bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial progenitor cell clonality and response to treatment in multiple myeloma
Authors: Kahn D. M. , Braunstein M. , Smith E. L. , Klueppelberg U. , Ozcelik T. , Batuman O. 
Published: March 2020

17546 Background: In multiple myeloma (MM), increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis, covary with disease activity and response to treatment. To understand the mechanisms of enhanced neoangiogenic function by EPCs in MM, we investigated whether EPCs and tumor cells share clonal identity, and related this finding to clinical progression. EPC clonality was analyzed by X-chromosome inactivation (XCI) and the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement. Methods: Hair root cells and confluent EPCs from 18 female patients were studied for XCI patterns by human androgen receptor assay (HUMARA). In 6 patients, EPCs were studied for the presence of IGH gene rearrangement using family-specific PCR primers for IGH variable genes (VH). Nine patients were treated with TDZ: thalidomide (100 mg/day), dexamethasone (10–40 mg for 4 days/3 weeks for 6 months, then reduced to 4 days/month), and zoledronate (4 mg/4 weeks). Results: Eleven of the 18 female patients displayed allelic XCI. Analysis of their EPCs for evidence of clonality revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these 7 patients, EPC XCI skewing was extreme (≥ 90% expression of a single allele) while in hair root cells XCI was random. Furthermore, sequencing of PCR products obtained with VH primers resulted in identification of the same product in EPCs and bone marrow cells in 67% (n = 4) of another 6 patients, while no IGH rearrangement was found in EPCs from healthy controls. 9 patients were subsequently treated with TDZ, 4 patients had clonal EPCs and Stage 2 MM, and 5 patients had non-clonal EPCs and Stage 3 MM. Despite having less advanced disease, patients whose EPCs were clonal had a significantly attenuated response to treatment with TDZ compared to patients whose EPCs were non-clonal (P = .05). Conclusions: Clonal identity between EPCs and neoplastic cells highlight the necessity to explore the thesis that MM cells and EPCs are derived from a progenitor cell capable of self-renewal and differentiation. The relationship between EPC clonality and impaired response to treatment underscores the pathogenic significance of EPCs in MM. No significant financial relationships to disclose.
Utility of bortezomib retreatment among patients with refractory multiple myeloma
Authors: Wolf J. L. , Leblanc MT A. L. , Battleman D. S. , Davis B. , Lyandres J. R. , Walters I. B. 
Published: March 2020

17549 Background: Bortezomib (VELCADE; Vc) has emerged as the standard of care for patients with relapsed or refractory multiple myeloma (MM). However, following initial Vc therapy, its utility in recurrent disease is unclear. This retrospective case series provides preliminary evidence of the safety and efficacy of Vc in the retreatment of patients with recurrent MM. Methods: An observational case series was developed based on a medical records review of all patients (N = 10) who completed Vc retreatment following completion of initial Vc therapy. Best response was measured as the greatest mean % reduction in the treatment response measure: serum/urine M-protein or plasma cells. Differences between initial treatment and retreatment efficacy and Vc-related hospitalizations were assessed using descriptive statistics. Results: During initial treatment 44% of patients responded to Vc (≥50% M-protein (3/9) or plasme cell reduction (1/9, 1 pt NA). At retreatment 50% of patients responded (5/10). Following initial Vc therapy, the median treatment-free interval was just over 13 months (56.6 weeks). One patient experienced a dose reduction due to peripheral neuropathy (grade 2) during retreatment, compared to two patients with neuropathy (grade 3) during initial treatment. Termination of therapy due to any unmanageable toxicity was much lower during retreatment (14.3% vs 62.5%). Finally, none of the patients were hospitalized for Vc-related events during retreatment, compared with two patients during initial treatment. Conclusions: Vc retreatment appears to be as effective as initial treatment in terms of response, and may actually yield less toxicity and hospitalizations. Even though this small sample size precluded statistical testing, the observed patterns are instructive and additional prospective trials are currently ongoing. However, based on these preliminary data, prolonged disease control may be achieved with repeated use. [Table: see text]
Prevalence of MGUS in a geriatric population in Turkey
Authors: Dizdar O. , Erman M. , Cankurtaran M. , Khalil M. , Yavuz B. , Ulger Z. , Ariogul S. , Pinar A. , Kars A. , Celik I. 
Published: March 2020

