Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases.

Among 2333 consecutive patients with myelofibrosis with myeloid metaplasia (MMM) seen at our institution, 91 fulfilled the World Health Organization (WHO) criteria for leukemic transformation (LT). All episodes of LT were myeloid in origin (acute myeloid leukemia [AML]) with all French-American-British (FAB) subtypes represented except M3; the most frequent subtypes were M7 (25.4%), M0 (22.4%), and M2 (17.9%). Cytogenetic studies during LT were available in 56 patients and revealed a clonal abnormality in 51 (91%): 30 patients had complex karyotype, 2 had core-binding factor gene lesions, and 18 had abnormalities of chromosome 5 or 7. Karyotypic evolution was documented in the majority of the patients in whom serial analysis was possible. In general, LT was fatal in 98% of the cases after a median of 2.6 months (range, 0-24.2 months). Twenty-four patients received AML-like induction chemotherapy that resulted in no complete remission: 41% reverted into chronic-phase disease and the incidence of treatment-related mortality was 33%. The remaining 67 patients received either supportive care alone (48 patients) or low-intensity chemotherapy (19 patients). Overall, survival was similarly poor in all 3 treatment categories. The outcome of LT in MMM with current therapies is dismal and either supportive care alone or appropriate clinical trials should be considered.

Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia.

OBJECTIVE: To present the results of a long-term analysis of 2 sequential phase 2 trials of thalidomide (alone or in combination) for palliation of myelofibrosis with myeloid metaplasia (MMM). PATIENTS AND METHODS: We analyzed (March 1999 to August 2003) initial and long-term outcomes from 36 patients with symptomatic MMM who had enrolled in either our thalidomide single-agent trial (n=15) or our trial of low-dose thalidomide (50 mg/d) combined with prednisone (n=21). RESULTS: Among the 36 study patients, 20 (56%) showed some improvement in their clinical course. Response rates for specific end points included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]), or splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone, as opposed to single-agent thalidomide, was better tolerated and more efficacious. After a median follow-up of 25 months (range, 20-56 months), 10 of 36 patients (28%) showed an ongoing response, including 8 patients in whom protocol treatment has been discontinued for a median of 21 months (range, 16-31 months). Durable treatment responses were documented for only anemia and thrombocytopenia. Treatment response was not affected by the baseline status of bone marrow fibrosis, angiogenesis, osteosclerosis, cytogenetics, or circulating myeloid progenitor (CD34) cell count. Unusual drug effects, all reversible, included leukocytosis (8 patients) and/or thrombocytosis (6 patients). CONCLUSIONS: Thalidomide (alone or combined with prednisone) is an effective first-line treatment of symptomatic anemia or thrombocytopenia in MMM. Thalidomide-based therapy has the potential to produce durable responses in MMM-associated cytopenias, even after discontinuation of the drug.

Characteristics of patients with vaginal rupture and evisceration.

OBJECTIVE: To characterize vaginal rupture and evisceration. METHODS: We reviewed medical records (1970-2001) for use of the diagnostic terms "vaginal rupture," "vaginal evisceration," and "ruptured enterocele." RESULTS: Twelve clinical cases were identified. Patients usually presented with pain, vaginal bleeding, and abdominal pressure. In 9 of 12 women, rupture was primarily associated with postmenopausal prolapse and a history of pelvic surgery. Women with a history of abdominal hysterectomy tended to rupture through the vaginal cuff, and those with a history of vaginal hysterectomy tended to rupture through a posterior enterocele. Premenopausal rupture in 1 woman occurred postcoitally and involved the posterior fornix. Prolapse recurrence after repair was limited to 1 woman. CONCLUSIONS: Vaginal rupture and evisceration should be considered in women presenting with acute vaginal bleeding and pelvic pain. Evaluation is especially important in postmenopausal women with a history of pelvic surgery. In some cases, surveillance after pelvic surgery may prevent rupture, evisceration, and incarceration. LEVEL OF EVIDENCE: II-3

A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia.

