Predicting Factors for a Favorable Pathologic Response to Neoadjuvant Therapy in Esophageal Cancer.

BACKGROUND: Favorable pathologic response(FPR) is a significant predictor for improved survival following Neoadjuvant therapy(NAT) in esophageal and gastroesophageal cancer(GEJ). Preoperative prediction of FPR could modify treatment plans. No reliable method for predicting FPR exists. We sought to identify preoperative predicting factors for FPR. MATERIALS AND METHODS: Retrospective analysis of patients with esophageal and GEJ cancer who underwent esophagectomy following (NAT). Univariate and multivariate analysis was used to identify preoperative predicting factors for FPR. A comparison of Tumor Regression Grade(TRG) was used to assess treatment response on overall survival(OS). RESULTS: Out of 121 patients, 82(67.8%) had neoadjuvant chemoradiation. FPR was observed in 60(49.6%). Female sex, Radiation therapy(RT), squamous cell carcinoma(SCC), lack of signet ring feature, and FDG avidity posttreatment were associated with FPR on univariate analysis. RT and SCC were associated with FPR (OR=3.9 and 4.0, respectively) on multivariate analysis. OS was lower among patients who did not achieve FPR to NAT(P=0.027). CONCLUSIONS: FPR is a predictor of improved OS. SCC and radiation therapy-based protocol were identified as major prediction factors of FPR in patients with esophageal and GEJ cancers.

Heat shock proteins HSP90, HSP70 and GRP78 expression in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma management consists mainly of surgical resection and is largely chemoresistant. There is ongoing effort to discover novel therapies for medullary thyroid carcinoma. Increased levels of heat shock proteins have been associated with multiple cancers and are being studied as potential therapeutic targets. The purpose of this study was to determine the expression levels of heat shock proteins 90 and 70 and of glucose related protein 78 in medullary thyroid carcinoma tissues compared with normal thyroid tissues. METHODS: 20 tissue specimens of medullary thyroid carcinoma and 10 specimens of thyroids without malignancy were analyzed by immunohistochemistry. RESULTS: Medullary thyroid carcinoma specimens showed 27% higher expression level of heat shock protein 90 immunostaining, and a 43% higher expression level of heat shock protein 70 immunostaining versus normal controls. These differences, however, were not statistically significant. A significantly higher expression level was noted for glucose related protein 78 in the medullary thyroid carcinoma specimens than in the controls. CONCLUSION: This study indicates increased expression levels of heat shock proteins 90 and 70 and glucose related protein 78 levels in medullary thyroid carcinoma. These findings, though preliminary imply that these proteins may have a role in medullary thyroid carcinoma's tumor biology and may have and future therapeutic options. Larger cohorts are needed to corroborate these results.

From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG).

Congenital disorders of glycosylation are a growing group of inborn errors of protein glycosylation. Cardiac involvement is frequently observed in the most common form, PMM2-CDG, especially hypertrophic cardiomyopathy. Dilated cardiomyopathy, however, has been only observed in a few CDG subtypes, usually with a lethal outcome. We report on cardiac pathology in nine patients from three unrelated Israeli families, diagnosed with dolichol kinase deficiency, due to novel, homozygous DK1 gene mutations. The cardiac symptoms varied from discrete, mild dilation to overt heart failure with death. Two children died unexpectedly with acute symptoms of heart failure before the diagnosis of DK1-CDG and heart transplantation could take place. Three other affected children with mild dilated cardiomyopathy at the time of the diagnosis deteriorated rapidly, two of them within days after an acute infection. They all went through successful heart transplantation; one died unexpectedly and 2 others are currently (after 1-5 years) clinically stable. The other 4 children diagnosed with mild dilated cardiomyopathy are doing well on supportive heart failure therapy. In most cases, the cardiac findings dominated the clinical picture, without central nervous system or multisystem involvement, which is unique in CDG syndrome. We suggest to test for DK1-CDG in patients with dilated cardiomyopathy. Patients with discrete cardiomyopathy may remain stable on supportive treatment while others deteriorate rapidly. Our paper is the first comprehensive study on the phenotype of DK1-CDG and the first successful organ transplantation in CDG syndrome.

Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel.

