Presented by the Kirsten ras in Colorectal Cancer Collaborative Group

Purpose: Many studies have evaluated the role of high levels of microsatellite instability (MSI) as a prognostic marker and predictor of the response to chemotherapy in colorectal cancer (CRC); however, the results are not conclusive. The aim of this study was to analyze the prognostic significance of high levels of MSI (MSI-H) in CRC patients in relation to fluorouracil-based chemotherapy. Experimental Design: In three different institutions, 1,263 patients with CRC were tested for the presence of MSI, and CRC-specific survival was then analyzed in relation to MSI status, chemotherapy, and other clinical and pathologic variables. Results: Two hundred and fifty-six tumors were MSI-H (20.3%): these were more frequently at a less advanced stage, right-sided, poorly differentiated, with mucinous phenotype, and expansive growth pattern than microsatellite stable carcinomas. Univariate and multivariate analyses of 5-year–specific survival revealed stage, tumor location, grade of differentiation, MSI, gender, and age as significant prognostic factors. The prognostic advantage of MSI tumors was particularly evident in stages II and III in which chemotherapy did not significantly affect the survival of MSI-H patients. Finally, we analyzed survival in MSI-H patients in relation to the presence of mismatch repair gene mutations. MSI-H patients with hereditary non–polyposis colorectal cancer showed a better prognosis as compared with sporadic MSI-H; however, in multivariate analysis, this difference disappeared. Conclusions: The type of genomic instability could influence the prognosis of CRC, in particular in stages II and III. Fluorouracil-based chemotherapy does not seem to improve survival among MSI-H patients. The survival benefit for patients with hereditary non–polyposis colorectal cancer is mainly determined by younger age and less advanced stage as compared with sporadic MSI-H counterpart.

Herein we describe the clinicopathologic and immunohistochemical features of 13 primary mucinous (colloid) carcinomas (MCs) of the lung, an uncommon and controversial tumor. The patients, 7 males and 6 females, ranged in age from 50 to 79 years (mean, 64.5 years). All the tumors presented as a peripheral solitary nodule with gelatinous cut-surface and well circumscribed but lacking a complete fibrous wall. The size ranged from 1 to 5.5 cm. Microscopically, they consisted of neoplastic elements floating in large mucin pools and focally lining the alveolar spaces. Eleven cases were predominantly composed of tall, columnar goblet cells (goblet cell-type MC), while 2 consisted of signet-ring tumor cells (signet-ring cell-type MC). Five tumors were incidentally discovered by chest radiographs, while the others were symptomatic. All patients underwent complete surgical resection (six lobectomies and seven wedge resections). Postoperative chemotherapy was performed in 3 cases. Overall, the median follow-up was 26 months (mean 33 months; range 9-95 months). All patients with goblet cell-type MC were alive and well, while the 2 patients with signet-ring cell-type MC died of disease. Immunohistochemically, all the 11 goblet cell-type MCs were strongly stained with CDX-2 and MUC2, 8 reacted with TTF-1, 6 with cytokeratin 20 (CK20), 9 with cytokeratin 7 (CK7), and 2 with MUC-5AC. Conversely, the two signet-ring cell-type MCs were stained with TTF-1, CK7, and MUC5AC but were negative for CDX-2, MUC2, and CK20. Surfactant apoprotein-A (SP-A) was positive in four goblet cell-type and one signet-ring cell-type MC. When compared with 10 mucinous bronchioloalveolar carcinomas (m-BAC), the latter reacted with CK7, CK20, MUC5AC, TTF-1, SP-A, CDX-2, and MUC2 in 100%, 90%, 100%, 30%, 10%, 0%, and 0% of the cases, respectively. In summary, MC of the lung represents an entity with two distinct clinicopathologic and immunophenotypic variants: 1) the goblet cell-type, presenting a more indolent clinical behavior and frequently co-expressing markers of intestinal and pulmonary differentiation; and 2) the more aggressive signet-ring cell-type, which retains only markers of pulmonary origin. On morphologic and immunohistochemical grounds, MCs are easily distinguishable from m-BAC. Since goblet cell-type MC strongly stains with CDX2, MUC2, and CK20, differential diagnosis with metastatic colorectal carcinoma is very challenging and requires appropriate clinical correlation.

Evolution of intratumoral genetic heterogeneity during colorectal tumor progression has not been investigated so far. Multiple sample areas in colorectal adenocarcinoma at early and advanced stages and in metastases were studied for the well-known genetic alterations: K-ras and p53 point mutations and loss of heterozygosity (LOH) on chromosomes 5q and 18q. In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. At the early stage, the last events that were produced, the p53 mutation and LOH of 18q, were also the most heterogeneous. At the advanced stage, the LOH of 5q and 18q were the most frequent heterogeneous events (67 and 58%, respectively). The intratumoral heterogeneity for mutations was significantly reduced, from the early to the advanced stages (from 60 to 20% for K-ras and from 70 to 20% for p53 ). On the other hand, a quasi absence of intratumoral genetic heterogeneity was observed for K-ras and p53 in distant metastasis. In conclusion, colorectal adenocarcinomas are characterized by marked intratumoral genetic heterogeneity. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.

Aim: Limbal cultures restore the corneal epithelium in patients with ocular burns. We investigated the biological parameters instrumental for their clinical success. Methods: We report a long-term multicenter prospective study on 152 patients carrying corneal destruction due to severe ocular burns, treated with autologous limbal cells cultured on fibrin and clinical-grade 3T3-J2 feeder cells. Clinical results were statistically evaluated both by parametric and nonparametric methods. Results: Clinical outcomes were scored as full success, partial success and failure in 66.05, 19.14 and 14.81% of eyes, respectively. The total number of clonogenic cells, colony size, growth rate and presence of conjunctival cells could not predict clinical results. Instead, the clinical data provided conclusive evidence that graft quality and likelihood of a successful outcome rely on an accurate evaluation of the number of stem cells detected before transplantation as holoclones expressing high levels of the p63 transcripti...