Single-agent thalidomide (THAL) at "conventional" doses (> 100 mg/d) has been evaluated in myelofibrosis with myeloid metaplasia (MMM) based on its antiangiogenic properties and the prominent neoangiogenesis that occurs in MMM. THAL monotherapy at such doses produces approximately a 20% response rate in anemia but is poorly tolerated (an adverse dropout rate of > 50% in 3 months). To improve efficacy and tolerability, we prospectively treated 21 symptomatic patients (hemoglobin level < 10 g/dL or symptomatic splenomegaly) with MMM with low-dose THAL (50 mg/d) along with a 3-month oral prednisone (PRED) taper (beginning at 0.5 mg/kg/d). THAL-PRED was well tolerated in all enrolled patients, with 20 patients (95%) able to complete 3 months of treatment. An objective clinical response was demonstrated in 13 (62%) patients, all improvements in anemia. Among 10 patients who were dependent on erythrocyte transfusions, 7 (70%) improved and 4 (40%) became transfusion independent. Among 8 patients with thrombocytopenia (platelet count < 100 x 10(9)/L), 6 (75%) experienced a 50% or higher increase in their platelet count. In 4 of 21 patients (19%), spleen size decreased by more than 50%. Responses observed were mostly durable after discontinuation of the PRED. The dose of THAL in this study (50 mg/d) was better tolerated than the higher doses used in previous studies. Adverse events associated with corticosteroid therapy were mild and transient. Clinical responses did not correlate with improvements in either intramedullary fibrosis or angiogenesis. THAL-PRED is well tolerated and preliminarily appears to be a promising drug regimen for treating cytopenias in patients with MMM.

Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome.

Antithymocyte globulin (ATG) has recently been popularized as an effective treatment in myelodysplastic syndrome (MDS). We treated 8 anemic MDS patients (refractory anemia [RA] and refractory anemia with excess blasts [RAEB-1]) with ATG (40 mg/kg/d for 4 days) and prednisone in a phase 2 trial. The study was stopped early according to a preset termination rule because of lack of efficacy. There were no salutary responses. Toxicities included serum sickness (in all patients), transient neutropenia and thrombocytopenia, diarrhea, vomiting, and syncope with a generalized seizure. At least 3 patients had the HLA-DR15 (DR2) allele. We conclude that the risk-benefit ratio of ATG in an unselected population of MDS patients may be unfavorable, and more work is needed to define the subset of patients who will respond to ATG before its widespread use can be recommended.

Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis.

This study examined the prognostic value of circulating peripheral blood plasma cells (PBPCs) in patients with primary systemic amyloidosis (AL). A sensitive slide-based immunofluorescence technique was used to assess 147 patients for circulating PBPCs. Circulating monoclonal plasma cells were quantified as a percentage of circulating cytoplasmic immunoglobulin-positive cells (PBPC%). The absolute circulating plasma cell count was also determined. When analyzed retrospectively, 24 (16%) of 147 patients were found to have detectable circulating PBPCs. Overall survival for patients with high PBPC%'s (> 1%) was poorer (median survival, 10 vs 29 months; P =.002). Similarly, overall survival for patients with high PBPC counts (> 0.5 x 10(6)/L) was significantly poorer (median, 13 vs 31 months; P =.003). Increased percentages of bone marrow plasma cells (BMPC%; P =.0004), increased levels of serum beta(2)-microglobulin (P =.04), and dominant cardiac amyloid involvement (P =.03) also predicted poorer survival. The combined consideration of circulating PBPCs and BMPC% identified low-, intermediate-, and high-risk groups with median survivals of 37.5, 15.5, and 10 months, respectively (P =.0003). Multivariate analysis revealed circulating PBPCs and BMPC% to be independent prognostic factors for survival. Patients with PBPC%'s of 2% or higher were significantly more likely to have a coexisting clinical diagnosis of multiple myeloma (50% vs 12%, P =.008). The prognostic value of circulating PBPCs may help select treatment for patients with AL.

Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.

