bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective analysis of gefitinib versus docetaxel in never-smoking patients with previously treated non-small-cell lung cancer (NSCLC)
Authors: Kogure Y. , Ueda S. , Nakamura Y. , Ebisawa M. , Asai G. , Takahashi T. , Yamamoto N.
Published: March 2020

17154

Background: Docetaxel has been standard for second line treatment of NSCLC. In ISEL study, subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers and Asians. It is not clear whether gefitinib has the clinical advantage in these selected patients with NSCLC. We aimed to compare the clinical benefit of gefitinib with that of docetaxel in never smoker previously treated with chemotherapy, retrospectively. Methods: We reviewed patients from August 2002 to September 2005 in Shizuoka Cancer Center. Patients with following conditions were analyzed: NSCLC, received gefitinib or docetaxel, never-smoker, not chemo-naived. We assessed the response rate, progression free survival (PFS) and over all survival for gefitinib and docetaxel respectively. Survival curves were calculated using the Kaplan Meier-method. Prognostic factors were estimated using multivariate analysis. Results: 108 patinets were selected. 69 patients were treated with gefitinib and 39 patients were treated with docetaxel. 28 patients overlapped each other. The patients treated with gefitinib following docetaxel and those with docetaxel following gefitinib were 17 and 13, respectively. 69 patients with gefitinib: the median age, 62 years (31–79); stage IIIB/IV, 14/55; ad/sq/ others, 61/3/5; PS 0/1/2/3, 19/35/13/2; prior therapy containing platinum regimen, 58. The response rate was 36%. 39 patients with docetaxel: the median age, 63 years (31–76); stage IIIB/IV, 8/31; ad/sq/others, 29/7/3; PS 0/1/2/3, 18/19/1/1; prior therapy containing platinum regimen, 34. The response rate was 10%. Gefitinib was superior in longer median PFS (148 days vs 43 days, p = 0.0002). Over all survivals were not significant between two arms. In multivariate analysis for PFS, following factors were significant: gefitinib therapy (hazard ratio 0.375, p = 0.0002); male (hazard ratio 1.854, p = 0.0011); good performance status (hazard ratio 0.450, p = 0.0057). Conclusions: Our results suggested that gefitinib therapy is very attractive for never smoker in the point of PFS. Many patients received cross-over therapies made difficult to analyze over all survival.

No significant financial relationships to disclose.
Gender difference in susceptibility to smoking in Korean lung cancer patients having smoking habits
Authors: Ryu J. , Lee H. , Cho J. , Kwak S. , Lee H. , Lee M. , Lee M. , Kim C.
Published: March 2020

17158

Background: There were some controversies whether women were more or less susceptible to the carcinogenic effect of cigarette smoke and the decline of forced expiratory volume in 1 second (FEV1) to pack-years compared to men. Methods: In this study, we included all lung cancer patients having smoking habits who was histologically diagnosed and performed pulmonary function testing at the time of diagnosis from September 2001 through December 2005. We estimated individual susceptibility to smoking using a formula (SI, susceptibility index) of (100% predicted FEV1)/pack-years. Results: Of 858 lung cancer patients, sex ratio (M/F) was 14.6 (803/55). Past smokers were in 236 (29.3%) for men, 11 (20.0%) for women. Most common hsitologic type was squamous cell carcinoma (477), adenocarcinoma (191), small cell carcinoma (147), adenosquamous cell carcinoma (14), large cell carcinoma (14), NSCLC cell type not specified (15). Pack-years were 41.3 ± 18.9 for men, 29.2 ± 20.4 for women (P = 0.000). FEV1 % was 78.7 ± 23.3 for men, 79.4 ± 22.9 for women (P = 0.832). As for SI, there were no differences between men (0.65 ± 1.1) and women (0.72 ± 1.6) (P = 0.688). Conclusions: Although lung cancer women having smoking habits showed lower pack-years, there were no gender differences in terms of FEV1 decline to cigarette smoking.

