bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of Tropomysin-Related Kinase B in Metastatic Human Pancreatic Cancer Cells
Authors: Sclabas Guido M. , Fujioka Shuichi , Schmidt Christian , Li Zhongkui , Frederick Wayne A.I. , Yang Wentao , Yokoi Kenji , Evans Douglas B. , Abbruzzese James L. , Hess Kenneth R. , Zhang Wei , Fidler Isaiah J. , Chiao Paul J.
Published: June 2022

Purpose: Pancreatic adenocarcinoma is currently the fourth leading cause of cancer death in the United States, and most pancreatic cancers develop locally advanced disease or metastasis at the time of diagnosis. The mechanisms by which it invades and metastasizes are not known.

Experimental Design: To identify the genes involved in pancreatic cancer metastasis, we analyzed the gene expression profiles between highly metastatic Colo357L3.6pl and parental Colo357FG pancreatic cancer cell lines using cDNA microarrays and confirmed differential gene expression by reverse transcription-PCR, Western blotting, and immunologic analysis of 54 samples from pancreatic cancer patients. The correlation with clinical outcome was also examined. The possible signaling pathways involved with tropomyosin-related kinase B (TrkB) were analyzed.

Results: Our findings showed that TrkB was overexpressed in the highly metastatic Colo357L3.6pl cells, which correlated with perineural invasion (P = 0.026), positive retroperitoneal margin (P = 0.0005), and shorter latency to development of liver metastasis (Cox proportional hazard ratio, 0.3; 95% confidence interval, 0.1-0.8; P = 0.01) in patient samples. Extracellular signal-regulated kinases 1 and 2 were activated and Elk-1 and AP-1 DNA binding activity was induced in Colo357L3.6pl cells. Furthermore, interleukin 8 and vascular endothelial growth factor were more strongly expressed in Colo357L3.6pl than Colo357FG cells, and these findings were confirmed in Colo357L3.6pl and Colo357FG orthotopic tumors.

Conclusion: These results suggest that overexpression of TrkB and activation of mitogen-activated protein kinase and AP-1, which may in turn induce the expression of vascular endothelial growth factor and interleukin 8, may mediate the cardinal clinical features of locally aggressive growth and metastasis of pancreatic cancer. Our results also imply that TrkB receptor may be a novel therapeutic target for pancreatic cancer.
The Thioredoxin-1 Inhibitor 1-Methylpropyl 2-Imidazolyl Disulfide (PX-12) Decreases Vascular Permeability in Tumor Xenografts Monitored by Dynamic Contrast Enhanced Magnetic Resonance Imaging
Authors: Jordan Bénédicte F. , Runquist Matthew , Raghunand Natarajan , Gillies Robert J. , Tate Wendy R. , Powis Garth , Baker Amanda F.
Published: June 2022

Purpose: The purpose of this study was to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to measure changes in tumor xenograft permeability produced by the antitumor thioredoxin-1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) and to assess the relationship to Trx-1 and vascular endothelial growth factor (VEGF) levels.

Experimental Design: DCE-MRI was used to monitor the dynamics of gadolinium-diethylenetriaminepentaacetic acid coupled bovine serum albumin as a macromolecular contrast reagent to measure hemodynamic changes in HT-29 human colon xenografts in immunodeficient mice treated with PX-12. Blood vessel permeability was estimated from the slope of the enhancement curves, and tumor vascular volume fraction from the ordinate. Tumor Trx-1 and VEGF was also measured.

Results: PX-12 caused a rapid 63% decrease in the average tumor blood vessel permeability within 2 hours of administration. The decrease lasted 24 hours and had returned to pretreatment values by 48 hours. The changes in vascular permeability were not accompanied by alterations in average tumor vascular volume fraction. There was a decrease in tumor and tumor-derived VEGF in plasma at 24 hours after treatment with PX-12, but not at earlier time points. However, tumor redox active Trx-1 showed a rapid decline within 2 hours following PX-12 administration that was maintained for 24 hours.

Conclusion: The rapid decrease in tumor vascular permeability caused by PX-12 administration coincided with a decrease in tumor redox active Trx-1 and preceded a decrease in VEGF. DCE-MRI responses to PX-12 in patients of Trx-1 inhibition at early time points and decreased VEGF at later times, may be useful to follow tumor response and even therapeutic benefit.
Age- and Disease-Related Methylation of Multiple Genes in Nonneoplastic Duodenum and in Duodenal Juice
Authors: Matsubayashi Hiroyuki , Sato Norihiro , Brune Kieran , Blackford Amanda Lapides , Hruban Ralph H. , Canto Marcia , Yeo Charles J. , Goggins Michael
Published: June 2022

Purpose: Methylation of CpG islands contributes to gene silencing during cancer development, and although some methylation alterations are promising diagnostic markers of cancer, some CpG islands are also methylated in normal tissues. We have previously observed that some normally unmethylated CpG islands that undergo methylation in pancreatic cancers are normally methylated in the adjacent duodenum. Because duodenal methylation patterns are an important consideration when sampling pancreatic tissues for pancreatic cancer methylation alterations, we determined the DNA methylation patterns of 24 genes in the normal duodenum of patients with pancreatic disease and related these patterns to demographic factors.

