Citations

Purpose The sixth edition of American Joint Committee on Cancer (AJCC) Cancer Staging Manual for colon cancer subdivided stage II into IIA (T3N0) and IIB (T4N0) and stage III into IIIA (T1-2N1M0), IIIB (T3-4N1M0), and IIIC (anyTN2M0). Subsequent analyses supported revised substaging of stage III because of improved survival for T1-2N2 versus T3-4N2 and T4N1 survival was more similar to T3-4N2 than to T3N1. The AJCC Hindgut Taskforce sought population-based validation that depth of invasion and nodal status interact to affect survival. Patients and Methods Surveillance, Epidemiology, and End Results (SEER) population-based data from January 1992 to December 2004 for 109,953 colon cancer patients were compared with National Cancer Data Base (NCDB) data on 134,206 patients. T4N0 cancers were stratified by tumors that perforate visceral peritoneum (T4a) versus tumors that invade or are adherent to adjacent organs or structures (T4b). N1 and N2 were stratified by number of involved positive lymph nodes (N+): N1a/N1b (1 v 2-3), N2a/N2b (4 to 6 v ≥ 7). Five-year observed and relative survival data were obtained for each TN category. Results SEER colon cancer analyses confirm that patients with T1-2N0 cancers have better survival than T3N0, T3N0 better than T4N0, T1-2N2 better than T3-4N2, and T4bN1 similar to T4N2. Patients with T4a lesions have better survival than T4b by N category. The number of positive nodes affects survival for each T category. Conclusion This SEER population-based colon cancer analysis is highly consistent with rectal cancer pooled analysis and SEER rectal cancer analyses, supporting the shift of T1-2N2 lesions from IIIC to IIIA/IIIB, shifting T4bN1 from IIIB to IIIC, subdividing T4/N1/N2, and revising substaging of stages II/III. Survival outcomes by TN category for colon and rectal cancer are strikingly similar.

Background— The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown. Methods and Results— SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death. Conclusions— ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000609.

Abstract Productive T cell activation requires efficient reorganization of the actin cytoskeleton. We showed previously that the actin-regulatory protein, hematopoietic lineage cell-specific protein 1 (HS1), is required for the stabilization of F-actin and Vav1 at the immunological synapse and for efficient calcium responses. The Tec family kinase IL-2-inducible T cell kinase (Itk) regulates similar aspects of T cell activation, suggesting that these proteins act in the same pathway. Using video microscopy, we show that T cells lacking Itk or HS1 exhibited similar defects in actin responses, extending unstable lamellipodial protrusions upon TCR stimulation. HS1 and Itk could be coimmunoprecipitated from T cell lysates, and GST-pulldown studies showed that Itk’s Src homology 2 domain binds directly to two phosphotyrosines in HS1. In the absence of Itk, or in T cells overexpressing an Itk Src homology 2 domain mutant, HS1 failed to localize to the immunological synapse, indicating that Itk serves to recruit HS1 to sites of TCR engagement. Because Itk is required for phospholipase C (PLC)γ1 phosphorylation and calcium store release, we examined the calcium signaling pathway in HS1−/− T cells in greater detail. In response to TCR engagement, T cells lacking HS1 exhibited diminished calcium store release, but TCR-dependent PLCγ1 phosphorylation was intact, indicating that HS1’s role in calcium signaling is distinct from that of Itk. HS1-deficient T cells exhibited defective cytoskeletal association of PLCγ1 and altered formation of PLCγ1 microclusters. We conclude that HS1 functions as an effector of Itk in the T cell actin-regulatory pathway, and directs the spatial organization of PLCγ1 signaling complexes.

