Malcolm A. Moore

Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium

We evaluated the ability of human recombinant granulocyte colony-stimulating factor (rhG-CSF) to prevent chemotherapy-induced neutropenia or to accelerate recovery from this complication and thus allow patients to receive full doses of antineoplastic agents on time, according to protocol design. Twenty-seven patients with transitional-cell carcinoma of the urothelium who were undergoing treatment with methotrexate, doxorubicin, vinblastine, and cisplatin were given rhG-CSF (up to 60 micrograms per kilogram of body weight per day) before their first cycle of combination chemotherapy, during the first cycle, or at both points. Treatment with rhG-CSF before chemotherapy resulted in a dose-dependent increase in the absolute neutrophil count. Treatment with rhG-CSF after chemotherapy significantly reduced the number of days (91 percent) per patient on which the absolute neutrophil count was 1000 per microliter or less (P = 0.0039), reduced the number of days (1 vs. 35) on which antibiotics were used to treat fever and neutropenia, and significantly increased the percentage (100 vs. 29 percent) of patients qualified to receive planned chemotherapy on day 14 of the treatment cycle (P = 0.0015). In addition, the incidence of mucositis was significantly decreased (11 vs. 44 percent, P = 0.041), as was its severity. These findings demonstrate that rhG-CSF is a potent stimulus of normal neutrophil proliferation and maturation. In addition, its administration can reduce both the hematopoietic and oral toxicity of chemotherapy.

Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer

PURPOSE Prior reports have indicated that patients with colon cancer who demonstrate high-level microsatellite instability (MSI-H) or defective DNA mismatch repair (dMMR) have improved survival and receive no benefit from fluorouracil (FU) -based adjuvant therapy compared with patients who have microsatellite-stable or proficient mismatch repair (pMMR) tumors. We examined MMR status as a predictor of adjuvant therapy benefit in patients with stages II and III colon cancer. METHODS MSI assay or immunohistochemistry for MMR proteins were performed on 457 patients who were previously randomly assigned to FU-based therapy (either FU + levamisole or FU + leucovorin; n = 229) versus no postsurgical treatment (n = 228). Data were subsequently pooled with data from a previous analysis. The primary end point was disease-free survival (DFS). RESULTS Overall, 70 (15%) of 457 patients exhibited dMMR. Adjuvant therapy significantly improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.93; P = .02) in patients with pMMR tumors. Patients with dMMR tumors receiving FU had no improvement in DFS (HR, 1.10; 95% CI, 0.42 to 2.91; P = .85) compared with those randomly assigned to surgery alone. In the pooled data set of 1,027 patients (n = 165 with dMMR), these findings were maintained; in patients with stage II disease and with dMMR tumors, treatment was associated with reduced overall survival (HR, 2.95; 95% CI, 1.02 to 8.54; P = .04). CONCLUSION Patient stratification by MMR status may provide a more tailored approach to colon cancer adjuvant therapy. These data support MMR status assessment for patients being considered for FU therapy alone and consideration of MMR status in treatment decision making.

Chemotaxis of primitive hematopoietic cells in response to stromal cell–derived factor-1

Stromal cell-derived factor-1 (SDF-1) provides a potent chemotactic stimulus for CD34(+) hematopoietic cells. We cultured mobilized peripheral blood (PB) and umbilical cord blood (CB) for up to 5 weeks and examined the migratory activity of cobblestone area-forming cells (CAFCs) and long-term culture-initiating cells (LTC-ICs) in a transwell assay. In this system, SDF-1 or MS-5 marrow stromal cells placed in the lower chamber induced transmembrane and transendothelial migration by 2- and 5-week-old CAFCs and LTC-ICs in 3 hours. Transmigration was blocked by preincubation of input CD34(+) cells with antibody to CXCR4. Transendothelial migration of CB CAFCs and LTC-ICs was higher than that of PB. We expanded CD34(+) cells from CB in serum-free medium with thrombopoietin, flk-2 ligand, and c-kit ligand, with or without IL-3 and found that CAFCs cultured in the absence of IL-3 had a chemotactic response equivalent to noncultured cells, even after 5 weeks. However, addition of IL-3 to the culture reduced this response by 20-50%. These data indicate that SDF-1 induces chemotaxis of primitive hematopoietic cells signaling through CXCR4 and that the chemoattraction could be downmodulated by culture ex vivo.

Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias

Antiangiogenic agents block the effects of tumor-derived angiogenic factors (paracrine factors), such as vascular endothelial growth factor (VEGF), on endothelial cells (EC), inhibiting the growth of solid tumors. However, whether inhibition of angiogenesis also may play a role in liquid tumors is not well established. We recently have shown that certain leukemias not only produce VEGF but also selectively express functional VEGF receptors (VEGFRs), such as VEGFR-2 (Flk-1, KDR) and VEGFR1 (Flt1), resulting in the generation of an autocrine loop. Here, we examined the relative contribution of paracrine (EC-dependent) and autocrine (EC-independent) VEGF/VEGFR signaling pathways, by using a human leukemia model, where autocrine and paracrine VEGF/VEGFR loops could be selectively inhibited by neutralizing mAbs specific for murine EC (paracrine pathway) or human tumor (autocrine) VEGFRs. Blocking either the paracrine or the autocrine VEGF/VEGFR-2 pathway delayed leukemic growth and engraftment in vivo, but failed to cure inoculated mice. Long-term remission with no evidence of disease was achieved only if mice were treated with mAbs against both murine and human VEGFR-2, whereas mAbs against human or murine VEGFR-1 had no effect on mice survival. Therefore, effective antiangiogenic therapies to treat VEGF-producing, VEGFR-expressing leukemias may require blocking both paracrine and autocrine VEGF/VEGFR-2 angiogenic loops to achieve remission and long-term cure.

Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase

Oncogenic Kit mutations are found in somatic gastrointestinal (GI) stromal tumors (GISTs) and mastocytosis. A mouse model for the study of constitutive activation of Kit in oncogenesis has been produced by a knock-in strategy introducing a Kit exon 11-activating mutation into the mouse genome based on a mutation found in a case of human familial GIST syndrome. Heterozygous mutant KitV558Δ/+ mice develop symptoms of disease and eventually die from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells is evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Therefore KitV558Δ/+ mice reproduce human familial GISTs, and they may be used as a model for the study of the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal.

Stage I testicular seminoma: results of adjuvant irradiation and surveillance.

PURPOSE To assess the results of treatment and patterns of relapse in a contemporary group of patients with stage I testicular seminoma managed by adjuvant radiation therapy (RT) and surveillance. PATIENTS AND METHODS Between January 1981 and December 1991, 364 patients with stage I seminoma were treated at Princess Margaret Hospital. Of these, 194 were treated with adjuvant RT (92% received a dose of 25 Gy in 20 fractions for 4 weeks) and 172 were managed by surveillance. Two patients were included in this series twice--both had postorchiectomy RT for stage I disease, developed a contralateral seminoma, and were placed on surveillance and analyzed for outcome of both primary tumors. The median follow-up period for patients treated with adjuvant RT was 8.1 years (range, 0.2 to 12), and for patients managed by surveillance, it was 4.2 years (range, 0.6 to 10.1). RESULTS The overall 5-year actuarial survival rate for all patients was 97%, and the cause-specific survival rate was 99.7%. Only one patient died of seminoma. Of 194 patients treated with RT, 11 have relapsed, with a 5-year relapse-free rate of 94.5%. Prognostic factors for relapse included histology, tunica invasion, spermatic cord involvement, and epididymal involvement. Twenty-seven patients developed disease progression on surveillance, which resulted in a 5-year progression-free rate of 81.9%. The only factor identified to predict progression on surveillance was age at diagnosis: patients aged < or = 34 years had a 26% risk of progression at 5 years, in contrast to a 10% risk of progression in those greater than 34 years of age. CONCLUSION The outcome of patients with stage I testicular seminoma is excellent, with only one of 364 patients (0.27%) dying of disease. In our experience, both a policy of adjuvant RT and of surveillance resulted in a high probability of cure. Our surveillance experience showed that four of five patients with stage I seminoma are cured with orchiectomy alone. The benefit of adjuvant RT was reflected in a decreased relapse rate. We have identified a number of prognostic factors for relapse in patients managed with both approaches, but further study of prognostic factors is required, particularly to identify patients at high risk of disease progression on surveillance.

Effects of Human Granulocyte Colony-Stimulating Factor in a Patient with Idiopathic Neutropenia

CHRONIC idiopathic neutropenia is characterized by maturational arrest of neutrophil precursors in the bone marrow and a circulating neutrophil count of less than 1500 cells per microliter. Other h...

