Journal of Experimental & Clinical Cancer Research, Jan 2, 2023
Background: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the rele... more Background: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. Methods: PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9 −/− mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. Results: PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the lowdensity lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9 −/− mice. Conclusions: Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.
Purpose:Intravenous delivery of oncolytic viruses often leads to tumor vascular shutdown, resulti... more Purpose:Intravenous delivery of oncolytic viruses often leads to tumor vascular shutdown, resulting in decreased tumor perfusion and elevated tumor hypoxia. We hypothesized that using 3TSR to normalize tumor vasculature prior to administration of an oncolytic Newcastle disease virus (NDV) would enhance virus delivery and trafficking of immunologic cell subsets to the tumor core, resulting in systemically enhanced immunotherapy and regression of advanced-stage epithelial ovarian cancer (EOC).Experimental Design:Using an orthotopic, syngeneic mouse model of advanced-stage EOC, we pretreated mice with 3TSR (4 mg/kg per day) alone or followed by combination with fusogenic NDV(F3aa) (1.0 × 108 plaque-forming units).Results:Treatment with 3TSR normalized tumor vasculature, enhanced blood perfusion of primary EOC tumors, and induced disease regression. Animals treated with combination therapy had the greatest reduction in primary tumor mass, ascites accumulation, and secondary lesions (50% of mice were completely devoid of peritoneal metastases). Combining 3TSR + NDV(F3aa) led to enhanced trafficking of immunologic cells into the primary tumor core.Conclusions:We have shown, for the first time, that NDV, like other oncolytic viruses, is a potent mediator of acute vascular shutdown and that preventing this through vascular normalization can promote regression in a preclinical model of advanced-stage ovarian cancer. This challenges the current focus on induction of intravascular thrombosis as a requisite for successful oncolytic virotherapy.See related commentary by Bykov and Zamarin, p. 1446
BACKGROUND. For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels... more BACKGROUND. For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear. METHODS. Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n 5 578), hormone-refractory prostate cancer (HRPC; n 5 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n 5 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; <64 nmol/mmol creatinine) or elevated (E; !64 nmol/mmol creatinine). RESULTS. After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/ OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N. CONCLUSIONS. Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of ske
Protracted venous infusion of 5-fluorouracil (5-FU) is a common treatment for patients with gastr... more Protracted venous infusion of 5-fluorouracil (5-FU) is a common treatment for patients with gastrointestinal malignancy. A central venous access device is required for safe and effective drug delivery. This study uses a survival analysis to compare the useful life and treatment completion success of tunelled centrally placed catheters (TCPCs) and peripherally inserted central catheters (PICCs). It also describes complications found with both devices. Data on insertion, complications, and removal of TCPCs and PICCs were collected on standardized forms, prospectively for initial PICCs and retrospectively for initial TCPCs. Survival of indwelling catheters was similar for both devices for the first 120 days, but after that TCPC survival was statistically better than that of PICCs (P = 0.051). Complications occurred in 61% of patients with TCPCs and 67% of patients with PICCs. The authors conclude that PICCs provide less invasive, more cost-effective, and easier to schedule central venous access for 5-FU infusion; however, their advantage over TCPCs decreases significantly in treatments lasting more than 120 days.
We have used cesium sulfate density gradient centrifugation to monitor the incorporation of 9-bet... more We have used cesium sulfate density gradient centrifugation to monitor the incorporation of 9-beta-D-arabinofuranosyladenine (ara-A) into L1210 cellular nucleic acids. The results demonstrate the specific incorporation of ara-A in L1210 DNA. We have also found a highly significant relationship between the formation of ara-A incorporated into DNA and loss of clonogenic survival. This relationship was maintained when using ara-A in the presence of the adenosine deaminase inhibitor deoxycoformycin. Furthermore, treatment with increasing concentrations of ara-A resulted in a greater proportion of ara-A residues at the 3'-terminus, consistent with this agent providing a poor primer terminus for elongating DNA strands. These findings are similar to those obtained previously with 1-beta-D-arabinofuranosylcytosine and suggest that the incorporation of arabinofuranosyl derivatives in DNA is one mechanism responsible for cell lethality.
