Tissue-specific and repeat length-dependent somatic instability of the X-linked dystonia parkinsonism-associated CCCTCT repeat.

X-linked dystonia-parkinsonism (XDP) is a progressive adult-onset neurodegenerative disorder caused by insertion of a SINE-VNTR-Alu (SVA) retrotransposon in the TAF1 gene. The SVA retrotransposon contains a CCCTCT hexameric repeat tract of variable length, whose length is inversely correlated with age at onset. This places XDP in a broader class of repeat expansion diseases, characterized by the instability of their causative repeat mutations. Here, we observe similar inverse correlations between CCCTCT repeat length with age at onset and age at death and no obvious correlation with disease duration. To gain insight into repeat instability in XDP we performed comprehensive quantitative analyses of somatic instability of the XDP CCCTCT repeat in blood and in seventeen brain regions from affected males. Our findings reveal repeat length-dependent and expansion-based instability of the XDP CCCTCT repeat, with greater levels of expansion in brain than in blood. The brain exhibits regional-specific patterns of instability that are broadly similar across individuals, with cerebellum exhibiting low instability and cortical regions exhibiting relatively high instability. The spectrum of somatic instability in the brain includes a high proportion of moderate repeat length changes of up to 5 repeats, as well as expansions of ~ 20- > 100 repeats and contractions of ~ 20-40 repeats at lower frequencies. Comparison with HTT CAG repeat instability in postmortem Huntington's disease brains reveals similar brain region-specific profiles, indicating common trans-acting factors that contribute to the instability of both repeats. Analyses in XDP brains of expansion of a different SVA-associated CCCTCT located in the LIPG gene, and not known to be disease-associated, reveals repeat length-dependent expansion at overall lower levels relative to the XDP CCCTCT repeat, suggesting that expansion propensity may be modified by local chromatin structure. Together, the data support a role for repeat length-dependent somatic expansion in the process(es) driving the onset of XDP and prompt further investigation into repeat dynamics and the relationship to disease.

Neoadjuvant chemoradiotherapy and total mesorectal excision in the management of locally advanced rectal carcinoma -- The PGH CRPoCan study group experience 2008-2009

INTRODUCTION: The use of neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision (TME) has shown promising results in the management of locally advanced rectal carcinoma, and is associated with improvement in local control, disease free survival (DFS) and overall survival (OS). However, these clinical endpoints cannot be properly assessed due to poor follow up among many patients. Other endpoints such as negative circumferential resection margins (CRM), pathologic complete response (pCR) and sphincter-preserving surgery (SPS) may serve as indirect means of assessing successful treatment. This study reports the experience of the Philippine General Hospital (PGH) Colorectal Polyp and Cancer (CRPoCan) Study Group in using neoadjuvant CRT and TME in the management of locally advanced rectal carcinoma, towards quality care.METHODS: The Integrated Surgical Information System (ISIS) database of the Department of Surgery, PGH was queried for rectal cancer patients with pretreatment clinical stage II and III disease that underwent neo-adjuvant CRT followed by TME between January 2008 and December 2009. The final surgical pathology reports of the subjects were reviewed for treatment response. Response was categorized as: (1) positive or negative CRM; and (2) with or without pCR. The study assessed whether SPS was done.RESULTS: Of 140 potential neoadjuvant CRT patients followed by TME, 82 patients completed the treatment. Thirty two of the patients who completed treatment (39%) were eligible since the other 50 patients (61%) had no post-operative histopathology results. Among those eligible, 10 patients (31%) had pCR. Only 1 patient had a positive CRM. Of the 14 patients whose tumor distance was ?5cm from the anal verge, only 1 patient underwent SPS. The small sample size was mainly attributed to low resources or treatment. Non-availability of post-operative histopathology results was due to poor record keeping. CONCLUSION: The PGH CRPoCan Study Group's use of neoadjuvant CRT followed by TME for locally advanced rectal carcinoma has resulted in acceptable numbers of pCR and clear CRM but has not translated into an increased number of SPS. Despite the limitations of the study, the institutionalization of the multidisciplinary team in the PGH CRPoCan Study Group and the implementation of the ISIS database program are considered the first steps towards quality health care.