bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of docetaxel therapy in elderly (≥70yrs) castration resistant prostate cancer (CRPC) patients enrolled in the Netherlands Prostate Study (NePro).
Authors: Los Maartje , Gerritse Frank L. , Meulenbeld Hielke Jodie , Roodhart Jeanine M.L. , van der Velden Ankie M.T. , De Wit Ronald ,   on behalf of the NePro Study group
Published: March 2020

e16059

Background: Prostate cancer truly is an age-associated disease, approximately half of prostate cancer patients in the Netherlands are aged 70 years or older at the time of diagnosis. However, age above 70 years has been an exclusion criterion in many clinical trials. Hence the knowledge about chemotherapy tolerance and toxicity in patients aged 70 years and above is limited. In this study we evaluated the influence of age on docetaxel chemotherapy in elderly (≥70yrs) castration resistant prostate cancer (CRPC) patients. Methods: Prostate cancer truly is an age-associated disease, approximately half of prostate cancer patients in the Netherlands are aged 70 years or older at the time of diagnosis. However, age above 70 years has been an exclusion criterion in many clinical trials. Hence the knowledge about chemotherapy tolerance and toxicity in patients aged 70 years and above is limited. In this study we evaluated the influence of age on docetaxel chemotherapy in elderly (≥70yrs) castration resistant prostate cancer (CRPC) patients. Results: We analyzed 568 patients (median age 68.1yrs, range 46-89yrs, 44.5% aged ≥70yrs). There was no relation between dosage and age (p=0.60). We found no significant differences between the number of dose reductions, TTP, overall survival, chemotherapy tolerance and toxicity up to the age of 80 years. However, when compared to younger men, men aged 80 years or above more frequently experienced grade 3/4 toxicity, were five times less likely to complete the first three treatment cycles at the intended dose (OR5.34, p=0.0052) and showed decreased overall survival (15.3mos versus 24.5mos in <80yrs group, p=0.020). Conclusions: In mCRPC, and possibly other cancer patients, up to the age of 80 years docetaxel chemotherapy is well tolerated with toxicity levels, tolerance and TTP comparable to that of younger patients. However, for chemotherapeutic treatment of patients aged 80 years and above an individual assessment should be made.
Lymph node metastases in endocervical adenocarcinoma: Correlation with Silva pattern of invasion.
Authors: Rutgers Joanne KL , Zaino Richard J , Young Robert H , Ronnett Brigitte M. , Longacre Teri A. , Alvarado-Cabrero Isabel , Park Kay J. , Roma Andres , Osann Kathryn , Silva Elvio ,   MD Anderson Collaborative Study: Endocervial Adenocarcinoma
Published: March 2020

e16518

Background: Endocervical adenocarcinoma (EA) is the 2nd most common uterine cervical malignancy (after squamous cell carcinoma). Early stage tumors are defined by depth of invasion (DOI); although used to guide nodal dissection, DOI not an entirely reliable criteria, and most patients have negative nodes. Thus, pathologic criteria that better predict risk of nodal metastases are needed. A prior study of 352 cases from 12 US and international institutions, with complete pathological and clinical follow-up averaging 52 months, found classifying EA by a newly proposed ‘Silva Pattern of Invasion’ (SPI) is the best predictor of nodal metastases. SPI are defined as A: no destructive stromal invasion or lymph-vascular invasion (LVI); B: small foci (<4 mm) of fragmented, angulated glands, solid aggregates or individual tumor cells associated with desmoplastia or LVI; and C: diffuse destructive invasion. Pattern A, 25% of cases, had no nodal metastases or recurrences. Approximately 25% were B, with 5% nodal metastases, 2% recurrence, and no tumor deaths. Pattern C cases: nodal metastases 23%, recurrences 21%, and death from tumor 9%. SPI appeared simple to diagnose, but a formal assessment of reproducibility is needed. Methods: Reproducibility for diagnosing SPI, and for the standard measurement of DOI is compared. Four Gynecological Pathologists, who have read the initial manuscript, but not involved in the original study nor from the participating institutions, and blinded to clinical information examine 1or 2 hematoxylin and eosin-stained glass slides from 90 cases from the original series. Results: 30 cases each of Pattern A, B, and C are reviewed. Kappa statistics will be estimated. With 90 samples, we will have >80% power to detect a true kappa of 0.7 in a test of the null hypothesis that kappa = 0.5 vs the alternative that kappa≠0.5 with equal frequencies in each SPI category. Conclusions: A good reproducibility outcome would indicate that the SPI could be applied in general practice. Accurate use of SPI requires examination of the entire lesion unless pattern B or C is found in the biopsy specimen. Use of the SPI system to guide nodal dissection will require validation in a large series.
Induction in locally advanced uterine cervix carcinoma with cisplatin, paclitaxel, and capecitabine: Response and tolerability.
Authors: Rodriguez-Riao Juan J. , Oblitas George , Colon Virgilio
Published: March 2020