17564 Background: In this study, we aimed to investigate the prevalence of monoclonal gammopathy of unknown significance (MGUS) in the geriatric population in Turkey, with their clinical and laboratory parameters. Methods: The study group consisted of all individuals who applied to the outpatient clinic of Geriatrics Department between January-December 2005 in Hacettepe University Hospital in Ankara, Turkey. This clinic serves patients older than 65 years of age either with various acute/chronic diseases or healthy individuals for check-up purposes. All the participants had serum protein electrophoresis (SPE) -and immunofixation as needed- along with their routine laboratory tests and bone mineral density (BMD) measurements. Patients with a monoclonal protein in their SPEs were further evaluated for the presence of multiple myeloma. Clinical and laboratory parameters of patients with MGUS were compared with a control group of randomly selected 100 individuals who did not have MGUS. Results: A total of 1012 patients were enrolled in the study. Monoclonal band was detected in 22 patients (2.17%). The majority of the M proteins (63%) were of Ig G type. Of the remainder, 32% were Ig A, and 5% Ig M. Further investigations in these patients depicted one patient to have multiple myeloma and one patient to have lung carcinoma. The remaining 20 patients were diagnosed as MGUS (1.97%). BMD measurements of the patients with MGUS were significantly lower than the control group. Median lumbar BMD t score was -2.66 (Interquartile range (IQR): −.72 −3.77) in MGUS patients and -1.76 (IQR: −0.50 −2.47) in controls (p = 0.007). The two groups were found to be comparable in terms of comorbid diseases and other laboratory parameters. Conclusions: The prevalence of MGUS above the age of 25 is 1%, above 50 it is 1.7%, and above 70 it is approximately 3%. In our study, the frequency of MGUS above 65 years of age was found to be 1.97%, which is a little lower than the above quoted figures. It must be noted that our study group was not population-based and chronic diseases may be more common than the general population, resulting in a higher prevalence of MGUS. Another finding was the lower BMD measurements in patients with MGUS. BMD data is limited in patients with MGUS in the literature and further studies are needed to elucidate whether there is an association or not. No significant financial relationships to disclose.
Recurrence after imatinib treatment for gastrointestinal stromal tumor: Japanese experience in a single institute
Authors: Sawaki A. , Mizuno N. , Takahashi K. , Nakamura T. , Tajika M. , Kawai H. , Inoue H. , Masatoshi A. , Ahmed Z. , Yamao K. 
Published: March 2020

19504 Background: Although imatinib is the most effective agent for metastatic gastrointestinal stromal tumors (GISTs), resistance to imatinib develops in most patients. While the effectiveness of an oral multitageted tyrosine kinase inhibitor for intolerant GIST is already reported, many of imatinib resistant patients are not available. We report clinical results of first imatinib and post imatinib treatment in a patient with metastatic or unresectable GIST. Methods: A retrospective review was undertaken in patients with metastatic or unresectable GIST treated with imatinib at Aichi Cancer Center Hospital between June 2001 and December 2005. Treatment schedule was four or six 100-mg capsules of imatinib orally once daily. Patients were evaluated for treatment, recurrence, and survival. Results: Forty-five patients (26 males and 43 metastatic patients) were treated with imatinib at first. The median age was 58 years (range 25–79). Primary tumor sites were as follow; stomach was 13, duodenum 9, small intestine except for duodenum 18, and colorectum 5. Metastatic sites were liver (21 patients), peritoneum (11 patients), both of them (10 patients), and the other (1 patient). The response rate (by RECIST) and PFS was 71.1% (32/45) and 24 months, respectively. Imatinib was well tolerated; only two patients stopped treatment due to nausea and vomiting. Twenty-six patients with disease progression were treated by the combination of many methods, and the following methods underwent as the second therapy; 9 patients underwent surgical resection, 7 patients underwent transarterial chemoembolization (TACE) for liver metastases, 9 patients enrolled in a clinical trial, and 9 patients continued imatininb because of clinical benefit and no other therapeutic options. PFS of surgery and TACE were 6 and 7 months, respectively. Out of 16 patients treated with surgery or TACE, 2 patients were well controlled by TACE more than 1 year. One patient, however, was suffering from intractable liver abscess after TACE. Conclusions: The efficacy and safety of imatinib for GIST is almost the same as in U.S. reports. TACE may be an effective treatment for liver metastases if new agents are not available. No significant financial relationships to disclose.
Risk of malignancy associated with chronic lymphocytic leukemia: A population based Canadian study
Authors: Pitz M. W. , Banerji V. , Demers A. A. , Nugent Z. , Strutinsky-Mason J. , Morales C. , Hewitt D. , Zhang H. , Gibson S. , Johnston J. B. , Seftel M. D. 
Published: March 2020