We have demonstrated recently that 5-fluorouracil (FUra) residues incorporate in eukaryotic DNA. ... more We have demonstrated recently that 5-fluorouracil (FUra) residues incorporate in eukaryotic DNA. In the present study, we extend these findings and monitor the effect of methotrexate on the formation of FUra DNA. The results demonstrate that methotrexate treatment has little effect on the incorporation of FUra or 5-fluorodeoxyuridine in DNA obtained from MCF-7 human breast carcinoma cells. More importantly, we demonstrate that FUra residues are excised from MCF-7 DNA and that methotrexate enhances the excision process. This excision of FUra from eukaryotic DNA may contribute to the cytotoxicity and mutagenicity of these fluorinated pyrimidines.
A prospective phase 2 study was conducted to evaluate the clinical utility of acupuncture-like tr... more A prospective phase 2 study was conducted to evaluate the clinical utility of acupuncture-like transcutaneous nerve stimulation (ALTENS) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Eligible cancer patients had a < 2 ECOG performance score, received neurotoxic chemotherapy, and developed CIPN symptoms for > two months. Randomization was used to eliminate bias in patient selection for ALTENS and was not to compare the effectiveness between the two treatments. ALTENS treatments were delivered using Codetron units. Bilateral acupuncture points included LI4 and LIV3, plus LI11 or ST36 were stimulated. Acupuncture treatments were administered to CV6, SP6, ST6, LI11, Bafeng, Baxie and selective Jing points bilaterally. Twelve treatments were delivered twice weekly over 6 to 8 weeks. The Modified Total Neuropathy Score (mTNS), Numbness Score, and Edmonton Symptom Assessment Score (ESAS) were assessed at baseline, treatment completion, plus at 3 and 6 months follow-up. The primary study endpoint was mTNS score at 6 months. We planned to recruit 23 patients into each group. After 30 patients were recruited, 2 were lost to follow-up at 3 months in the ALTENS group and 3 in the acupuncture group. The research team decided to recruit all remaining consecutive patients only to the ALTENS group to ensure an adequate evaluation of ALTENS, the primary object of evaluation. There were 27 patients in the ALTENS group, with an average symptom duration of 10 months after chemotherapy. Twenty four and 23 patients completed the 3 and 6 month followup respectively. The median mTNS scores were 7.1, 4.0, 3.6 and 3.1 at baseline, treatment completion, 3 and 6 months follow-up, respectively. One-way ANOVA analysis showed a significant improvement in mTNS scores (p<0.001) at 6 months. Numbness scores were also significantly improved at 6 months. ESAS pain scores and perception of well-being scores analyses were inconclusive. There were no significant reported side effects of ALTENS. There were only 13 patients in the acupuncture group and the number was insufficient for either an independent or a comparative analysis. The results of this study suggests that ALTENS significantly reduces the mTNS scores and numbness in patients suffering from CIPN symptoms.
We have demonstrated previously the presence of 5-fluorouracil (FUra) residues in L1210 DNA. Thes... more We have demonstrated previously the presence of 5-fluorouracil (FUra) residues in L1210 DNA. These findings have been extended to the MCF-7 human breast carcinoma cell line. Cesium sulfate gradient centrifugation has been used to separate the MCF-7 RNA and DNA fractions. Alkali and RNase digests have also been used to remove any possible RNA contaminating the DNA fraction. The purified DNA has been analyzed by high-pressure liquid chromatography following digestion to nucleotides and nucleosides. The results demonstrate that FUra residues are detectable in the DNA of these human breast carcinoma cells following exposure to either FUra of 5-fluorodeoxyuridine. Further, the extend of FUra incorporation in both MCF-7 RNA and DNA is similar with either fluorinated pyrimidine. We also demonstrate that the FUra incorporation in DNA from this human cell line can be enhanced by concurrent incubation with thymidine.
The HL-60 human leukemic promyelocyte can be induced to mature into terminally differentiated cel... more The HL-60 human leukemic promyelocyte can be induced to mature into terminally differentiated cells using certain nucleosides and chemotherapeutic agents. The mechanisms responsible for this induction of differentiation, however, remain unclear. We have monitored the effects of two specific inhibitors of DNA synthesis to determine whether slowing of DNA polymerization can induce HL-60 differentiation. The results demonstrate that cytosine arabinoside (ara-C) induces nonspecific esterase activity in HL-60 cells and increases surface expression of the monocyte antigen MY-4. The results also demonstrate that aphidicolin, an inhibitor of DNA polymerase which is not incorporated in DNA, induces similar phenotypic changes. The induction of differentiation by both agents was accompanied by loss of clonogenic potential as monitored by colony formation in methylcellulose. These observations suggest that terminal differentiation of HL-60 cells can be induced by drugs known to inhibit DNA synthesis.