e16521

Background: Cervix cancer is a public health problem in developing countries, and the locally advanced disease is the most common stage and patiente with complete response after concurrent radiotherapy and cisplatin is low. In this study we use induction chemotherapy in orden to reduce the tumor before radiotherapy administration. Methods: 47 patients with pathological confirmed cervix cancer stage Ib2 to IVa received induction chemotherapy for three cycles with cisplatin, paclitaxel and capecitabine prior to treatment with concurrent chemotherapy-radiotherapy. The primary end points were clinical response rate, pathological response and imaging after induction and secondary end point was safety (NCI toxicity version 3.0). Results: A total of 47 patients found that the average age was 45 years, stage IIB was the most common, squamous histology representing 89.4% of the patients. The clinical response rate was 100%, without disease progression during the period of following. Pathological complete response was 48.9%. The most common hematologic toxicity was anemia (55%) and grade 3 neutropenia (14.8%) but both were manageable, all patients had hand-foot syndrome and alopecia. Neuropathy grade 3 was 12.7%. Conclusions: Induction chemotherapy whith cisplatin, paclitaxel and capecitabine for three cycles prior to standard treatment offers an effective and safety alternative in patients with locally advanced cervical carcinoma.
Efficacy and safety of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with recurrent gynaecological cancer and peritoneal carcinomatosis.
Authors: Reymond Marc A , Solass Wiebke , Giger-Pabst Urs , Strumberg Dirk , Zieren Jurgen , Tempfer Clemens
Published: March 2020

e16523

Background: Peritoneal carcinomatosis (PC) is common in ovarian (OC) and other gynaecological cancers. We have developed an innovative therapy, Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), which improves local tumor drug uptake and can be combined with systemic chemotherapy. PIPAC achieves outstanding local biodisponibility with low systemic exposure. Liver and renal toxicity are minimal. The procedure is safe for health workers. We present first results obtained in end-stage PC from gynaecological origin. Methods: Since 1.12.2011 we have performed 18 PIPAC applications in 9 end-stage PC patients with OC (n = 4), papillary (n = 3), tuba (n = 1) and cervix (n = 1) cancer. Mean age was 64.6 ± 16 years. In 4 instances, PIPAC was combined with cytoreductive surgery. Patients were followed-up until Dec, 2012 or until death. Tumor response was assessed by macroscopy (PCI) and microscopy. Results: No intraoperative complication was noted. Mean operating time (PIPAC alone) was 97 ± 20 min. PIPAC could be repeated at 6-weeks intervals (4x: n = 1; 3x: n = 3: 1x: n = 5). In one case, adhesions prevented iterative PIPAC. No adverse event > 2 CTCAE was noted after PIPAC alone. Six patients are alive. Median survival has not been reached after a mean follow-up of 8 months, actuarial survival after one year is 58,3%. Four patients were eligible for response assessment after repeated PIPAC. One showed complete remission (CR), three partial remission (PR). Performance index (Karnofsky) increased from 62 ± 17 % to 82 ± 5 % after therapy. Conclusions: These first results are promising. PIPAC can induce a regression of PC in advanced, therapy-resistant gynaecological cancers. PIPAC is well tolerated and can improve patient’s performance. First survival data are encouraging. PIPAC will now be evaluated in a phase-II clinical trial with cisplatin and doxorubicine (EudraCT 2012-004397-26) in therapy-resistant, recurrent OC.
Clinical outcomes and alternative chemotherapy (CT) options in patients (pts) with de novo carboplatin (carbo)-resistant stage III or IV ovarian cancer (CA) based on the drug-induced apoptosis (MiCK) assay.
Authors: Burrell Matthew O. , Stany Michael , Rutledge James , Salom Emery Manuel , Penalver Manuel , Hallquist Allan , Presant Cary A.
Published: March 2020