Experimental Design: The nonneoplastic duodenal mucosa of 158 patients with pancreatic carcinoma and 41 patients with chronic pancreatitis was analyzed using methylation-specific PCR and combined bisulfite restriction analysis. Secretin-stimulated pancreatic/duodenal juice from 15 individuals undergoing endoscopic investigation for upper gastrointestinal disease was also analyzed.

Results: Low-level methylation was detectable by methylation-specific PCR in the nonneoplastic duodenum of many patients with pancreatic cancer and chronic pancreatitis as well as in the pancreaticoduodenal secretions of patients without pancreaticobiliary disease. For many genes, the prevalence of methylation increased with age and was more prevalent in patients with pancreatic cancer than in age-matched patients with chronic pancreatitis.

Our results indicate that strategies to detect pancreatic cancer using aberrantly methylated genes should rely on analysis of pure pancreatic juice rather than on pancreatic juice collected within the duodenal lumen. Patients who develop pancreatic cancer may have a greater propensity to methylate CpG islands than age-matched controls.
Vaccination of Dendritic Cells Loaded with Interleukin-12-Secreting Cancer Cells Augments In vivo Antitumor Immunity: Characteristics of Syngeneic and Allogeneic Antigen-Presenting Cell Cancer Hybrid Cells
Authors: Suzuki Takuji , Fukuhara Tatsuro , Tanaka Masashi , Nakamura Akira , Akiyama Kenichi , Sakakibara Tomohiro , Koinuma Daizo , Kikuchi Toshiaki , Tazawa Ryushi , Maemondo Makoto , Hagiwara Koichi , Saijo Yasuo , Nukiwa Toshihiro
Published: June 2022

Cancer immunotherapy by fusion of antigen-presenting cells and tumor cells has been shown to induce potent antitumor immunity. In this study, we characterized syngeneic and allogeneic, murine macrophage/dendritic cell (DC)-cancer fusion cells for the antitumor effects. The results showed the superiority of allogeneic cells as fusion partners in both types of antigen-presenting cells in an in vivo immunotherapy model. A potent induction of tumor-specific CTLs was observed in these immunized conditions. In addition, the immunization with DC-cancer fusion cells was better than that with macrophage-cancer fusion cells. Both syngeneic and allogeneic DC-cancer fusion cells induced higher levels of IFN-γ production than macrophage-cancer fusion cells. Interestingly, allogeneic DC-cancer fusion cells were superior in that they efficiently induced Th1-type cytokines but not the Th2-type cytokines interleukin (IL)-10 and IL-4, whereas syngeneic DC-cancer fusion cells were powerful inducers of both Th1 and Th2 cytokines. These results suggest that allogeneic DCs are suitable as fusion cells in cancer immunotherapy. To further enhance the antitumor immunity in the clinical setting, we prepared DCs fused with IL-12 gene-transferred cancer cells and thus generated IL-12-secreting DC-cancer fusion cells. Immunization with these gene-modified DC-cancer fusion cells was able to elicit a markedly enhanced antitumor effect in the in vivo therapeutic model. This novel IL-12-producing fusion cell vaccine might be one promising intervention for future cancer immunotherapy.
Down-Regulation of S100C Is Associated with Bladder Cancer Progression and Poor Survival
Authors: Memon Ashfaque Ahmed , Sorensen Boe Sandahl , Meldgaard Peter , Fokdal Lars , Thykjaer Thomas , Nexo Ebba
Published: June 2022

Purpose: The goal of this study was to identify proteins down-regulated during bladder cancer progression.

Experimental design: By using comparative proteome analysis and measurement of mRNA, we found a significant down-regulation of S100C, a member of the S100 family of proteins, in T24 (grade 3) as compared with RT4 (grade 1) bladder cancer cell lines. Moreover, quantification of the mRNA level revealed that decreased expression of the protein reflects a low level of transcription of the S100C gene. Based on this observation, we quantified the S100C mRNA expression level with real-time PCR in bladder cancer biopsy samples obtained from 88 patients followed for a median of 23 months (range, 1-97 months).

Results: We found a significantly lower mRNA expression of S100C in connective tissue invasive tumors (T1, P = 0.0030) and muscle invasive tumors [(T2-T4), P < 0.0001] compared with superficial tumors (Ta). A negative correlation between S100C and histopathologic grade (P = 0.0003) was also observed. Furthermore, the papillary type showed higher expression of S100C than did the solid type of the tumor (P < 0.0001). Importantly, we found that loss of S100C was associated with survival in bladder cancer patients (P = 0.0006).

Conclusions: Our results show that low expression of S100C is associated with poor survival in patients with bladder cancer. Furthermore, loss of S100C in T1 as compared with Ta stage tumors emphasize that S100C expression is suppressed early during bladder cancer development.
Gene Copy Number Change Events at Chromosome 20 and Their Association with Recurrence in Gastric Cancer Patients
Authors: Yang Sang Hwa , Seo Min Young , Jeong Ha Jin , Jeung Hei-Cheul , Shin Jihye , Kim Sang Chul , Noh Sung Hoon , Chung Hyun Cheol , Rha Sun Young
Published: June 2022

Purpose: This study examined the gene copy number change events at chromosome 20 in gastric cancer, and their possible relationship with recurrence using cDNA microarray-based comparative genomic hybridization.