No significant financial relationships to disclose.
Prognostic implications of caspase-3 expression in patients with diffuse large B-cell lymphoma (DLBCL)
Authors: Elsawy W. H. , Abdel Kader M. , Elfar A. , Gharib A. , Eltrhony S. , Dorgham Y.
Published: March 2020

17500

Background: Caspase-3 activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase-2 and caspase-3. The following study was designed to evaluate the correlation between Caspase-3 and the clinical outcome in patients with diffuse large B-cell lymphoma. Methods: Caspase-3 was determined by both immunohistochemistry and by quantitative reverse-transcription PCR in 49 previously untreated patients with diffuse large B-cell lymphoma. Results: Caspase-3 was positive in 69.4% of the patients by immunostaining and Tumor cells displayed a diffuse cytosolic expression in 51% of patients. The median value of Caspase-3mRNA within the group by quantitative PCR was 1. Caspase-3mRNA level was μ1 in 28 patients and <1 in 21 patients. Caspase-3 expression was associated with higher tumor stage (P = 0.03), elevated serum lactate dehydrogenase levels (P = 0.02), and the International Prognostic Index (P = 0.0001). Patients with Caspase-3-positive immunostaining had a significantly higher complete response rate to chemotherapy and a longer overall survival than Caspase-3-negative patients. Also, patients with tumor cells expressing diffuse cytosolic immunostaining for caspase-3 had a poor prognosis when compared with those expressing a punctate staining (P > 0.0004 log-rank). A low caspase-3 mRNA expression by quantitative RT-PCR was also associated with a poor prognosis, although this was not statistically significant. In addition, patients with a high TUNEL positivity had a low survival probability (P > 0.02). Conclusions: Our results suggest that Caspase-3 activation or its lack may be a powerful independent predictor of response and survival in previously untreated diffuse large B-cell lymphomas.

No significant financial relationships to disclose.
Rituximab resistance and its association with changes in the internal domain of CD20 antigen and down-regulation of pro-apoptotic protein Bax and Bak in both rituximab-resistant cell lines (RRCL) and diffuse large B-cell lymphoma (DLBCL) patient (pt) samples
Authors: Reddy N. M. , Hernandez-Ilizaliturri F. J. , Olejniczak S. , Knight J. , Czuczman M. S.
Published: March 2020

17509

Background: Resistance to rituximab (R) has been observed in lymphoma pts. To define the molecular basis for rituximab resistance we developed various RRCL and previously demonstrated changes in CD20 structure, membrane reorganization following rituximab exposure and deregulation of pro-apoptotic proteins Bax/Bak leading to rituximab/chemotherapy resistance. In our current work we evaluated changes in the structure/expression of CD20 and/or pro-apoptotic proteins in primary tumor specimens from DLBCL pts treated with rituximab in combination with CHOP (R-CHOP). Methods: We obtained frozen lymphoid material from patients with DLBCL who achieved a remission (sensitive lymphoma) or failed (resistant lymphoma) R-CHOP therapy. Protein lysates were obtained from each sample. Structural changes in CD20 were determined by Western blotting using various antibodies recognizing epitopes located in the internal (GST77 and 1439) and external domain (rituximab) of CD20. In addition, we studied the expression of Bax and Bak. Results: Variability in the expression and structure of CD20 was found in the pt samples. Rituximab binding to its surface CD20 antigen was preserved in all patients. However, differences in C- and N-terminal expression were found across DLBCL specimens. In addition, down-regulation of Bax/Bak was observed in some pts with resistant lymphomas. Patients who responded to R-CHOP were noted to either have an intact CD20 and/or express Bax/Bak. On the other hand, resistant lymphomas had altered CD20 isoforms and a downregulation of Bax/Bak. Conclusions: Our current preliminary data suggests a positive correlation to our pre-clinical data generated from B-cell NHL cell-lines and will be evaluated in a larger number of primary NHL tumor specimens.

No significant financial relationships to disclose.
Body mass index (BMI) and physical activity in long-term lymphoma survivors: A pilot study
Authors: Thompson C. A. , Cerhan J. R. , Laplant B. R. , Maurer M. J. , Clark M. M. , Sloan J. A. , Rummans T. A. , Thomas R. J. , Habermann T. M.
Published: March 2020

17511

Background: There is no published data regarding BMI changes in survivors of adult lymphoma. Methods: In October of 2004, we mailed a 23-page survey to 95 randomly selected patients from a population of 2,485 of patients from the Mayo Tumor Registry who had survived lymphoma from 5 to 20 years. 56 completed the survey for a 68% participation rate. Body mass index (BMI) was calculated using clinical height and weight in the medical record at the time of diagnosis and self-reported weight in the survey response. Physical activity was self-reported. Based on their pattern of response, patients were categorized into a stage of change of current exercise (precontemplation, contemplation, preparation, action, or maintenance). Mood disturbance (depression, anxiety, and distress) and quality of life (QOL) were self-reported using the CES-D, POMS, STAI, FACT-G, and LASA questionnaires. Scores were transformed to a scale of 0–100 (higher score meaning higher functioning) to allow comparisons with a difference of 10 points considered significant. Results: The median age at completion of the questionnaire was 62 years (range: 25–85). The median time since diagnosis was 11 years (range: 6–20). Regular fitness, defined as a stage of change for exercise of action or maintenance, was reported by 48% of the respondents. The median BMI at diagnosis was 25.6 and the median at time of questionnaire was 27.0, which is a statistically significant change. Change in BMI, BMI at diagnosis, and BMI at time of questionnaire had no correlation with level of physical activity. Obese patients had a mean score of 72 points on the LASA, which was significantly lower than normal and underweight patients (mean 86) and overweight patients (mean 84). Conclusions: A small, but significant increase in body mass index was noted in long-term lymphoma survivors from the time of diagnosis to long-term follow-up. Patients who were obese at time of diagnosis may have lower quality of life down-the-road, as measured by the LASA years following treatment. This data represents the first information about body mass index in survivors of adult lymphoma. Further larger studies are needed to confirm these preliminary data and to evaluate other aspects of health behavior in long-term survivors of lymphoma.