Meat,fish and fat intake in relation to subsite-specific risk of colorectal cancer.The Fukuoka Colorectal Cancer Study

High intake of red meat has been associated with increased risk of colorectal cancer in Western countries. There has been much interest in the role of n‐3 polyunsaturated fatty acids (PUFA) in colorectal cancer prevention, but epidemiological findings are limited and inconsistent. The objective of our study was to examine associations of meat, fish and fat intake with risk of colorectal cancer, paying particular attention to the subsite within the colorectum. Data were from the Fukuoka Colorectal Cancer Study, a population‐based case‐control study, covering 782 cases and 793 controls. Diet was assessed by interview, using newly developed personal‐computer software for registering semiquantitative food frequencies. The intake of beef/pork, processed meat, total fat, saturated fat or n‐6 PUFA showed no clear association with the overall or subsite‐specific risk of colorectal cancer. There was an almost significant inverse association between n‐3 PUFA and the risk of colorectal cancer; the covariate‐adjusted odds ratio for the highest (median 3.94 g/day) versus lowest (median 1.99 g/day) quintile of energy‐adjusted intake was 0.74 (95% confidence interval 0.52–1.06, trend P = 0.050). The consumption of fish and fish products was similarly inversely related to the risk although the association was not statistically significant. These associations were more evident for distal colon cancer; adjusted odds ratio for the highest versus lowest quintile of n‐3 PUFA intake was 0.56 (95% confidence interval 0.34–0.92, trend P = 0.02). Our findings do not support the hypothesis that consumption of red meat increases colorectal cancer risk but do suggest that high intake of fish may decrease the risk, particularly of distal colon cancer. (Cancer Sci 2007; 98: 590–597)

Marrow cytogenetic and cell-culture analyses of the myelodysplastic syndromes: Insights to pathophysiology and prognosis

Marrow cytogenetic and granulocyte-macrophage colony formation (CFU-GM) studies were performed on 34 previously untreated patients with documented myelodysplastic syndromes seen between January 1978 and June 1982. All patients were managed without chemotherapy until progression to acute leukemia was observed. All 10 patients with exclusively abnormal marrow metaphases developed acute leukemia (100%) while only one (7%) of 14 patients with solely normal marrow metaphases subsequently developed leukemia (p less than 0.001). Three (42%) of the seven patients with both normal and abnormal marrow metaphases developed acute leukemia. Fifteen (86%) of the 19 patients with either large cluster or no growth patterns developed acute leukemia while only two (13%) of 15 patients with either small cluster or colony forming growth patterns developed acute leukemia (p less than 0.001). Abnormal marrow cytogenetic status correlated with abnormal marrow CFU-GM growth pattern (p less than 0.05). Analysis of CFU-GM sensitivity to inhibition by prostaglandin E was performed in 12 patients. Nine patients showed CFU-GM refractoriness to inhibition by prostaglandin E. Seven of these patients eventually developed leukemia. Three patients had CFU-GMs which were initially sensitive to prostaglandin E inhibition. In these three patients, a loss of CFU-GM sensitivity to prostaglandin E was observed prior to their progression to morphologically identifiable acute leukemia.

A Phase II Trial with Pharmacodynamic Endpoints of the Proteasome Inhibitor Bortezomib in Patients with Metastatic Colorectal Cancer

Purpose: To evaluate the effects of the proteasome inhibitor bortezomib on tumor growth in patients with advanced colorectal cancer, and to explore the relationship between correlative studies and clinical outcome. Design: Bortezomib (1.3 mg/m2) was administered i.v. on days 1, 4, 8, and 11 of a 21-day cycle. Tumor response was assessed after every two cycles. Tumor biopsies were done prior to treatment and on day 9 of the first treatment cycle. Biopsies were examined for Ser32/36-IκB, Ser276-nuclear factor κB (NFκB), hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX), p53, and microvessel density using immunohistochemistry. Results: Nineteen patients received 42 cycles (range 1-4) of bortezomib. No objective response was seen; three patients had stable disease at cycle 2, two patients had progressive disease after cycle 1, and 11 patients had progressive disease at cycle 2. Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity. The median time to progression was 5.1 weeks (95% confidence interval, 5.1-11.1 weeks). There was a significant increase in the expression of HIF-1α relative to its transcriptional target CAIX following bortezomib, and a similar effect was also observed in a companion study using a human tumor xenograft model. Expression of p53, Ser276-NFκB, and Ser32/36-IκB was unchanged. Conclusion: Single agent bortezomib is inactive in metastatic colorectal cancer. Using this regimen, there was no detectable effect on NFκB, but a significant accumulation of HIF-1α was seen relative to CAIX. This suggests that proteasome inhibition alters the response to tumor hypoxia, and further investigation of this effect is indicated.