00001). None of the nine patients with complete tumor disappearance displayed both microfoci and lymph node metastasis. Only one local recurrence developed in a patient with multiple MMF. One out of nine pT0 or TRG1 patients (11.1%) had distant metastases compared with 15 out of 59 pT1-4 or TRG2-5 (25.4%, P = 0.70). Conclusions: A remarkable incidence of MMF was found following chemoradiation. However, when this therapy induced complete regression of primary tumor (pT0-TRG1), we found that node metastases and neoplastic MMF also disappeared. These features should be confirmed to assess the impact of these microfoci in treatment decision making in rectal cancers. © 2006 Society of Surgical Oncology.

PURPOSE: The survival advantage of preoperative radiotherapy in patients with rectal cancer is still a matter of debate, because its incremental benefit in the total mesorectal excision setting is unclear. This study was designed to evaluate early and long-term results of preoperative radiotherapy plus intraoperative radiotherapy in a homogeneous population of T3 middle and lower rectal cancer patients submitted to total mesorectal excision. METHODS: A series of 113 patients with middle and lower T3 rectal cancer consecutively submitted to total mesorectal excision at a single surgical unit from 1991 to 1997 were divided into two groups according to type of neoadjuvant treatment: preoperative radiotherapy (38 Gy) plus intraoperative radiotherapy (10 Gy; n = 69), and no preoperative treatment (total mesorectal excision; n = 44). Standard statistical analyses were used to evaluate early (downstaging, intraoperative factors, hospital morbidity, and mortality rates) and long-term results (recurrence and survival). RESULTS: Overall, 68.2 percent of patients were downstaged by the preoperative regimens (TO specimens in 3 cases). Postoperative complications were comparable in the two groups. Five-year, disease-specific survival was 81.4 and 58.1 percent in preoperative radiotherapy plus intraoperative radiotherapy group and total mesorectal excision group, respectively (P = 0.052). Corresponding figures for disease-free survival were 73.1 and 57.2 percent in the two groups, respectively (P = 0.096). The rates of local recurrence at five years were 6.6 and 23.2 percent in preoperative radiotherapy plus intraoperative radiotherapy and total mesorectal excision groups, respectively (P = 0.017). CONCLUSIONS: Preoperative radiotherapy plus intraoperative radiotherapy associated with total mesorectal excision reduce local recurrence rate and improve survival in T3 rectal cancer compared with total mesorectal excision alone.