20020 Background: Patients with Chronic Lymphocytic Leukemia (CLL) may have an increased risk of other malignancies. Available literature reports on malignancies that develop after the diagnosis of CLL, but does not discuss malignancies that precede the diagnosis of CLL. Methods: All patients diagnosed with CLL between 01/1998 and 12/2003 were extracted from the provincial cancer registry and a centralized flow cytometry database. All other malignancies were obtained from the cancer registry. Dates of diagnoses were compared. A malignancy within 30 days before or after the diagnosis of CLL was considered synchronous with that diagnosis. Results were compared with the age-adjusted incidence of cancer in the province, excluding CLL. Results: Of the 713 cases of CLL, 333 invasive cancers and 38 in situ neoplasia were identified before, synchronous to, or after the diagnosis of CLL. Synchronous malignancies occurred in 4% of cases. The Standardized Incidence Ratio (SIR) for other malignancy subsequent to CLL was 1.40 (95% confidence interval [CI] 1.09–1.80) derived from 65 tumors for males, and 1.29 (95% CI 0.90–1.80) from 35 tumors for females. Mean time to diagnosis of subsequent cancer was 2.0 years (standard deviation[SD] 1.5). The SIR for other malignancy in the 5 years preceding the diagnosis of CLL was 1.36 (95% CI 0.93–1.94) from 31 tumors for males and 0.77 (95% CI 0.54–1.08) from 35 tumors for females. Mean time from diagnosis of preceding malignancy to CLL was 9.4 years (SD 8.7). Conclusions: In this population based study, patients with CLL are at increased risk of other invasive and in situ cancers. This risk is apparent after but not before the diagnosis of CLL, particularly in males. The mechanism of this increased risk may be acquired with the presence of CLL through an underlying but undetermined mechanism, as opposed to an inherent or more longstanding predisposition to malignancy. No significant financial relationships to disclose.
Successful classification of metastatic carcinoma of known primary using the CUPPRINT
Authors: Horlings H. M. , Warmoes M. O. , Kerst J. M. , Helgason H. , De Jong D. , Van ’t Veer L. 
Published: March 2020

20028 Background: It is critical for treatment decisions of metastatic disease to identify the primary tumor of the metastases, since the choice of optimal therapy depends on the correct diagnosis of the primary. Routine diagnostic evaluation is not sufficient to detect the primary site in 2–4% of all patients with pathology proven malignancy who present with metastatic disease. Currently the diagnostic yield is approximately between 20% and 30% for these patients. Microarray-based gene expression profiling has shown great promise to improve this. Methods: A microarray database was constructed of 497 frozen and 127 paraffin embedded (FFPE) samples representing 51 tumor types of both primary and metastatic tumors. The microarray database contained 22,000 gene-expression measurements for each sample. From the microarray database, we used an algorithm to search for gene combinations optimal for multi-tumor classification. This optimal gene-set was printed on 8-pack slides. These “1 × 3” glass slides contain eight mini-arrays with 1900 probes allowing for 8 simultaneous hybridizations, CUPPRINT. A k-nearest-neighbor-algorithm using this optimal gene-set was developed to discriminate between the 51 tumor types. We have independently verified the accuracy of this classification algorithm using FFPE samples from patients with metastases from 90 known and 50 unknown primary carcinomas. The expression data will be compared with clinicopathological data and an additional immunological panel of cytokeratin 7, cytokeratin 20, carcinogen embryonic antigen, CD 10, thyroid transcription factor 1, renal cell carcinoma, thyrogobulin, calcitonin, estrogen, progesterone, prostate specific antigen and CA 125. Results: The microarray based assay was able to classify correctly the primary site in 36 of 41 samples done so far (88% accuracy). The immunological panel showed a discriminative immunophenotype in 73% of these cases. For 49 known and 50 unknown primary tumors comparison between gene expression and clinicopathological investigations is currently pending. Conclusion: CUPPRINT, a microarrays based assay, is capable to accurately determine the tumor site of origin for a metastatic lesion. [Table: see text]
Changes in tumor biological markers during primary systemic chemotherapy (PST)
Authors: Solomayer E. , Neubauer H. , Beck V. , Huober J. , Vogel U. , Fehm T. 
Published: March 2020