Experimental Design: Thirty pairs of gastric tumor and normal gastric tissues were used in the cDNA microarray-based comparative genomic hybridization. The cDNA microarrays containing 17,000 sequence-verified human gene probes were used in a direct comparison design, where genomic DNAs from the normal and tumor tissues were labeled with fluorescent dyes Cy3 and Cy5, respectively, and cohybridized. Genes with log2 (Cy5/Cy3) ≥ 0.58 in at least one case were selected as the amplified genes. In order to search for the association between gene copy number changes and the recurrence status, patients were grouped according to their recurrence status. Gene selection between the two groups was done, and each patient was given a score based on the sum of the selected genes' ratios. Logistic regression analysis was carried out in order to determine if the score of a group of patients was correlated with a recurrence.

Results: A group of genes including NCOA6, CYP24A1, PTPN1, and ZNF217 was amplified in gastric cancer. Another group of 39 genes, whose sum of copy number change levels was significantly associated with a poor prognosis for recurrence, was selected (P < 0.05).

Conclusion: Ninety-six amplified genes at chromosome 20 of gastric cancer are reported. A scoring system based on gene copy changes at chromosome 20 can provide an independent patient grouping system that can distinguish patient recurrence status and survival.
Classic and Molecular Cytogenetic Analyses Reveal Chromosomal Gains and Losses Correlated with Survival in Head and Neck Cancer Patients
Authors: Bérgamo Nádia Aparecida , da Silva Veiga Luciana Caricati , dos Reis Patricia Pintor , Nishimoto Inês Nobuko , Magrin José , Kowalski Luiz Paulo , Squire Jeremy A. , Rogatto Sílvia Regina
Published: June 2022

Purpose: Genetic biomarkers of head and neck tumors could be useful for distinguishing among patients with similar clinical and histopathologic characteristics but having differential probabilities of survival. The purpose of this study was to investigate chromosomal alterations in head and neck carcinomas and to correlate the results with clinical and epidemiologic variables.

Experimental Design: Cytogenetic analysis of short-term cultures from 64 primary untreated head and neck squamous cell carcinomas was used to determine the overall pattern of chromosome aberrations. A representative subset of tumors was analyzed in detail by spectral karyotyping and/or confirmatory fluorescence in situ hybridization analysis.

Results: Recurrent losses of chromosomes Y (26 cases) and 19 (14 cases), and gains of chromosomes 22 (23 cases), 8 and 20 (11 cases each) were observed. The most frequent structural aberration was del(22)(q13.1) followed by rearrangements involving 6q and 12p. The presence of specific cytogenetic aberrations was found to correlate significantly with an unfavorable outcome. There was a significant association between survival and gains in chromosomes 10 (P = 0.008) and 20 (P = 0.002) and losses of chromosomes 15 (P = 0.005) and 22 (P = 0.021). Univariate analysis indicated that acquisition of monosomy 17 was a significant (P = 0.0012) factor for patients with a previous family history of cancer.

Conclusions: The significant associations found in this study emphasize that alterations of distinct regions of the genome may be genetic biomarkers for a poor prognosis. Losses of chromosomes 17 and 22 can be associated with a family history of cancer.
Subcellular Localization of p27kip1 Expression Predicts Poor Prognosis in Human Ovarian Cancer
Authors: Rosen Daniel G. , Yang Gong , Cai Kathy Qi , Bast Robert C. , Gershenson David M. , Silva Elvio G. , Liu Jinsong
Published: June 2022

Purpose: The cyclin-dependent kinase inhibitor p27kip1 regulates cellular progression from G1 to S phase. Several studies have shown that loss of p27kip1 protein expression is associated with disease progression in various malignancies. The purpose of this study was to evaluate the subcellular localization of this cyclin-dependent kinase inhibitor in a large cohort of primary ovarian carcinomas and compare the results with clinicopathologic variables and overall survival.

Experimental Design: Subcellular localization of p27kip1 was first assessed by Western blotting in nuclear and cytoplasmic extract from 13 cases of ovarian carcinoma. Subcellular localization of the p27kip1 protein was evaluated using tissue microarrays containing 421 cases of ovarian carcinoma.

Results: The presence of p27kip1 in the cytoplasm regardless of the nuclear stain correlated strongly with late-stage disease (P < 0.03), extent of cytoreduction (P = 0.03), and shorter disease-specific survival (P < 0.0001).

Conclusion: Cytoplasmic localization of p27kip1 predicts poorer prognosis in ovarian carcinoma, particularly in late-stage disease.
Gene Expression in Kidney Cancer Is Associated with Cytogenetic Abnormalities, Metastasis Formation, and Patient Survival
Authors: Sültmann Holger , Heydebreck Anja von , Huber Wolfgang , Kuner Ruprecht , Buneβ Andreas , Vogt Markus , Gunawan Bastian , Vingron Martin , Füzesí Laszlo , Poustka Annemarie
Published: June 2022