No significant financial relationships to disclose.
Prediction of response to therapy with clarithromycin/lenalidomide/dexamethasone (BIRD) in multiple myeloma using FDG-PET
Authors: Coleman M. , Kostakoglu L. , Goldsmith S. J. , Liu M. , Christos P. , Jayabalan D. S. , Niesvizky R.
Published: March 2020

17530

Background: End points based on functional imaging data hold promise to better define and stratify response. As a metabolic imaging modality, FDG-PET can characterize tumor aggressiveness and thus can serve as an early surrogate for therapy response. The combination therapy with BIRD augments tumor mass reduction and improves response in patients with multiple myeloma (MM). The purpose of this study is to determine the value of pre-therapy FDG-PET in predicting therapy response in MM patients undergoing BIRD therapy. Methods: A total of 13 patients with MM (mean age: 60 ± 11) underwent a whole body FDG-PET scan at initial staging prior to BIRD therapy. FDG uptake was qualitatively evaluated in 5 different patterns:minimally diffuse (score 1), focal (score 2), multifocal (score 3), diffuse (score 4) and extramedullary (score 5). Standardized uptake values (SUVmax) were obtained in osseous and extramedullary lesions for quantitative evaluation. Mean SUVmax were also calculated in 14 representative anatomic sites in the axial and appendicular skeleton in 20 age-matched control patients with no osseous malignancy. Ratios of the mean lesion SUVmax to the mean SUVmax in corresponding osseous sections from the control group were calculated. A score was obtained for each patient to reflect disease extent or severity by adding the ratios for each individual lesion. The qualitative and quantitative scores were correlated with the standard response criteria. Results: The results are summarized in the following Table . The pre-therapy qualitative and quantitative scores correlated well with the percent therapy response to BIRD regimen (r = −0.58, p = 0.04 and r = −0.53, p = 0.06, respectively). Conclusions: The pre-therapy FDG-PET scoring system we have developed appears to correlate with the subsequent therapy response to BIRD regimen. Expanded number of patients are warranted to confirm the results of this study.

[Table: see text]

No significant financial relationships to disclose.
Hodgkin’s lymphoma among veterans: Does race matter?
Authors: Komrokji R. S. , Mekan S. F. , Safa M. M. , Nahleh Z. A. , Pancoast J. R. , Muhleman A. F. , Jazieh A. R.
Published: March 2020

17538

Background: Racial disparities in Hodgkin’s lymphoma (HL) are not well studied. Earlier studies suggested that black patients received less treatment and had worse outcome. The VA health care system offers a platform to study those racial differences given similar other variables and socioeconomic status among those patients. Methods: This was a retrospective analysis. The VA Central Cancer Registry (VACCR) database was used to identify patients with HL diagnosed between 1995 and 2005. There are approximately 120 VA medical centers diagnosing and/or treating patients with cancer. Data are entered by tumor registrars at the VA medical centers. This site aggregates the data collected by the medical centers’ cancer registries. Data was extrapolated and analyzed using bio-statistical software SPSS. Results: There were 1009 patients with HL at the VA system, 801 white and 183 black patients. Twenty-five patients from other racial groups were excluded from this analysis. The median age of presentation among blacks was 50.8 years compared to 53.8 years among whites (P-value 0.026). More white patients had family history of HL. Black patients had a higher incidence lymphocyte depleted histological subtype 33 (18.0%) vs. 75 (9.4%) and whites had a higher prevalence of nodular sclerosing subtype, 260 (32.5%) vs. 32 (17.5%). Other baseline characteristics such as sex, history of smoking, alcohol, and radiation exposure were similar. Presence of bulky disease and stage of lymphoma at presentation were also similar. Similar proportion of patients received chemotherapy among the two groups, 70 % for blacks and 69% for whites. Among blacks 19.7 % of patients received radiation while 25.5 % white patients did (P-value 0.24). The 5-year overall survival of blacks was 53 % years as opposed to 54% for whites (P-value 0.93) Conclusions: The presenting features, risk factors are similar across black and white races among VA population. Blacks are more likely to present with lymphocyte depleted type of HD. The treatment and outcome of HL among blacks are not different from whites within the VA system.