20035 Background: Tumorbiological factors including HER2, estrogen receptor and progesterone receptor status are routinely determined prior neoadjuvant chemotherapy. Based on these results adjuvant treatment decisions regarding trastuzumab and endocrine therapy are made. However, the expression of these markers may be altered by cytotoxic therapy. Therefore, tumorbiological factors including HER2, ER, PR, ki-67 were studied in 87 patients treated before and after primary systemic therapy. Method: Corresponding cut-core biopsies and postchemotherapy surgical specimens were available from 87 patients treated with neoadjuvant chemotherapy. HER2, ER, PR and ki-67 were immunohistochemically assessed. Results: Pathological response rate was 69%. No significant changes were seen for ER receptor expression. Four tumors positive for ER changed to ER negative. In contrast, 13 initially PR-positive tumors were classified PR-negative after cytotoxic therapy (p < 0.05). A significant change was also observed for HER2 status. Eleven tumors which were negative prior to PST did overexpress HER2 in the post chemotherapy surgical specimen. Median ki-67 index decreased from 30% before PST to 13% after treatment (p < 0.01). Only reduction of ki-67 was associated with pathological response to PST. Conclusion: HER2 status as well as ER and PR status should be reevaluated on post-chemotherapy surgical specimens since changes can be observed. The clinical relevance of these changes regarding therapy response to adjuvant endocrine therapy or trastuzumab has yet to be determined. No significant financial relationships to disclose.
Thymoquinone, a component of the herb Nigella sativa, suppresses proliferation and viability of prostate cancer cells by down-regulating androgen receptor and E2F-1
Authors: Kaseb A. O. , Tejwani S. , Chinnakannu K. , Barrack E. , Reddy P. 
Published: March 2020

20038 Background: Prostate cancer (CaP) that relapses following androgen-ablation therapy is hormone refractory, yet its growth continues to depend on androgen receptor (AR). Therefore, a curative strategy must include structural elimination of AR. Thymoquinone (TQ) is a component of Nigella sativa, an herb that has been used for thousands of years for a variety of diseases including cancer. We examined TQ effect on AR and cell cycle regulatory proteins required for proliferation and viability of CaP cells. Methods: Inhibitory effect of TQ on DNA synthesis and proliferation of exponentially growing LNCaP cells was assessed by 3H-thymidine incorporation into DNA and MTS assay respectively. We examined TQ effect on AR and cell cycle regulatory proteins by Western blot analysis. The effect of TQ on cell cycle progression was determined using synchronized LNCaP cells. Western blots were then used to analyze equal amounts of protein isolated from cells at regular intervals during their progression through the cell cycle in the presence or absence of TQ. Results: We observed a dose-dependent increase in the inhibitory effect of TQ on DNA synthesis and proliferation of LNCaP cells. We also observed a significant decrease in AR and E2F-1, and a dramatic increase in p21, p27, and pRB, and Bax. Synchronized LNCaP cells treated with TQ failed to enter S phase. Western blot analysis revealed that TQ treatment of synchronized cells resulted in: (i) a significant decrease in AR, that normally increases in early- to late-G1phase, and E2F-1, that normally increases in late-G1phase (ii) down-regulation of cyclins A and E, Cdks-2 and 4, and Cdc-6 (iii) induction of p53 and p27. Conclusion: These observations demonstrate that TQ inhibits proliferation and viability of prostate cancer cells by decreasing AR and E2F-1 levels and inducing the proteins that cause cell cycle arrest and promote apoptotic events. Thus TQ may prove to be an effective treatment of hormone refractory CaP and a promising chemo- and/or radiation- sensitizing agent in adjuvant therapy as well. This could represent a novel approach for treatment of prostate cancer by an herbal agent that was shown to spare normal cells in previous studies. No significant financial relationships to disclose.
Evaluation of mRNA markers for micrometastases detection by RT-PCR in lymph nodes (LN), peripheral blood (PB) and bone marrow (BM) of breast cancer patients (pts)
Authors: Morelle A. M. , Frasson A. , Zerwes F. , Alves S. , Devenz G. , Silveira C. M. , Nectoux A. V. , Wagner M. , Garicochea B. 
Published: March 2020