Abstract Among 200 patients with primary myelofibrosis, karyotype at diagnosis was abnormal in 83 (42%). To assess their individual prognostic impact, specific cytogenetic abnormalities with more than or equal to 5 informative cases were identified and the rest grouped separately as “other abnormalities.” Median survival in patients with sole +9 (n = 6), sole 20q− (n = 21), sole 13q− (n = 8), normal karyotype (n = 117), “other abnormalities” (n = 28), complex karyotype (n = 13), and sole +8 (n = 7) were “not reached,” 112, 105, 80, 46, 34, and 28 months, respectively (P = .01). Accordingly, 4 cytogenetic risk groups were considered: (1) favorable (sole +9, 20q−, or 13q−), (2) normal, (3) unfavorable (complex karyotype or sole +8), and (4) “other abnormalities.” Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)–independent prognostic value of both 4-way and 2-way (ie, favorable/normal vs unfavorable/other abnormalities; IPSS-adjusted hazard ratio = 0.37; 95% confidence interval, 0.24-0.58) cytogenetic risk categorization (P < .01). The ability to prognostically dissect a specific IPSS category has major therapeutic implications.

Purpose The purpose was to compare open and arthroscopic acromioclavicular joint (ACJ) resection. Methods We retrospectively reviewed 103 patients (105 shoulders) who underwent ACJ resection between 2000 and 2005. There were 56 women and 47 men with a mean age of 48 years. The mean duration of follow‐up was 51 months (range, 15 to 91 months). Arthroscopic ACJ resection by use of a direct approach was performed in 81 shoulders (group A), and open ACJ resection was performed in 24 shoulders (group B). Results were graded according to pain relief both subjectively and objectively with cross‐body adduction testing and direct palpation of the ACJ, subjective shoulder value, Constant score, and improved function. Results The Constant scores increased from 50 (range, 34 to 65) to 89 (range, 39 to 100) in group A ( P < .0001) and from 46 (range, 22 to 63) to 87 (range, 43 to 100) in group B ( P < .0001). There was no statistical difference in the postoperative normalized Constant score between group A and group B ( P = .47). Pain with cross‐body adduction testing and palpation of the ACJ improved in 76 shoulders (94%) in group A and 22 shoulders (92%) in group B. No patients had signs or symptoms of ACJ anteroposterior instability. Revision ACJ resection was performed in 5 patients (5 shoulders [6.2%]) in group A and 1 shoulder (4.2%) in group B ( P = .37). The radiographs of the patients who underwent revision showed that 3 patients (3.7%) from group A had regrowth of the distal clavicle; in addition, 2 patients (2.5%) from group A and 1 patient (4.3%) from group B had incomplete distal clavicle excision. Conclusions This study did not show a significant difference in the outcome between arthroscopic and open ACJ resection. Incomplete excision and regrowth of the distal clavicle are the most common causes of revision. Although only the arthroscopic group showed a small percentage of patients (3.7%) with regrowth of the distal clavicle, the number is too small to assume that this complication is the result of the arthroscopic technique only. Level of Evidence Level IV, therapeutic case series.

Peripheral arterial disease (PAD) is common in patients with severe coronary artery disease (CAD) and is considered a relative contraindication to external enhanced counterpulsation (EECP), but there are no data that define the efficacy and safety of EECP in patients with PAD. The International EECP Patient Registry (IEPR) was used to compare initial post-therapy and 2-year follow-up clinical outcomes and adverse event rates in patients with and without PAD. From January 2002 to October 2004, 2126 patients were enrolled in the IEPR, of whom 493 (23%) had a history of PAD. Immediately following EECP, the reduction in angina (≥ 1 Canadian Cardiovascular Society class) was similar in patients with and without PAD (76.6% vs 79.0%, p = 0.27) as was improvement in the Duke Activity Score Index (DASI) score (+4.7% vs +6.1%, p < 0.001). Both angina reduction and DASI score improvement were sustained at 2 years. PAD patients discontinued EECP more frequently (12.0% vs 8.5%, p < 0.05), but lower extremity ulceration did not occur more frequently in patients with PAD (3.7% vs 2.7%, p = 0.26). Rates of death (17.1% vs 8.6%, p < 0.001) and myocardial infarction (9.5% vs 5.0%, p < 0.001) were, as expected, higher in patients with PAD compared to patients without PAD at 2 years. In conclusion, while PAD patients constitute a high-risk cohort with known higher adverse event rates, EECP led to similar short- and long-term improvements in angina and quality of life for individuals with PAD compared to those without PAD.