Aim In Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging s... more Aim In Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging sometimes complemented with somatostatin receptor scintigraphy (SRS). This study assessed the diagnostic accuracy of 6-[ 18 F]fluoro-3,4-dihydroxyphenylalanine (18 F-FDOPA) PET/CT in neuroendocrine tumors. Methods We prospectively included 27 patients with either suspected carcinoid (n = 6, with all prior tests negative) or with an established diagnosis of intestinal carcinoid tumor (n = 21) from two Canadian treatment centers. Findings of 18 F-FDOPA PET/CT were compared with SRS, CT, and combined SRS/CT using a composite reference standard comprising all available imaging, biochemistry, surgery, and follow-up data. Sensitivity was calculated per patient, per body region, and per lesion. The contribution to patient management was estimated from the feedback of attending physicians. Results In documented carcinoid patients, 18 F-FDOPA PET/CT identified disease in 20 of 21 patients (patientbased sensitivity 95%). In 56 positive regions, 18 F-FDOPA PET/CT detected 53, CT detected 34, SRS detected 34, and CT + SRS detected 39 regions, leading to region-based sensitivities of 95, 61, 62, and 71%, respectively. Lesionbased sensitivities were 96, 69, 50, and 72%, respectively. In the six patients with suspected disease only, one CT scan was positive, but 18 F-FDOPA PET/CT was negative for all. 18 F-FDOPA PET contributed to patient management in 12/21 patients (57%). Conclusion 18 F-FDOPA PET/CT proved to be an excellent modality for staging of carcinoid tumor patients, with superior performance compared with currently applied methods in Canada. In patients with suspected disease with negative prior imaging investigations, 18 F-FDOPA was not helpful. Nucl Med Commun 33:322-330 c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
In a double-blind phase I study, healthy male volunteers were randomly assigned to receive clenti... more In a double-blind phase I study, healthy male volunteers were randomly assigned to receive clentiazem, a benzothiazepine calcium channel blocker (n = 24), or placebo (n = 3). Clentiazem
1 Background: To test if long term AAT when combined with RT in these patients (pts) with prostat... more 1 Background: To test if long term AAT when combined with RT in these patients (pts) with prostate cancer (PC) will improve cancer control outcomes as well as overall survival (OS). Methods: Post-RP pts with pT3,N0 or with pT2,N0 (and positive margins) who have an elevated PSA were entered on a phase III, double-blinded, placebo-controlled trial of RT alone (64.8 Gy in 1.8 Gy fractions) vs RT + AAT (24 months of bicalutamide, 150mg daily) during and after RT. The primary end point is OS. Results: From 3/98 to 3/03, 771 eligible pts (median age 65) were randomized to RT + AAT (387) or RT alone (383). Pretreatment characteristics were balanced. 672 (87%) had a PSA nadir after RP of &lt; 0.5 ng/mL. 655 (85%) had an entry PSA value of &lt;1.6, 115 (15%) had an entry PSA of 1.6-3.9. Median follow-up was 7.1 years. Actuarial OS at 7 years was 91% for RT + AAT and 86% for RT alone. Too few primary end-point events have occurred to allow a statistical comparison between groups. Freedom from PSA progression (FFP) at 7 years was 57% for RT + AAT and 40% for RT alone (P &lt; 0.0001); for 226 pts with GS &lt; 7 were 63% and 50% (P&lt;0.02), for 411 GS 7 these were 55% and 39% (P&lt;0.0006), and for 134 GS 8-10 were 56% and 26% (P &lt; 0.0008). The 7-yr cumulative incidence of metastatic PC was less in the RT and AAT arm, 7% vs 13% in the RT arm (p&lt;0.041). Late grade 3-4 toxicities were similar in both arms. By category the combined grade 3-4 toxicities for RT + AAT and RT alone were: bladder 6% vs 5% bowel 2% vs 1%, cardiac 3% vs 2%. Gynecomastia (mostly grades 1-2) differed significantly, 89% vs15%. In the RT + AAT arm grade 3 was the highest liver toxicity, which occurred in 3 pts. Conclusions: The addition of 24 months of bicalutamide 150 mg daily during and after RT significantly improved FFP and reduced the incidence of metastatic PC without adding significantly to RT toxicity. The significance of benefit in OS, as well analysis of risk-stratified subsets, wait longer follow-up. No significant financial relationships to disclose.