20068 Background: Previous RT-PCR study showed that hMAM and CEA mRNA could be detected in 95% and 78% breast carcinomas, respectively. Analyzed in normal LN, these two markers were the only ones not expressed, compared to other mRNA markers which could be detected in a variable number of cases (Marchetti 2001). We evaluate the expression of CEA and hMAM mRNA in breast cancer pts in order to investigate if the identification of these transcripts could be correlated to in the LN, PB and BM. Methods: Tumor, normal gland, LN and PB were obtained from 49 breast cancer pts who have been referred to surgery during the period of Jun/2000 to Jan/2004.BM could be obtained from 21 of these cases. Before the manipulation of the tumor, 5 mL of PB was collected and 5 mL of BM was aspirated from the iliac crest. First level axillary LN were sectioned in two. One of the halves was immediately frozen in liquid nitrogen. CEA and hMAM transcripts have been analysed by RT-PCR. Results: Tumors were positive for CEA in 38 (77.6%) cases and LN were positive in 15 cases (36.7%). 6/49 pts expressed CEA in normal breast (12.2%). Five of these, tumor also expressed CEA. Two pts (4.1%) showed CEA expression in PB and in BM. One patient expressed CEA in BM but not in PB. All pts that showed expression in PB, BM and LN, also showed transcript of CEA in tumor. hMAM transcripts were found in 39 (79.6%) normal gland tissue and in 41 of tumor samples (85.7%). LN were positive to hMAM in 12 cases (24.5%). 5 of these (10.2%) were also positive in PB and BM samples. The pts showing hMAM expression in PB, BM and LN also showed its expression in neoplasic tissue. Analyzing both markers, two pts showed the expression of CEA and hMAM in the PB and BM samples. In 21 of the 49 cases the comparison of hMAM and CEA was possible to be performed in all tissues. CEA and hMAM expression associated to larger number of LN affected. Conclusions: CEA and hMAM transcripts can be detected in majority of breast cancer tissue. Specificity of hMAM seems to be higher than CEA, which can be detected in more than 10% of non-tumor breast tissue. Synchronicity of CEA or hMAM expression in the tumor and in extra-mammary sites was high, suggesting that these markers may provide an interesting strategy for follow-up micrometastatic disease. No significant financial relationships to disclose.
Banoxantrone (AQ4N), tissue CYP 450 targeted prodrug: The results of a phase I study using an accelerated dose escalation
Authors: Sarantopoulos J. , Tolcher A. W. , Wong A. , Goel S. , Beeram M. , Lam G. , Desai K. , Woody K. , Mani S. , Papadopoulos K. P. 
Published: March 2020

2011 Background: AQ4N was rationally designed to have anti-tumor activity following bioreduction by tissue cytochrome P450 to AQ4, an active DNA topoisomerase II inhibitor. Preclinical studies demonstrated AQ4N selectively targets lymphoid tissues and hypoxic tumor tissues. This study assessed the maximum tolerated dose (MTD), pharmacokinetic (PK), and pharmacodynamic (PD) of repeated weekly dosing of AQ4N in patients (pts) with advanced cancers. Methods: AQ4N was administered IV on Days 1, 8, and 15 of a 28-day cycle in the following dose cohorts 12, 24, 48, 96, 192, 384, 768, and 1200 mg/m2. Accelerated titration design 2B was employed and the MTD was defined by ≤ 33% of 6 pts with a drug-related dose limiting toxicity (DLT). Response was assessed every 8 weeks by RECIST. Results: 16 pts were enrolled. A single pt per cohort was treated up to 384 mg/m2. At 1200 mg/m2, 2 of 5 pts experienced a DLT (Grade 5 respiratory distress and Grade 3 fatigue). A total of 5 pts were treated without toxicity at the 768 mg/m2, and established this dose as MTD. One pt in the 1200 mg/m2 cohort died during the trial from acute complications of metastatic soft tissue sarcoma and respiratory distress. The most common adverse events (AE) observed were fatigue (63%), anorexia (38%), nausea (38%), vomiting (38%), peripheral edema (25%), and diarrhea (25%). 6 pts experienced 8 serious AEs. Anticipated blue coloration of skin and body fluids was observed. One pt (48 mg/m2) with renal cancer has had stable disease for > 12 months. The PK was linear over all doses studied. At 768 mg/m2 (n=4), the Day 1 AQ4N Cmax was 99.8 ± 27.0 μg/mL, AUC0-∞ was 259.5 ± 67.8 μg·h/mL, and T1/2 was 3.9 ± 0.7 h (range 3.1–4.8 h). A predictable dose-related and exposure related decrease in lymphocytes and neutrophils were observed. Conclusions: AQ4N is well tolerated when administered on a weekly schedule. AQ4N levels sufficient for anti-neoplastic activity in pre-clinical models are achieved with weekly dosing at 768 mg/m2. AQ4N monotherapy and combination trials with chemo- and radiation therapy are planned. [Table: see text]