BACKGROUND: The molecular mechanisms that underlie colorectal cancer (CRC) include microsatellite instability (MSI), chromosomal instability, and the CpG island methylator phenotype. There is evidence to suggest that CRC incidence varies among different ethnic populations worldwide. The authors of this report hypothesized that environmental factors and lifestyle differences among various ethnic groups may differentially influence the epigenetic regulation of tumor suppressor genes in CRC. METHODS: In the current study, microdissection and DNA extraction were performed on 128 samples of CRC from Israeli patients (85 Jews and 43 Arabs). MSI analysis, mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) protein expression levels, and MLH1 promoter methylation were investigated by combined bisulfite restriction analysis. The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) valine-to-glutamic acid mutation at residue 600 was investigated by direct DNA sequencing. RESULTS: High MSI (MSI-H), MLH1 methylation, and BRAF mutations were observed in 11.6%, 9.4%, and 23.5% of Jews, respectively, and in 16.2%, 17.6%, and 20.9% of Arabs, respectively (P value nonsignificant). MLH1 promoter methylation was observed in 22.6% of microsatellite-stable (MSS) tumors and in 53.8% of MSI-H tumors (P < .015). Extensive methylation (covering both 5' and 3' promoter regions) was present in all MSI-H tumors with loss of MLH1 expression. BRAF mutation was observed in 15.6% and 46.1% of MSS tumors and MSI-H tumors, respectively (P < .007). BRAF mutation was observed in 66%, 22.2%, and 14.7% of patients who had tumors with extensive MLH1 promoter methylation, methylation of the 5' region alone, or without methylation, respectively (P < .006). CONCLUSIONS: There was no difference in molecular signatures examined between Jewish and Arab patients with CRC in Israel. Extensive promoter methylation was associated with MLH1 inactivation, MSI, and BRAF mutation.

Follicular lymphoma with extensive gastrointestinal tract involvement: follow-up by capsule endoscopy.

Follicular lymphoma with gastrointestinal tract involvement is rare. We describe the case of a young woman with follicular lymphoma with multiple nodular lesions involving segments of the proximal jejunum and terminal ileum. The presenting symptom was chronic diarrhea. The diagnosis was made by endoscopy with histologic examination of the mucosal lesions of the proximal and distal small intestine, immunohistochemical staining, and molecular analysis. The initial spread and pattern of the small bowel involvement, as well as treatment response, were evaluated by videocapsule endoscopy. The application of molecular analysis along with immunophenotypic evaluation has made it possible to precisely diagnose follicular lymphoma. In the present case, the use of capsule endoscopy improved the evaluation of the extent of small bowel involvement prior to and following treatment.

Primary squamous cell carcinoma (SqCC) of the breast.

Primary squamous cell carcinoma (SqCC) of the breast is a rare tumor that presents a unique biologic behavior. Thus, it challenges the justification for routine axillary dissection and adjuvant therapy. A MEDLINE search of all reported cases of primary SqCC of the breast was performed. Data on lymph node status, estrogen receptor (ER) and progesterone receptor (PR) status, and surgical and adjuvant treatment modalities were collected. We add three cases from our own experience. SqCC has several unique biologic characteristics; it is associated with a lower rate of lymph node metastasis at presentation (22% vs. 40-60% for infiltrating ductal carcinoma [IDC]) and a significant rate of distant metastasis without lymph node involvement. ER and PR receptor levels are usually very low. Because lymph node involvement plays a lesser prognostic and therapeutic role in this disease, we propose a more selective approach (i.e., sentinel node biopsy). The issue of adjuvant treatment remains unresolved, owing to lack of data. Surgical and medical treatment of SqCC of the breast should be tailored to fit its distinct biologic characteristics. The 5-fluorouracil-doxorubicin-cisplatin combination may be warranted in lieu of the combinations used for IDC.

Risk factors for lymph node metastases in breast ductal carcinoma in situ with minimal invasive component.

HYPOTHESIS: Clinical and pathological variables may be predictors of axillary dissemination in T1mic and T1a breast carcinoma. DESIGN: Retrospective medical chart review. SETTING: University-affiliated tertiary referral center. PATIENTS: All patients diagnosed as having ductal carcinoma in situ (DCIS) with microinvasion between January 1, 1988, and December 30, 1998. MAIN OUTCOME MEASURES: Pathology slides were reviewed according to the 1997 Cancer Staging Manual put forth by the American Joint Committee on Cancer. The number of involved ducts was noted. Patients with no invasive component or invasive components larger than 5 mm were excluded. Pathological and clinical variables were analyzed for their effect on axillary lymph node metastases. RESULTS: The study group included 57 women aged 37 to 71 years (median, 60 years), 37 with T1mic disease and 20 with T1a. Modified radical mastectomy was performed in 29 patients (18 with T1mic and 11 with T1a) and breast-preserving surgery in 28 (19 with T1mic and 9 with T1a). Forty-three patients (28 with T1mic and 15 with T1a) underwent axillary lymph node dissection. Axillary involvement was detected in 3 patients in each group. Forty-seven patients received adjuvant therapy (radiotherapy alone, or with hormones or chemotherapy). Follow-up was 3 to 120 months (median, 40 months). One patient was unavailable for follow-up, another died of disseminated disease, and a third developed contralateral primary carcinoma. Comedo DCIS (P<.03) and the number of DCIS-involved ducts (P<.002) in the T1mic group, and nuclear grade 3 (P<.001) in both groups, were independent significant predictors of axillary metastases. CONCLUSIONS: The significant rate of axillary metastases in T1a and T1mic breast tumors makes axillary staging a must. High nuclear grade, comedo DCIS, and high number of DCIS-involved ducts may predict axillary metastasis and should be considered when axillary dissection is done selectively.