see how thoroughly parents are pre¬ paring their children. One of the public libraries did have t... more see how thoroughly parents are pre¬ paring their children. One of the public libraries did have two excellent books for teenagers.
3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in p... more 3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of < 0.5 ng/ml. 649 (85%) had an entry PSA value of <1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median ...
Journal of Experimental & Clinical Cancer Research, Jan 2, 2023
Background: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the rele... more Background: PCSK9 regulates cholesterol homeostasis and promotes tumorigenesis. However, the relevance of these two actions and the mechanisms underlying PCSK9's oncogenic roles in melanoma and other cancers remain unclear. Methods: PCSK9's association with melanoma was analysed using the TCGA dataset. Empty vector (EV), PCSK9, gain-of-function (D374Y), and loss-of-function (Q152H) PCSK9 mutant were stably-expressed in murine melanoma B16 cells and studied for impact on B16 cell-derived oncogenesis in vitro and in vivo using syngeneic C57BL/6 and Pcsk9 −/− mice. Intratumoral accumulation of cholesterol was determined. RNA-seq was performed on individual tumor types. Differentially-expressed genes (DEGs) were derived from the comparisons of B16 PCSK9, B16 D374Y, or B16 Q152H tumors to B16 EV allografts and analysed for pathway alterations. Results: PCSK9 expression and its network negatively correlated with the survival probability of patients with melanoma. PCSK9 promoted B16 cell proliferation, migration, and growth in soft agar in vitro, formation of tumors in C57BL/6 mice in vivo, and accumulation of intratumoral cholesterol in a manner reflecting its regulation of the lowdensity lipoprotein receptor (LDLR): Q152H, EV, PCSK9, and D374Y. Tumor-associated T cells, CD8 + T cells, and NK cells were significantly increased in D374Y tumors along with upregulations of multiple immune checkpoints, IFNγ, and 143 genes associated with T cell dysfunction. Overlap of 36 genes between the D374Y DEGs and the PCSK9 DEGs predicted poor prognosis of melanoma and resistance to immune checkpoint blockade (ICB) therapy. CYTH4, DENND1C, AOAH, TBC1D10C, EPSTI1, GIMAP7, and FASL (FAS ligand) were novel predictors of ICB therapy and displayed high level of correlations with multiple immune checkpoints in melanoma and across 30 human cancers. We observed FAS ligand being among the most robust biomarkers of ICB treatment and constructed two novel and effective multigene panels predicting response to ICB therapy. The profiles of allografts produced by B16 EV, PCSK9, D374Y, and Q152H remained comparable in C57BL/6 and Pcsk9 −/− mice. Conclusions: Tumor-derived PCSK9 plays a critical role in melanoma pathogenesis. PCSK9's oncogenic actions are associated with intratumoral cholesterol accumulation. PCSK9 systemically affects the immune system, contributing to melanoma immune evasion. Novel biomarkers derived from the PCSK9-network effectively predicted ICB therapy responses.