Current diagnosis of renal cancer consists of histopathologic examination of tissue sections and classification into tumor stages and grades of malignancy. Until recently, molecular differences between tumor types were largely unknown. To examine such differences, we did gene expression measurements of 112 renal cell carcinoma and normal kidney samples on renal cell carcinoma–specific cDNA microarrays containing 4,207 genes and expressed sequence tags. The gene expression patterns showed deregulation of complete biological pathways in the tumors. Many of the molecular changes corresponded well to the histopathologic tumor types, and a set of 80 genes was sufficient to classify tumors with a very low error rate. Distinct gene expression signatures were associated with chromosomal abnormalities of tumor cells, metastasis formation, and patient survival. The data highlight the benefit of microarrays to detect novel tumor classes and to identify genes that are associated with patient variables and tumor properties.
Phase I/II Study of the Rituximab-EPOCT Regimen in Combination with Granulocyte Colony-Stimulating Factor in Patients with Relapsed or Refractory Follicular Lymphoma Including Evaluation of Its Cardiotoxicity Using B-Type Natriuretic Peptide and Troponin T Levels
Authors: Niitsu Nozomi , Khori Mika , Hayama Miyuki , Kajiwara Koichi , Higashihara Masaaki , Tamaru Jun-ichi
Published: June 2022

Purpose: Standard treatment for relapsed or refractory follicular lymphoma has not been established. Doxorubicin is often given during the initial treatment. The dosage or drugs chosen for salvage therapy are limited by doxorubicin-induced cardiomyopathy.

Experimental Design: The R-EPOCT (rituximab with etoposide, vincristine, pirarubicine, cyclophosphamide, and prednisone) regimen, in which less cardiotoxic pirarubicine is used instead of doxorubicin, with granulocyte colony-stimulating factor (G-CSF) was administered to 20 patients with relapsed or refractory follicular lymphoma. The safety (especially cardiotoxicity) and efficacy of this regimen were studied. As markers of cardiotoxicity, serum troponin T and plasma B-type natriuretic peptide (BNP) levels were measured.

Results: Adverse reactions occurred in 14 of the 20 patients and mainly consisted of grade 3/4 hematologic toxicity. In the evaluation of cardiotoxicity, the BNP level was slightly elevated before the treatment in two patients and the BNP level did not significantly increase after R-EPOCT treatment. The troponin T level was undetectable before and after the treatment in all patients. The response rate was 100%, with complete remission in 16 patients (80%). G-CSF administration increased both Fc γ receptor type I expression on neutrophils and antibody-dependent cellular cytotoxicity activity. There were no significant differences in the levels of Fc γ receptor type I expression nor antibody-dependent cellular cytotoxicity activity after three or five cycles of the treatment.

Conclusion: We conclude that the combination of R-EPOCT and G-CSF is well tolerated. This regimen was not cardiotoxic. We are planning a randomized trial to compare the efficacy between R-EPOCT and a combination of R-EPOCT with G-CSF.
Immune-Mediated Inhibition of Metastases after Treatment with Local Radiation and CTLA-4 Blockade in a Mouse Model of Breast Cancer
Authors: Demaria Sandra , Kawashima Noriko , Yang Anne Marie , Devitt Mary Louise , Babb James S. , Allison James P. , Formenti Silvia C.
Published: June 2022

Purpose: Ionizing radiation therapy (RT) is an important component in the management of breast cancer. Although the primary tumor can be successfully treated by surgery and RT, metastatic breast cancer remains a therapeutic challenge. Here we tested the hypothesis that the combination of RT to the primary tumor with CTLA-4 blockade can elicit antitumor immunity inhibiting the metastases.

Experimental Design: The poorly immunogenic metastatic mouse mammary carcinoma 4T1 was used as a model. Mice were injected s.c. with 4T1 cells, and treatment was started 13 days later when the primary tumors measured 5 mm in average diameter. Mice were randomly assigned to four treatment groups receiving: (1) control IgG (IgG), (2) RT + IgG, (3) 9H10 monoclonal antibody against CTLA-4, (4) RT + 9H10. RT was delivered to the primary tumor by one or two fractions of 12 Gy. 9H10 and IgG were given i.p. thrice after RT.

Results: Consistent with the fact that 4T1 is poorly immunogenic, 9H10 alone did not have any effect on primary tumor growth or survival. RT was able to delay the growth of the primary irradiated tumor, but in the absence of 9H10 survival was similar to that of control mice. In contrast, mice treated with RT + 9H10 had a statistically significant survival advantage. The increased survival correlated with inhibition of lung metastases formation and required CD8+ but not CD4+ T cells.

Conclusions: The combination of local RT with CTLA-4 blockade is a promising new immunotherapeutic strategy against poorly immunogenic metastatic cancers.
Therapy of Small Subcutaneous B-Lymphoma Xenografts with Antibodies Conjugated to Radionuclides Emitting Low-Energy Electrons
Authors: Michel Rosana B. , Rosario Adriane V. , Andrews Philip M. , Goldenberg David M. , Mattes M. Jules
Published: June 2022

Purpose: Radionuclides emitting low-energy electrons (Auger and conversion electrons of <50 keV) are potentially useful for cancer therapy when conjugated to an antibody, because they can irradiate the cell to which they bind while producing relatively little irradiation of surrounding cells and tissues. We showed previously the ability of such antibody conjugates to treat micrometastatic, disseminated human B-lymphoma in a severe combined immunodeficient mouse model using an anti-CD74 antibody. In this study, we have evaluated the ability of such conjugates to treat s.c. tumors.

Experimental Design: Severe combined immunodeficient mice were injected s.c. with Raji, Daudi, or RL B-lymphoma human tumor cells. Antibodies to CD74, CD20, or HLA-DR were radiolabeled with 111In or 125I and injected i.v. at various times starting at day 5, and tumor growth was monitored. Controls included the testing of unlabeled antibodies, labeled nonreactive antibodies, and a combination of the two.