PURPOSE: To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma. EXPERIMENTAL DESIGN: Four hundred patients with the following disorders were studied: MGUS (76 patients); smoldering (indolent; early-stage) multiple myeloma (SMM; 112 patients); newly diagnosed, active multiple myeloma (MM; 99 patients); relapsed (advanced) multiple myeloma (RMM; 26 patients); and primary amyloidosis (AL; 87 patients). Forty-two normal control BM samples were studied for comparison. BM angiogenesis was studied in a blinded manner by immunohistochemical staining for CD34 to identify microvessels. RESULTS: The median (range) microvessel density (MVD) per x400 high power field was 1.3 (0-11) in the controls, 1.7 (0-10) in AL, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in newly diagnosed MM, and 20 (6-47) in RMM; P < 0.001. MVD was significantly higher in MGUS, SMM, newly diagnosed MM, and RMM compared with controls and AL; P < 0.001. MVD was not significantly different between controls and AL. By grading, high-grade angiogenesis was present in 0% of controls and AL, 1% of MGUS, 3% of SMM, 29% of newly diagnosed MM, and 42% of RMM; P < 0.001. MVD correlated with the BM plasma cell labeling index (rho = 0.46, P < 0.001) and BM plasma cell percentage (rho 0.5, P < 0.001). Survival was 28 months in SMM and newly diagnosed MM with high-grade angiogenesis, compared with 53 months for those with low- and intermediate-grade angiogenesis; P = 0.02. CONCLUSIONS: BM angiogenesis progressively increases along the spectrum of plasma cell disorders, from the more benign MGUS stage to advanced myeloma, indicating that angiogenesis may be related to disease progression.

Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia.

In a phase 2 study, 23 patients with myelofibrosis with myeloid metaplasia were treated with imatinib mesylate at a constant dose of 400 mg/d. Treatment was held in 16 patients (70%), after 1 to 12 weeks, because of side effects (neutropenia, 6 patients; musculoskeletal pain, 5 patients; thrombocytosis, 4 patients; edema, 3 patients; diarrhea and hyperbilirubinemia, 1 patient). Including patients in whom retreatment at a reduced dose was possible, 11 patients (48%) were able to continue treatment beyond 3 months. None of the patients experienced a response in anemia, and only 2 had partial responses in splenomegaly. A greater than 50% increase in platelet count was documented in 11 (48%) patients, but not in those with baseline platelet counts of less than 100 x 10(9)/L. In vitro, imatinib mesylate caused variable degrees of growth suppression of myeloid and erythroid progenitors that unfortunately did not translate into clinical benefit.

Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia.

The lack of diagnostic certainty in some patients makes it difficult to distinguish between primary and secondary forms of thrombocytosis. To augment current diagnostic studies for thrombocytosis, we retrospectively evaluated clinical records and bone marrow trephine specimens of 183 patients with thrombocytosis-164 with essential thrombocythemia (ET), 19 with reactive thrombocytosis (RT)-for bone marrow angiogenesis, bone marrow megakaryocyte c-Mpl staining, and morphologic evidence of megakaryocyte proliferation. Angiogenesis was increased in patients with ET compared with healthy controls (P <.0001) and patients with RT (P =.006). In addition, an increase in angiogenesis was associated with certain disease features such as splenomegaly (P =.004) and reticulin fibrosis (P =.005). Decreased megakaryocyte c-Mpl staining was observed in a heterogeneous pattern in ET compared with healthy controls (P <.0001) and RT (P <.0001). Histologic stratifying criteria incorporating increased angiogenesis, decreased megakaryocyte c-Mpl expression, and marked megakaryocyte proliferation in the bone marrow was highly sensitive (97%) and specific (95%) for distinguishing ET from RT (P <.0001). However, with the current duration of follow-up available on the patients, none of the histologic features evaluated have yet demonstrated prognostic value for subsequent clinical course, vascular events, or survival.

Short-term quality-of-life outcomes following laparoscopic-assisted colectomy vs open colectomy for colon cancer: a randomized trial.