Purpose:Intravenous delivery of oncolytic viruses often leads to tumor vascular shutdown, resulti... more Purpose:Intravenous delivery of oncolytic viruses often leads to tumor vascular shutdown, resulting in decreased tumor perfusion and elevated tumor hypoxia. We hypothesized that using 3TSR to normalize tumor vasculature prior to administration of an oncolytic Newcastle disease virus (NDV) would enhance virus delivery and trafficking of immunologic cell subsets to the tumor core, resulting in systemically enhanced immunotherapy and regression of advanced-stage epithelial ovarian cancer (EOC).Experimental Design:Using an orthotopic, syngeneic mouse model of advanced-stage EOC, we pretreated mice with 3TSR (4 mg/kg per day) alone or followed by combination with fusogenic NDV(F3aa) (1.0 × 108 plaque-forming units).Results:Treatment with 3TSR normalized tumor vasculature, enhanced blood perfusion of primary EOC tumors, and induced disease regression. Animals treated with combination therapy had the greatest reduction in primary tumor mass, ascites accumulation, and secondary lesions (50% of mice were completely devoid of peritoneal metastases). Combining 3TSR + NDV(F3aa) led to enhanced trafficking of immunologic cells into the primary tumor core.Conclusions:We have shown, for the first time, that NDV, like other oncolytic viruses, is a potent mediator of acute vascular shutdown and that preventing this through vascular normalization can promote regression in a preclinical model of advanced-stage ovarian cancer. This challenges the current focus on induction of intravascular thrombosis as a requisite for successful oncolytic virotherapy.See related commentary by Bykov and Zamarin, p. 1446
BACKGROUND. For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels... more BACKGROUND. For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear. METHODS. Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n 5 578), hormone-refractory prostate cancer (HRPC; n 5 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n 5 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; <64 nmol/mmol creatinine) or elevated (E; !64 nmol/mmol creatinine). RESULTS. After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/ OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N. CONCLUSIONS. Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of ske
Protracted venous infusion of 5-fluorouracil (5-FU) is a common treatment for patients with gastr... more Protracted venous infusion of 5-fluorouracil (5-FU) is a common treatment for patients with gastrointestinal malignancy. A central venous access device is required for safe and effective drug delivery. This study uses a survival analysis to compare the useful life and treatment completion success of tunelled centrally placed catheters (TCPCs) and peripherally inserted central catheters (PICCs). It also describes complications found with both devices. Data on insertion, complications, and removal of TCPCs and PICCs were collected on standardized forms, prospectively for initial PICCs and retrospectively for initial TCPCs. Survival of indwelling catheters was similar for both devices for the first 120 days, but after that TCPC survival was statistically better than that of PICCs (P = 0.051). Complications occurred in 61% of patients with TCPCs and 67% of patients with PICCs. The authors conclude that PICCs provide less invasive, more cost-effective, and easier to schedule central venous access for 5-FU infusion; however, their advantage over TCPCs decreases significantly in treatments lasting more than 120 days.
We have used cesium sulfate density gradient centrifugation to monitor the incorporation of 9-bet... more We have used cesium sulfate density gradient centrifugation to monitor the incorporation of 9-beta-D-arabinofuranosyladenine (ara-A) into L1210 cellular nucleic acids. The results demonstrate the specific incorporation of ara-A in L1210 DNA. We have also found a highly significant relationship between the formation of ara-A incorporated into DNA and loss of clonogenic survival. This relationship was maintained when using ara-A in the presence of the adenosine deaminase inhibitor deoxycoformycin. Furthermore, treatment with increasing concentrations of ara-A resulted in a greater proportion of ara-A residues at the 3'-terminus, consistent with this agent providing a poor primer terminus for elongating DNA strands. These findings are similar to those obtained previously with 1-beta-D-arabinofuranosylcytosine and suggest that the incorporation of arabinofuranosyl derivatives in DNA is one mechanism responsible for cell lethality.
We have demonstrated recently that 5-fluorouracil (FUra) residues incorporate in eukaryotic DNA. ... more We have demonstrated recently that 5-fluorouracil (FUra) residues incorporate in eukaryotic DNA. In the present study, we extend these findings and monitor the effect of methotrexate on the formation of FUra DNA. The results demonstrate that methotrexate treatment has little effect on the incorporation of FUra or 5-fluorodeoxyuridine in DNA obtained from MCF-7 human breast carcinoma cells. More importantly, we demonstrate that FUra residues are excised from MCF-7 DNA and that methotrexate enhances the excision process. This excision of FUra from eukaryotic DNA may contribute to the cytotoxicity and mutagenicity of these fluorinated pyrimidines.