Results: Therapy of s.c. B-lymphoma was more difficult than therapy of tumor cells that had been injected i.v. Although large, macroscopic tumors were not effectively treated, therapy was effective on s.c. Daudi tumors on day 36 after injection of this slowly growing tumor, with an 111In anti-CD74 antibody given in two doses. An anti-CD20 antibody labeled with either 111In or 125I was able to effectively treat s.c. RL tumors when given as late as day 16 after tumor inoculation. The largest tumors that were effectively treated were macroscopic thin discs (<2 mm in diameter) growing on the mesentery.

Conclusion: These results extend previous evidence that antibody conjugates with emitters of low-energy electrons can be effective therapeutic agents for micrometastatic cancer.
Sustained Tumor Regression of Human Colorectal Cancer Xenografts Using a Multifunctional Mannosylated Fusion Protein in Antibody-Directed Enzyme Prodrug Therapy
Authors: Sharma Surinder K. , Pedley R. Barbara , Bhatia Jeetendra , Boxer Geoffrey M. , El-Emir Ethaar , Qureshi Uzma , Tolner Berend , Lowe Helen , Michael N. Paul , Minton Nigel , Begent Richard H. J. , Chester Kerry A.
Published: June 2022

Purpose: Antibody-directed enzyme prodrug therapy (ADEPT) requires highly selective antibody-mediated delivery of enzyme to tumor. MFE-CP, a multifunctional genetic fusion protein of antibody and enzyme, was designed to achieve this by two mechanisms. First by using a high affinity and high specificity single chain Fv antibody directed to carcinoembryonic antigen. Second by rapid removal of antibody-enzyme from normal tissues by virtue of post-translational mannosylation. The purpose of this paper is to investigate these dual functions in an animal model of pharmacokinetics, pharmacodynamics, toxicity, and efficacy.

Experimental Design: MFE-CP was expressed in the yeast Pichia pastoris and purified via an engineered hexahistidine tag. Biodistribution and therapeutic effect of a single ADEPT cycle (1,000 units/kg MFE-CP followed by 70 mg/kg ZD2767P prodrug at 6, 7, and 8 hours) and multiple ADEPT cycles (9-10 cycles within 21-24 days) was studied in established human colon carcinoma xenografts, LS174T, and SW1222.

Results: Selective localization of functional enzyme in tumors and rapid clearance from plasma was observed within 6 hours, resulting in tumor to plasma ratios of 1,400:1 and 339:1, respectively for the LS174T and SW1222 models. A single ADEPT cycle produced reproducible tumor growth delay in both models. Multiple ADEPT cycles significantly enhanced the therapeutic effect of a single cycle in the LS174T xenografts (P = 0.001) and produced regressions in the SW1222 xenografts (P = 0.0001), with minimal toxicity.

Conclusions: MFE-CP fusion protein, in combination with ZD2767P, provides a new and successful ADEPT system, which offers the potential for multiple cycles and antitumor efficacy. These results provide a basis for the next stage in clinical development of ADEPT.
Gene Expression Profiling of Breast Cancer in Relation to Estrogen Receptor Status and Estrogen-Metabolizing Enzymes: Clinical Implications
Authors: Kristensen Vessela N. , Sørlie Therese , Geisler Jurgen , Langerød Anita , Yoshimura Noriko , Kåresen Rolf , Harada Nobuhiro , Lønning P.E. , Børresen-Dale Anne-Lise
Published: June 2022

Interactions between luminal epithelial cells and their surrounding microenvironment govern the normal development and function of the mammary gland. Estradiol plays a key role in abnormal intracellular signaling, which contributes to the development and progression of breast tumors. The present article summarizes the results from a microarray whole genome gene expression analysis as well as a quantitative analysis of the mRNA expression of members of the estradiol metabolic and signaling pathways in the tumors of postmenopausal breast cancer patients. The analysis of the variation in whole genome gene expression resulted in a tumor classification comprising several distinct groups with distinct expression of the estrogen receptor (ER). The parallel study on the expression of only nine mRNA transcripts of members of the estradiol pathways resulted in two main clusters, representing ER− and ER tumors. The mRNA expression of the estradiol-metabolizing enzymes did not follow the expression of the ER in all cases, leading to the recognition of several further subclasses of tumors. When the tumor classes obtained by whole genome gene expression analysis were compared with those obtained by independent quantitation of the estradiol-metabolizing enzymes, a statistically significant association between both classification groups was observed. These findings point to a possible association between development of a tumor with a particular expression profile and its capacity to synthesize estradiol as measured by the expression of the transcripts for the necessary key enzymes. Further, whole genome expression patterns were studied in 12 patients treated with anastrozole. Using significance analysis of microarrays, we identified 298 genes significantly differently expressed between partial response and progressive disease groups.
Therapeutic Observations in MCF-7 Aromatase Xenografts
Authors: Brodie Angela , Jelovac Danijela , Macedo Luciana , Sabnis Gauri , Tilghman Syreeta , Goloubeva Olga
Published: June 2022