CONTEXT: Laparoscopic-assisted colectomy (LAC) has emerged as the preferred minimally invasive surgical strategy for diseases of the colon. The safety and efficacy of LAC for colon cancer are unknown, and the nature and magnitude of any quality-of-life (QOL) benefit resulting from LAC for colon cancer is also unknown. OBJECTIVE: To compare short-term QOL outcomes after LAC vs open colectomy for colon cancer. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized controlled trial (Clinical Outcomes of Surgical Therapy [COST]). Between September 1994 and February 1999, 37 of 48 centers provided data for the QOL component of the trial for 449 consecutive patients with clinically resectable colon cancer. MAIN OUTCOME MEASURES: Scores on the Symptoms Distress Scale (SDS), Quality of Life Index, and a single-item global rating scale at 2 days, 2 weeks, and 2 months postoperative; duration of postoperative in-hospital analgesic use; and length of stay. RESULTS: Of 449 patients, 428 provided QOL data. In an intention-to-treat analysis comparing SDS pain intensity, SDS summary, QOL Index summary, and global rating scale scores at each time point, the only statistically significant difference observed between groups was the global rating scale score for 2 weeks postsurgery. The mean (median) global rating scale scores for 2 weeks postsurgery were 76.9 (80) for LAC vs 74.4 (75) for open colectomy (P =.009). While in the hospital, patients assigned to LAC required fewer days of both parenteral analgesics compared with patients assigned to open colectomy (mean [median], 3.2 [3] vs 4.0 [4] days; P<.001) and oral analgesics (mean [median], 1.9 [1] vs 2.2 [2] days; P =.03). CONCLUSION: Only minimal short-term QOL benefits were found with LAC for colon cancer compared with standard open colectomy. Until ongoing trials establish that LAC is as effective as open colectomy in preventing recurrence and death from colon cancer, this procedure should not be offered to patients with colon cancer.

Veno-occlusive disease of the liver after blood and marrow transplantation: analysis of pre- and post-transplant risk factors associated with severity and results of therapy with tissue plasminogen activator.

We reviewed our blood and marrow transplantation (BMT) database from April 1982 to July 1996 and identified 111 of 474 patients with serum bilirubin concentration (SBR) > or = 34 micromol/l for two consecutive days within the first 20 days after related allogeneic or autologous BMT. Of the 111, 73 fulfilled the Seattle criteria for veno-occlusive disease of the liver (VOD) and had no other obvious cause for liver dysfunction. The patients were 16-60 years old (median, 39 years), and 41 were male (56%). Fourteen patients (19%) had autologous BMT, and 59 (81%) had allogeneic BMT. Twenty-eight (38%), 12 (16%), and 33 (45%) patients had severe, moderate, and mild VOD, respectively, by Seattle criteria. None of 23 patients with maximum (max) SBR > or = 257 micromol/l survived, all patients with max SBR < or = 128 micromol/l survived, and 7 of 15 patients (47%) with max SBR 128-257 micromol/l survived. The only pre-transplantation risk factor predictive of severe VOD was advanced disease state (P = 0.035), and the only transplant factors that predicted severe VOD were max SBR (P = 0.01) and maximum blood urea level (P = 0.03). Ten patients (all with creatinine levels > or = 150 micromol/l) were treated with tissue plasminogen activator; only two had a significant response and only one survived beyond day 120.

Prevalence and Prognostic Significance of Neuroendocrine Differentiation in Colorectal Carcinomas.

The prognostic significance of neuroendocrine differentiation in colorectal carcinoma is uncertain. We analyzed 289 moderately differentiated (grades II and Ill) colorectal carcinomas for neuroendocrine differentiation by immunohistochemistry and in situ hybridization. The tumors were divided into three groups based on the presence of and the numbers of neuroendocrine cells, with group I having no neuroendocrine cells, group II having <1 positive cell/mm(2), and group Ill with >1 positive cell/mm(2). In situ hybridization with probes for chromogranin A and B detected almost twice as many neuroendocrine cells as did immunostaining with an antibody for chromogranin A. There was no prognostic difference associated with the presence or absence of neuroendocrine differentiation in this group of moderately differentiated carcinomas. These results indicate that the presence of neuroendocrine cells detected by expression of chromogranin protein or mRNA does not influence prognosis in moderately differentiated colorectal carcinomas.