A prospective phase 2 study was conducted to evaluate the clinical utility of acupuncture-like tr... more A prospective phase 2 study was conducted to evaluate the clinical utility of acupuncture-like transcutaneous nerve stimulation (ALTENS) for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). Eligible cancer patients had a < 2 ECOG performance score, received neurotoxic chemotherapy, and developed CIPN symptoms for > two months. Randomization was used to eliminate bias in patient selection for ALTENS and was not to compare the effectiveness between the two treatments. ALTENS treatments were delivered using Codetron units. Bilateral acupuncture points included LI4 and LIV3, plus LI11 or ST36 were stimulated. Acupuncture treatments were administered to CV6, SP6, ST6, LI11, Bafeng, Baxie and selective Jing points bilaterally. Twelve treatments were delivered twice weekly over 6 to 8 weeks. The Modified Total Neuropathy Score (mTNS), Numbness Score, and Edmonton Symptom Assessment Score (ESAS) were assessed at baseline, treatment completion, plus at 3 and 6 months follow-up. The primary study endpoint was mTNS score at 6 months. We planned to recruit 23 patients into each group. After 30 patients were recruited, 2 were lost to follow-up at 3 months in the ALTENS group and 3 in the acupuncture group. The research team decided to recruit all remaining consecutive patients only to the ALTENS group to ensure an adequate evaluation of ALTENS, the primary object of evaluation. There were 27 patients in the ALTENS group, with an average symptom duration of 10 months after chemotherapy. Twenty four and 23 patients completed the 3 and 6 month followup respectively. The median mTNS scores were 7.1, 4.0, 3.6 and 3.1 at baseline, treatment completion, 3 and 6 months follow-up, respectively. One-way ANOVA analysis showed a significant improvement in mTNS scores (p<0.001) at 6 months. Numbness scores were also significantly improved at 6 months. ESAS pain scores and perception of well-being scores analyses were inconclusive. There were no significant reported side effects of ALTENS. There were only 13 patients in the acupuncture group and the number was insufficient for either an independent or a comparative analysis. The results of this study suggests that ALTENS significantly reduces the mTNS scores and numbness in patients suffering from CIPN symptoms.
We have demonstrated previously the presence of 5-fluorouracil (FUra) residues in L1210 DNA. Thes... more We have demonstrated previously the presence of 5-fluorouracil (FUra) residues in L1210 DNA. These findings have been extended to the MCF-7 human breast carcinoma cell line. Cesium sulfate gradient centrifugation has been used to separate the MCF-7 RNA and DNA fractions. Alkali and RNase digests have also been used to remove any possible RNA contaminating the DNA fraction. The purified DNA has been analyzed by high-pressure liquid chromatography following digestion to nucleotides and nucleosides. The results demonstrate that FUra residues are detectable in the DNA of these human breast carcinoma cells following exposure to either FUra of 5-fluorodeoxyuridine. Further, the extend of FUra incorporation in both MCF-7 RNA and DNA is similar with either fluorinated pyrimidine. We also demonstrate that the FUra incorporation in DNA from this human cell line can be enhanced by concurrent incubation with thymidine.
The HL-60 human leukemic promyelocyte can be induced to mature into terminally differentiated cel... more The HL-60 human leukemic promyelocyte can be induced to mature into terminally differentiated cells using certain nucleosides and chemotherapeutic agents. The mechanisms responsible for this induction of differentiation, however, remain unclear. We have monitored the effects of two specific inhibitors of DNA synthesis to determine whether slowing of DNA polymerization can induce HL-60 differentiation. The results demonstrate that cytosine arabinoside (ara-C) induces nonspecific esterase activity in HL-60 cells and increases surface expression of the monocyte antigen MY-4. The results also demonstrate that aphidicolin, an inhibitor of DNA polymerase which is not incorporated in DNA, induces similar phenotypic changes. The induction of differentiation by both agents was accompanied by loss of clonogenic potential as monitored by colony formation in methylcellulose. These observations suggest that terminal differentiation of HL-60 cells can be induced by drugs known to inhibit DNA synthesis.