In previous studies using a xenograft model with tumors of human estrogen receptor (ER)–positive breast cancer cells transfected with aromatase (MCF-7Ca), we explored the antitumor efficacy of treatment combining the nonsteroidal aromatase inhibitor letrozole with tamoxifen. However, treatment with this combination resulted in tumor suppression similar to tamoxifen alone but was less effective than letrozole alone. Clinical findings with the nonsteroidal inhibitor anastrozole in combination with tamoxifen (ATAC trial) were consistent with our results. Although letrozole was the most effective single agent in the model, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors adapted to growth during letrozole treatment, we determined the expression of proteins in tumors during letrozole treatment compared with the tumors of control mice. We found that tumors initially up-regulated the ER, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the mitogen-activated protein kinase cascade (p-Raf, p-MEK1/2, and p-MAPK) but not Akt were increased in tumors no longer responsive to letrozole. The results suggest that tumor cells adapt to estrogen deprivation during letrozole treatment by activation of alternate signaling pathways. When letrozole was combined with the pure antiestrogen fulvestrant, which down-regulates ER, the combination was extremely effective. Tumors regressed by 45% and were maintained without growth for the duration of the experiment (29 weeks). Thus, achieving more complete estrogen blockade may delay development of hormone-independent signaling pathways regulating proliferation.
Estrogen, Estrogen Plus Progestin Therapy, and Risk of Breast Cancer
Authors: Colditz Graham A.
Published: June 2022

Epidemiologic evidence relating use of postmenopausal hormones to risk of breast cancer by nature relies on trends in prescribing practices. Data on the adverse effect of combination estrogen plus progestin used for long durations has only become available over the past decade. Evidence is reviewed relating estrogen alone and estrogen plus progestin to increased risk of breast cancer. Whereas current evidence indicates that longer duration of use increases risk of invasive breast cancer regardless of formulation, the rate of increase in risk is greater for combination estrogen plus progestin therapy. Although data are limited, continuous combined therapy and sequential therapy seem to have comparable impact on breast cancer risk. Combination therapy is more strongly related to lobular breast cancer than is estrogen alone. Unresolved issues remain about dose of estrogen and progestin in relation to risk, and about identification of women for whom short-term use to relieve menopausal symptoms may be safe and effective.
Exemestane for Breast Cancer Prevention: A Feasible Strategy?
Authors: Lønning Per E.
Published: June 2022

Third-generation aromatase inhibitors and inactivators have been successfully implemented in therapy of metastatic breast cancer, and three large phase III trials have revealed superiority compared with tamoxifen monotherapy in the adjuvant setting. Notably, each of these trials recorded a substantial reduction in contralateral breast cancer among patients exposed to the aromatase inhibitor/inactivator. A major concern in implementing use of these compounds in the preventive setting relates to potential detrimental effects of estrogen suppression on bone and lipid metabolism. Recent data from a placebo-controlled study now reveal 2 years of treatment with exemestane compared with placebo to have moderate effects on bone metabolism and plasma lipid profile, supporting further evaluation of exemestane as a potential preventive agent for breast cancer in postmenopausal women.
Pemetrexed in Malignant Pleural Mesothelioma
Authors: Hazarika Maitreyee , White Robert M. , Booth Brian P. , Wang Yong-Cheng , Lee Ham Doo Y. , Liang Cheng Yi , Rahman Atiqur , Gobburu Jogarao V.S. , Li Ning , Sridhara Rajeshwari , Morse David E. , Lostritto Richard , Garvey Patricia , Johnson John R. , Pazdur Richard
Published: June 2022

Purpose: This report describes the data and analysis leading to the approval of pemetrexed (LY 231514, MTA, Alimta, Eli Lilly and Co., Indianapolis, IN) by the U.S. Food and Drug Administration (FDA) of a New Drug Application for the treatment of malignant pleural mesothelioma (MPM).

Experimental Design: The FDA review of the efficacy and safety of pemetrexed assessed in a randomized clinical trial of 448 patients with unresectable MPM comparing pemetrexed plus cisplatin with cisplatin alone, as well as preclinical pharmacology and chemistry data, are described. The basis for marketing approval is discussed.

Results: In one randomized, single-blind, multicenter international trial, 226 patients were randomized to the pemetrexed and cisplatin arm and 222 patients were randomized to cisplatin alone. Median survival times were 12.1 months for pemetrexed and cisplatin and 9.3 months for cisplatin (P = 0.021; hazard ratio, 0.766; 95% confidence interval, 0.61-0.96). Myelosuppression, predominantly neutropenia, was the most common toxicity of pemetrexed plus cisplatin. Other common adverse events were fatigue, leucopenia, nausea, dyspnea, vomiting, chest pain, anemia, thrombocytopenia, and anorexia.

Conclusions: Pemetrexed in combination with cisplatin was approved by the FDA on February 4, 2004 for the treatment of patients with MPM whose disease is either unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m2 intra venous infusion over 10 minutes on day 1 of each 21-day cycle in combination with 75 mg/m2 cisplatin infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B12 injections before the start and during therapy to reduce severe toxicities. Patients should also receive corticosteroids with the chemotherapy to decrease the incidence of skin rash. Approval was based on a demonstration of survival improvement in a single randomized trial. Response rates and time to tumor progression were not included in product labeling because of inconsistencies in assessments among the investigators, independent radiologic reviewers, and the FDA, reflecting the difficulty of radiographic assessments in malignant mesothelioma. Complete prescribing information is available on the FDA Web site at http://www.fda.gov/cder/approval/index.htm.
Therapeutic Drug Monitoring of Golimumab for the Prediction of Long-Term Clinical Remission in Patients with Ulcerative Colitis
Authors: Tawa Hideki , Kakimoto Kazuki , Numa Keijiro , Kinoshita Naohiko , Kawasaki Yuka , Tatsumi Yoshihiro , Koshiba Ryoji , Nakata Satoshi , Hirata Yuki , Ota Kazuhiro , Sakiyama Naokuni , Kojima Yuichi , Koubayashi Eiko , Nishikawa Hiroki , Takeuchi Toshihisa , Inoue Takuya , Fukunishi Shinya , Miyazaki Takako , Nakamura Shiro , Higuchi Kazuhide
Published: June 2022