No significant financial relationships to disclose.
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.

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A study of US-based Indian and Pakistani population with cancer diagnosis reported in the SEER database from 1988 to 2002
Authors: Hossain A. , Sehbai A. , Abraham J.
Published: March 2020

20116

Background: Southeast Asian population comprises about 1.5% of the US population and one of the rapidly growing ethnic groups. This is the first study in US-based Indian and Pakistani patients with new diagnosis of cancer analyzing the epidemiologic data. Methods: SEER cancer incidence database have reported cancer incidence from 13 SEER registries from 1973 to 2002. Frequency sessions were performed and descriptive parameters were calculated regarding age, sex, marital status, vital statistics, stage, grade, tumor sites and other diagnostic tests employed. Results: About 11% of the estimated Indian and Pakistani population live in the 13 SEER registry areas. A total of 4,229 cases were reported since 1988 in this subcategory, which is about 0.03% of the total reported cases. 2148 (50.8%) were male and 2081 (49.2%) were female (p = 0.821). Average age at diagnosis was 51 years in male and 53 years in female (p = 0.7295). Table shows the incidence of different cancers compiled from American Cancer Society (ACS) (2005)1, SEER2 and World Health Organization (WHO) (2002)3 databases. Conclusions: Oral cavity cancer in males, and Breast and cervical cancer in females are common malignancies in India and Pakistan. Our study shows that prostate and breast cancer are most common in males and females in US-based Indian and Pakistani population respectively. Immigrants change their demographics regarding cancers and these differences could be attributed to multiple factors. This data may also have implications in terms of earlier screening of cancer in this population and earlier intervention.

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No significant financial relationships to disclose.
Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer (FOCUS)
Authors: Seymour M. T. , Braun M. S. , Richman S. D. , Daly C. , Thompson L. C. , Meade A. , Parmar M. , Allan J. M. , Selby P. , Quirke P.
Published: March 2020

2022

Background: We present data on putative markers of chemotherapy toxicity from patients randomized to receive fluorouracil alone (FU), or FU+irinotecan (Ir), or FU+oxaliplatin (Ox). Methods: 1188 patients randomized to the FOCUS trial (ASCO 05 #3518) were analyzed. First-line therapy was FU in two thirds of patients, and FU+ either Ir or Ox in one third. Second-line Ir and Ox were administered to 29% and 14% of patients respectively. DNA was extracted from formalin-fixed, paraffin embedded (FFPE) blocks. Assessed DNA polymorphisms included TSER, TS1494, DPD IVS14 + 1G>A, MTHFR C667T, MLH1 -93, UGT1A1*28, ABCB1 C3435T, GSTP1 105Val, XRCC1 Q399R and ERCC2 K751Q. The primary endpoint was chemotherapy delay or dose-reduction due to toxicity during the first 12 weeks of treatment. The secondary endpoint was incidence of CTC toxicity. The Chi-squared test was used to assess for associations. Results: In this exploratory analysis no molecular factors were observed to be associated with the primary endpoint (all p values >0.1). Furthermore, no polymorphism predicted severe CTC toxicity in patients receiving FU alone (all p values >0.1). XRCC1 variant allele carriers were at increased risk of severe CTC toxicity from Ir. Combined analysis of patients treated with first and second-line Ir appeared to show a significant association between toxicity and the presence of the variant XRCC1 allele across genotypes (57% versus 52% versus 38%; p=0.006). The UGT1A1*28 was not associated with Ir toxicity. No oxaliplatin markers predicted CTC toxicity. Conclusions: None of the assessed polymorphisms were significantly associated with the primary endpoint. Our results do not support the use of pharmacogenomics in routine clinical practice. In contrast to other studies the UGT1A1*28 VNTR was not associated with irinotecan toxicity . However, the XRCC1 Q399R polymorphism was associated with increased toxicity in patients receiving irinotecan, and these data may warrant further investigation, and independent confirmation.

No significant financial relationships to disclose.
Pharmacokinetic and pharmacodynamic analysis of topotecan administered in combination with PS 341 in patients with advanced malignancy
Authors: Tomita M. , Xin L. , Freeman B. , Twomey S. , Pizzorno G. , Murren J. R.
Published: March 2020

2033

Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m2. Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted.

No significant financial relationships to disclose.