Anatomy of the muscular subpulmonary infundibulum with regard to the Ross procedure

BACKGROUND: To clarify the precise anatomical relationship of the muscular subpulmonary infundibulum. METHODS: Eleven hearts were dissected, and microscopic sections taken through the arterial trunks of a 37-week-old fetus and of a neonate. The anatomy was also investigated during operative Ross procedures. RESULTS: The sinotubular junctions of the pulmonary and aortic roots cross obliquely. The leaflets of the pulmonary valve are lifted away from the ventricular septum by the free-standing subpulmonary infundibulum, whereas the aortic valve is deeply wedged between the atrioventricular junctions. The muscular infundibulum spirals around the aortic root, being longest below the right-facing aortic sinus and shortest below the left. The first septal perforating artery pierces the septum below the shortest part of the infundibulum, sometimes within a millimeter of the pulmonary valvar hinge, but a muscular sleeve lifts the pulmonary leaflets from the septal musculature. CONCLUSIONS: The pulmonary valvar leaflets are supported entirely by free-standing musculature, having no direct relationship with the ventricular septum. This makes possible the Ross procedure.     

Randomized placebo-controlled study of low-dose warfarin for the prevention of central venous catheter-associated thrombosis in patients with cancer.

PURPOSE: In this multicenter, randomized, placebo-controlled clinical trial, we studied whether warfarin 1 mg daily reduces the incidence of symptomatic central venous catheter (CVC) -associated thrombosis in patients with cancer. PATIENTS AND METHODS: Two hundred fifty-five patients with cancer who required a CVC for at least 7 days were randomly assigned to receive warfarin 1 mg or placebo. RESULTS: There were 11 (4.3%) symptomatic CVC-associated thromboses among 255 patients, with no difference in the incidence of symptomatic CVC-associated thrombosis between patients taking warfarin 1 mg daily (six of 130 patients; 4.6%) and patients taking placebo (five of 125 patients; 4.0%; hazard ratio, 1.20; 95% CI, 0.37 to 3.94). Warfarin had no effect on CVC life span (84 days v 63 days in control and warfarin groups, respectively; 95% confidence limit, -16 to 55 days; P = .09), and it did not affect the number of premature CVC removals (23.2% v 25.4% in control and warfarin groups, respectively; 95% confidence limit of difference -8.34 to 12.71; P = .68) or the frequency of major bleeding episodes (2% v 0% in control and warfarin groups, respectively; P = .5, Fisher's exact test). CONCLUSION: Symptomatic CVC-associated thrombosis in patients with cancer, although significant, is less common than previously reported. In this study, the administration of warfarin 1 mg daily did not reduce the incidence of symptomatic CVC-associated thrombosis in patients with cancer. However, the low rate of symptomatic CVC-associated thrombosis means that a much larger trial is required to address this issue definitively.     

Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27.

PURPOSE: Experience with sentinel node biopsy (SNB) after neoadjuvant chemotherapy is limited. We examined the feasibility and accuracy of this procedure within a randomized trial in patients treated with neoadjuvant chemotherapy. PATIENTS AND METHODS: During the conduct of National Surgical Adjuvant Breast and Bowel Project trial B-27, several participating surgeons attempted SNB before the required axillary dissection in 428 patients. All underwent lymphatic mapping and an attempt to identify and remove a sentinel node. Lymphatic mapping was performed with radioactive colloid (14.7%), with lymphazurin blue dye alone (29.9%), or with both (54.7%). RESULTS: Success rate for the identification and removal of a sentinel node was 84.8%. Success rate increased significantly with the use of radioisotope (87.6% to 88.9%) versus with the use of lymphazurin alone (78.1%, P = .03). There were no significant differences in success rate according to clinical tumor size, clinical nodal status, age, or calendar year of random assignment. Of 343 patients who had SNB and axillary dissection, the sentinel nodes were positive in 125 patients and were the only positive nodes in 70 patients (56.0%). Of the 218 patients with negative sentinel nodes, nonsentinel nodes were positive in 15 (false-negative rate, 10.7%; 15 of 140 patients). There were no significant differences in false-negative rate according to clinical patient and tumor characteristics, method of lymphatic mapping, or breast tumor response to chemotherapy. CONCLUSION: These results are comparable to those obtained from multicenter studies evaluating SNB before systemic therapy and suggest that the sentinel node concept is applicable following neoadjuvant chemotherapy.     

Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.     

Novel targeted drugs for the treatment of multiple myeloma: from bench to bedside.

Multiple myeloma remains an incurable plasma cell neoplasm. New insights into its pathogenesis have identified signaling pathways that have become potential therapeutic targets. It has clearly been established that intracellular regulatory proteins and interactions between malignant plasma cells and the bone marrow microenvironment play an important role in their survival and drug resistance. Several new agents associated with molecular targets are currently being investigated to design new treatment strategies aimed at prolonging survival and improving quality of life. This review illustrates their mechanisms of action and the possible future clinical applications.     

Extended rituximab therapy in Waldenström's macroglobulinemia

BackgroundWaldenström's macroglobulinemia (WM) is a CD20 expressing B-cell malignancy represented by the pathological diagnosis of IgM secreting lymphoplasmacytic lymphoma. Major response rates of 30% have been reported in most studies with standard dose rituximab, i.e. 4 weekly infusions at 375 mg/m²/week.MethodsIn an effort to increase rituximab activity in WM, an extended dose schedule employing two sets of four (375 mg/m²/week) infusions at weeks 1–4 and 12–16 was evaluated. Expression of the complement resistance antigens CD46, CD55 and CD59 was also evaluated on tumor cells pre- and post-therapy to determine impact on response.ResultsTwenty-nine patients were enrolled and 26 patients completed the intended therapy. On an intent to treat analysis, 14 (48.3%) patients achieved a partial response, and 5 (17.2%) patients achieved a minor response. Responses were observed in 18/24 (75%) patients with a serum IgM level of <6000 mg/dl, and only 1 of 5 (20%) patients with a level of >6000 mg/dl (P = 0.03). The median time to best response was 17 months, and only 2 of 19 responding patients progressed with a median follow-up of 29 months. No differences in baseline expression of the complement resistance antigens CD46, CD55 and CD59 were observed among responding and non-responding patients, although post-therapy CD55 expression was higher in non-responding patients (P = 0.002).ConclusionsThese data show that extended rituximab therapy is active and may lead to more major responses over standard dose rituximab in WM. WM patients with serum IgM levels of <6000 mg/dl are more likely to benefit from extended rituximab therapy.     

Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstr?m's macroglobulinemia.

PURPOSE: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. RESULTS: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms. CONCLUSION: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.     

Pedicle marrow signal intensity changes in the lumbar spine: a manifestation of facet degenerative joint disease

Objective. Signal intensity changes in lumbar pedicles, similar to those described in vertebral body endplates adjacent to degenerated discs, have been described as an ancillary sign of spondylolysis on MRI. The purpose of this study was to determine whether pedicle marrow signal intensity changes also occur in association with facet degenerative joint disease. Design. Eighty-nine lumbar spine MRI examinations without spondylolysis were reviewed for marrow signal intensity changes in pedicles and vertebral bodies as well as for facet degenerative joint disease. Results. Five percent (46/890) of lumbar pedicles in 23 patients had marrow signal intensity changes. Ninety-one percent (42/46) of the abnormal pedicles had adjacent degenerative joint disease of the facets, while only 21% (189/890) of normal pedicles had adjacent facet degenerative joint disease (p<0.001). Eighty-nine percent (41/46) of the pedicles with marrow signal intensity changes had adjacent degenerative disc disease. Conclusions. Pedicle marrow signal intensity changes are not a specific sign of spondylolysis; they are commonly seen with adjacent facet degenerative joint disease in the absence of spondylolysis. Pedicle marrow signal intensity changes are probably a response to abnormal stresses related to abnormal motion or loading caused by the degenerative changes in the spinal segment. Received: 2 May 2000 Revision requested: 18 July 2000 Revision received: 25 August 2000 Accepted: 1 September 2000