Background and Aims: A considerable number of patients with ulcerative colitis (UC) who initially respond to golimumab (GLM), an anti-TNF-α antibody, gradually lose clinical response. Therapeutic drug monitoring has been proposed to optimize serum anti-TNF-α antibody concentrations before the loss of response; however, little is known about ideal serum GLM concentrations. We aimed to evaluate whether the serum GLM trough levels (TLs) early after the initiation of induction therapy affect the long-term outcomes in UC and to identify the early GLM TLs that should be targeted for better long-term outcomes. Methods: Thirty-one patients were prospectively evaluated. The primary outcome was clinical remission at 54 weeks, and we measured the serum GLM TLs at weeks 6, 10, and 14. Receiver operating characteristic (ROC) curves were constructed to identify optimal GLM TL thresholds early after induction therapy that were associated with clinical remission at week 54. Results: The GLM TL at week 14, but not at weeks 6 or 10, was significantly associated with clinical remission at week 54 (median [IQR] 1.6 [1.3–1.6] μg/mL vs. 0.9 [0.6–1.3] μg/mL; p = 0.04). The area under the ROC curve for GLM TLs at week 14 was 0.78. We identified a week-14 GLM TL of 1.1 μg/mL as the target threshold for achieving clinical remission at week 54. Conclusion: Our results demonstrate the value of early serum GLM TLs in predicting the long-term outcomes of GLM for patients with UC.
Treatment with Living Drugs: Pharmaceutical Aspects of CAR T Cells
Authors: Holzinger Astrid , Abken Hinrich
Published: June 2022

Background: Adoptive therapy with genetically modified T cells achieves spectacular remissions in advanced hematologic malignancies. In contrast to conventional drugs, this kind of therapy applies viable autologous T cells that are ex vivo genetically engineered with a chimeric antigen receptor (CAR) and are classified as advanced therapy medicinal products. Summary: As “living drugs,” CAR T cells differ from classical pharmaceutical drugs as they provide a panel of cellular capacities upon CAR signaling, including the release of effector molecules and cytokines, redirected cytotoxicity, CAR T cell amplification, active migration, and long-term persistence and immunological memory. Here, we discuss pharmaceutical aspects, the regulatory requirements for CAR T cell manufacturing, and how CAR T cell pharmacokinetics are connected with the clinical outcome. Key Messages: From the pharmacological perspective, the development of CAR T cells with high translational potential needs to address pharmacodynamic markers to balance safety and efficacy of CAR T cells and to address pharmacokinetics with respect to trafficking, homing, infiltration, and persistence of CAR T cells.
O uso da bandagem elástica Kinesio no controle da sialorréia em crianças com paralisia cerebral
Authors: Ribeiro Mariana de Oliveira , Rahal Renata de Oliveira , Kokanj Andréa Siqueira , Bittar Daniela Pimenta
Published: June 2022

Objetivo: Verificar a eficiência da bandagem elástica Kinesio no controle de deglutição de saliva em crianças com paralisia cerebral. Material e Método: A pesquisa foi realizada no Setor Escolar da Associação de Assistência à Criança Deficiente (AACD). Participaram 42 crianças com idades entre 4 e 15 anos (média = 8 anos e 9 meses), de ambos os sexos, com diagnóstico de paralisia cerebral e queixa de sialorréia. Foi realizado um checklist com os pais da criança com perguntas referentes a sialorréia e posteriormente realizadas duas escalas para pontuação da freqüência e da gravidade dessa. Foram realizadas oito aplicações da Kinesio Tape na musculatura supra-hióidea e então, o checklist e as escalas foram reaplicados. Resultados: Verificou-se que houve redução estatisticamente significante nos parâmetros utilizados para verificação da sialorréia, sendo eles: número de toalhas utilizadas por dia para secar a baba, pontuação na escala de freqüência e pontuação na escala de gravidade da sialorréia. Conclusão: Conclui-se que o método Kinesio Taping é eficaz na melhora do controle de deglutição de saliva em crianças com Paralisia Cerebral.
Botulinum Toxin Type A in the treatment of myofascial pain related to masticatory muscles
Authors: Sposito Maria Matilde de Mello , Teixeira Stephanie Alderete Feres
Published: June 2022

Objective: To systematize the scientific evidence on the efficacy of botulinum toxin type A in the treatment of myofascial pain related to masticatory muscles. Method: A bibliographical search was made in the PubMed Central Journal and Allergan Product Literature databases - botulinum toxin (APL) encompassing the past 12 years, with the descriptors: “myofascial pain,” “botulinum toxin,” “treatment,” “masticatory muscles”. The methodological quality of the studies was evaluated through the Jadad scale. Four randomized, double-blind, clinical trial studies were selected. Results: It was found that the research on the use of botulinum toxin type A for myofascial pain contributed to improving the treatments that existed until that time for this clinical condition. Conclusion: The need for more studies and forms of evaluating precisely and quantitatively is essential in order to find a definitive answer on the efficacy and safety of this treatment.
Relação entre força e ativação da musculatura glútea e a estabilização dinâmica do joelho: revisão sistemática da literatura
Authors: Morais Lucas Martins de , Faria Christina Danielli Coelho de Morais
Published: June 2022