Aim In Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging s... more Aim In Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging sometimes complemented with somatostatin receptor scintigraphy (SRS). This study assessed the diagnostic accuracy of 6-[ 18 F]fluoro-3,4-dihydroxyphenylalanine (18 F-FDOPA) PET/CT in neuroendocrine tumors. Methods We prospectively included 27 patients with either suspected carcinoid (n = 6, with all prior tests negative) or with an established diagnosis of intestinal carcinoid tumor (n = 21) from two Canadian treatment centers. Findings of 18 F-FDOPA PET/CT were compared with SRS, CT, and combined SRS/CT using a composite reference standard comprising all available imaging, biochemistry, surgery, and follow-up data. Sensitivity was calculated per patient, per body region, and per lesion. The contribution to patient management was estimated from the feedback of attending physicians. Results In documented carcinoid patients, 18 F-FDOPA PET/CT identified disease in 20 of 21 patients (patientbased sensitivity 95%). In 56 positive regions, 18 F-FDOPA PET/CT detected 53, CT detected 34, SRS detected 34, and CT + SRS detected 39 regions, leading to region-based sensitivities of 95, 61, 62, and 71%, respectively. Lesionbased sensitivities were 96, 69, 50, and 72%, respectively. In the six patients with suspected disease only, one CT scan was positive, but 18 F-FDOPA PET/CT was negative for all. 18 F-FDOPA PET contributed to patient management in 12/21 patients (57%). Conclusion 18 F-FDOPA PET/CT proved to be an excellent modality for staging of carcinoid tumor patients, with superior performance compared with currently applied methods in Canada. In patients with suspected disease with negative prior imaging investigations, 18 F-FDOPA was not helpful. Nucl Med Commun 33:322-330 c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
In a double-blind phase I study, healthy male volunteers were randomly assigned to receive clenti... more In a double-blind phase I study, healthy male volunteers were randomly assigned to receive clentiazem, a benzothiazepine calcium channel blocker (n = 24), or placebo (n = 3). Clentiazem
1 Background: To test if long term AAT when combined with RT in these patients (pts) with prostat... more 1 Background: To test if long term AAT when combined with RT in these patients (pts) with prostate cancer (PC) will improve cancer control outcomes as well as overall survival (OS). Methods: Post-RP pts with pT3,N0 or with pT2,N0 (and positive margins) who have an elevated PSA were entered on a phase III, double-blinded, placebo-controlled trial of RT alone (64.8 Gy in 1.8 Gy fractions) vs RT + AAT (24 months of bicalutamide, 150mg daily) during and after RT. The primary end point is OS. Results: From 3/98 to 3/03, 771 eligible pts (median age 65) were randomized to RT + AAT (387) or RT alone (383). Pretreatment characteristics were balanced. 672 (87%) had a PSA nadir after RP of &lt; 0.5 ng/mL. 655 (85%) had an entry PSA value of &lt;1.6, 115 (15%) had an entry PSA of 1.6-3.9. Median follow-up was 7.1 years. Actuarial OS at 7 years was 91% for RT + AAT and 86% for RT alone. Too few primary end-point events have occurred to allow a statistical comparison between groups. Freedom from PSA progression (FFP) at 7 years was 57% for RT + AAT and 40% for RT alone (P &lt; 0.0001); for 226 pts with GS &lt; 7 were 63% and 50% (P&lt;0.02), for 411 GS 7 these were 55% and 39% (P&lt;0.0006), and for 134 GS 8-10 were 56% and 26% (P &lt; 0.0008). The 7-yr cumulative incidence of metastatic PC was less in the RT and AAT arm, 7% vs 13% in the RT arm (p&lt;0.041). Late grade 3-4 toxicities were similar in both arms. By category the combined grade 3-4 toxicities for RT + AAT and RT alone were: bladder 6% vs 5% bowel 2% vs 1%, cardiac 3% vs 2%. Gynecomastia (mostly grades 1-2) differed significantly, 89% vs15%. In the RT + AAT arm grade 3 was the highest liver toxicity, which occurred in 3 pts. Conclusions: The addition of 24 months of bicalutamide 150 mg daily during and after RT significantly improved FFP and reduced the incidence of metastatic PC without adding significantly to RT toxicity. The significance of benefit in OS, as well analysis of risk-stratified subsets, wait longer follow-up. No significant financial relationships to disclose.
see how thoroughly parents are pre¬ paring their children. One of the public libraries did have t... more see how thoroughly parents are pre¬ paring their children. One of the public libraries did have two excellent books for teenagers.
3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in p... more 3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of < 0.5 ng/ml. 649 (85%) had an entry PSA value of <1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median ...
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