O joelho recebe, absorve e dissipa importante parte das forças impostas por atividades diárias, como marcha, subir e descer degraus e saltos. Dada a grande demanda imposta a esta articulação, as disfunções no joelho são muito comuns. A capacidade para responder a esta demanda parece estar relacionada com as funções da musculatura do quadril, que parece ter um papel importante nas características biomecânicas, dentre elas a estabilidade dinâmica, da articulação do joelho. Objetivo: Realizar revisão sistemática da literatura para apontar as possíveis características e ações da musculatura glútea relacionadas com a estabilização dinâmica do joelho e investigar a eficácia de programas de intervenção direcionados à musculatura glútea na melhora de desfechos funcionais ou sintomatológicos relacionados às disfunções na articulação do joelho. Métodos: Revisão sistemática desenvolvida de acordo com o protocolo PRISMA (Preferred Report Items for Systematic Reviews and Meta-Analyses). Foram realizadas buscas nas bases de dados eletrônicas MEDLINE, SCIELO, COCHRANE, LILACS e PEDro, conforme estratégia de busca dada pela combinação de termos referentes ao assunto da pesquisa. Critérios de inclusão: estudos publicados até março de 2016, amostra de indivíduos com idade entre 18 e 60 anos, sem restrição de idioma de publicação, ter envolvido a avaliação ou o tratamento de alguma característica da musculatura do quadril relacionando à estabilização dinâmica do joelho. Resultados: Dos 109 estudos encontrados, onze foram incluídos por atenderem aos critérios de inclusão. Destes, oito (73%) foram do tipo observacional exploratório e três (27%) ensaio clínico aleatorizado (ECA) (5≤PEDro≤8). Todos os ECA incluíram adultos jovens, do sexo feminino, com síndrome da dor femoropatelar e avaliaram o músculo glúteo médio. Segundo os resultados da maioria dos estudos, os músculos glúteos apresentam relação com a manutenção do alinhamento do membro inferior no plano frontal, reduzindo o valgo dinâmico em atividades funcionais, sendo mais importante a magnitude da ativação muscular do que o tempo desta ativação. Os ECA evidenciaram a importância de se intervir no fortalecimento da musculatura glútea em programas de reabilitação do joelho: em indivíduos sintomáticos com síndrome da dor femoropatelar houve melhora funcional e sintomatológica significativa após este tipo de intervenção, que foi realizada associada ao tratamento convencional no joelho ou tronco. Conclusão: A magnitude de ativação e a força muscular dos músculos glúteos têm papel importante na estabilidade dinâmica do joelho. Intervenções nestas musculaturas, associadas ao tratamento convencional, são eficazes para melhora de desfechos funcionais e sintomatológicos relacionados à articulação do joelho.
Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial
Authors: Uphaus Timo , Richards Toby , Weimar Christian , Neugebauer Hermann , Poli Sven , Weissenborn Karin , Imray Christopher , Michalski Dominik , Rashid Hisham , Loftus Ian , Rummey Christian , Ritter Martin , Hauser Till-Karsten , Münch Götz , Gröschel Klaus , Poppert Holger
Published: June 2022

Background:

Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis.

Methods:

International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up.

Results:

Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88–1.53)/1.05 (95% CI, 0.78–1.42;
P
=0.629)/0.63 (95% CI, 0.43–0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21–0.99];
P
=0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37–1.42];
P
=0.343).

Conclusions:

Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT01645306.
The prevalence of self-reported mental illness among those imprisoned in New South Wales across three health surveys, from 2001 to 2015
Authors: Browne Christie C , Korobanova Daria , Yee Natalia , Spencer Sarah-Jane , Ma Trevor , Butler Tony , Dean Kimberlie
Published: June 2022

Objective:

The prevalence of mental illness among those in prison is much higher than in the community; however, very few studies have examined whether rates have changed over time, in line with increasing self-reported rates in the community.

Methods:

This study compares the prevalence of self-reported mental illness, self-harm and suicidal thoughts/behaviours, and drug and alcohol use across three waves (2001, 2009 and 2015) of health surveys involving men and women in New South Wales prisons and compared these rates with published community-level findings.

Results:

The prevalence of those reporting any mental health diagnosis increased significantly across the three surveys, even after adjustment for socio-demographic and criminal justice variables that also changed over time. Individuals surveyed in 2015 were more likely to report a mental health diagnosis than those surveyed in 2001 (adjusted odds ratio = 2.66, 95% confidence interval = [2.16, 3.27]). The prevalence of self-harm and suicidal thoughts and behaviours remained stable across the three surveys, while self-reported regular drug use decreased over the period. Women experienced a far greater burden of mental illness than men across all three surveys and experienced more growth in the prevalence of most psychiatric disorders.

Conclusion:

These findings have important implications for public and prison health systems given the poor social, health and criminal justice outcomes of those imprisoned with mental illness, both in custody and post-release.