e16525

Background: In order to understand platinum-resistant ovarian CA better, we evaluated the outcomes of pts with in vitro carbo resistance and CT alternatives based on the MiCK assay. Methods: 77 pts with primary stage III or IV ovarian CA previously untreated with CT had a MiCK assay prior to therapy. The MiCK assay was performed as described (J Trans Med 2012; 10:162). Physicians did not receive the results of the assay prior to CT. The time to recurrence in pts treated with standard carbo+paclitaxel CT who had in vitro de novo carbo resistance (carbo KU<1 in the MiCK assay) was compared to time to recurrence in pts treated with carbo+paclitaxel with no in vitro resistance (carbo KU>1) using the log-rank test. The pattern of assay sensitivity to other drugs was analyzed. Results: In pts with de novo carbo resistance in the MiCK assay who were treated with carbo+paclitaxel, the median time to recurrence was only 5.0 months compared to 16 months in pts with carbo sensitivity (p = 0.01). In patients with de novo carbo resistance, 63% of pts were still sensitive (KU>1) to cisplatin in the MiCK assay. For those pts resistant to carbo in the MiCK assay, alternative active CTs were cisplatin 63%, docetaxel 50%, cisplatin+gemcitabine 60%, topotecan 25%, liposomal doxorubicin 20%, etoposide 50%, gemcitabine 17% and cyclophosphamide 50%. The MiCK assay was able to rank individual drugs and combinations with highest drug induced apoptosis for individual patients. Conclusions: Pts with de novo in vitro carbo resistance have more rapid relapse, and can be prospectively rapidly identified before initial CT (time required for MiCK assay 48 hours). Alternative drugs or combinations with in vitro activity (still using drugs within national evidence based treatment guidelines) can be identified with the MiCK assay. This suggests that for pts with relapsing disease with clinically apparent carbo resistance, the MiCK assay can identify individualized CT for such pts. This study gives the framework for a prospective randomized phase III trial of assay-directed CT versus standard CT in platinum-resistant ovarian CA. Clinical trial information: NCT 00443196.
Exploratory study of histopathological characteristics of cervical cancer in an African (Tanzania) population.
Authors: Bravaccini Sara , Chiadini Elisa , Puccetti Maurizio , Serra Patrizia , Masalu Nestory Andrew , Tumedei Maria Maddalena , Rengucci Claudia , Ulivi Paola , Rocca Andrea , Zoli Wainer , Amadori Dino ,   African Italian Cooperative Oncology Group (AFRICOG)
Published: March 2020

e16530

Background: In Tanzania, cervical cancer is the leading cause of death after breast cancer, with the majority of tumors diagnosed at a very advanced stage. Little information is available on the characteristics of cervical cancer in Sub-Saharan African women. We aimed to evaluate histopathological features of cervical cancers and relative margins in a group of African women and to characterize HPV infection. Methods: Tissue samples from32 Tanzanian women with invasive cervical cancer were evaluated in the Biosciences Laboratory of our Institute (IRCCS IRST, Meldola, Italy) as part of a global cancer control project currently ongoing in close cooperation with the Bugando Medical Center of Mwanza, Tanzania. Results: 24/32 (75%) women had squamous carcinoma and 4/32 (12.5%) had adenocarcinoma of the cervix. The HPV test was performed in the entire series but DNA amplification by pyrosequencing was only possible in 27/32 (84.4%). The presence of HPV infection was confirmed in 26/27 (96.3%) cases in both tumor and relative margins. Typization of the virus revealed that a high percentage of the women had HPV 16 virus of whom 12 (46.2 %) had African type 1 and 4 (15.4%) African type 2. Conclusions: A major problem in the cancer tissue samples from the Tanzanian patients was the poor evaluability of DNA amplification due to suboptimal fixation which compromised tissue morphology. Our preliminary study shows that cervical cancer in Tanzanian women is characterized by a very high frequency of HPV-positive tumors, with a high prevalence of HPV 16 African type 1 and 2 infections. The substantial number of HPV infections could explain the high rate of cervical cancer and subsequent mortality in this African population. [Table: see text]
Concurrent chemoradiation therapy in cervical cancer: Prognostic factors, toxicity, and long-term survival in a center of reference for gynecologic cancer.
Authors: Gil-Martin Marta , Olivera Mivael , Pardo Beatriz , Bellobi Cinta , Navarro-Perez Valentín , Marin i Borras Susanna
Published: March 2020

e16539

Background: Concurrent chemoradiation therapy has been the standard treatment in locally advanced cervical cancer since 1999, and our institution is a centre of reference for treatment of this pathology. Methods: In a homogeneous series of 288 patients treated between 1996 and December 2011, survival data, prognostic factors and toxicity of the treatment have been analyzed. The treatment includes external beam radiotherapy, concurrent weekly chemotherapy and brachytherapy. Results: Median age of the patients is 54 years old, and the FIGO classification for disease stages shows 14.6% IB2, 47.1% IIB, 24.4% III, and 7.8% IVA. Squamous cell carcinoma (77.4%) and adenocarcinoma (16.8%) are the most common histologies. After a median follow-up of 4.4 years, the 5-year overall survival rate is 80.2%. Classified by diagnostic stage, they are 85% in IB2, 76% in IIB, 70% in III, and 68% in IVA. The main location for recurrence is cervix (11.8%), and the most common site for distant disease is lung (4.8%). For patients with disease progression, 24.4% have local and distant recurrence. After local recurrence, radical surgery with pelvic exenteration was practised in 6 cases, 5 of them are still alive. In the multivariate analysis, the prognostic factors for overall survival that have been identified with a statistical significance, are HPV and HIV infection, high stages of disease and older patients. Performance status ≥1 and brachytherapy have only a significant value in the univariate analysis. The acute toxicity grade ≥3 was observed in 19.4% of patients (14.1% haematological). The most frequent low grade toxicity was 46.3% haematological, 40% of bowel-related toxicity, 38.9% of nausea and vomiting, and 8.1% of renal dysfunction. Chronic toxicity grade ≥3 has been only seen in 1.2% of patients (renal dysfunction), and in the low grades, it is a 6% of bowel-related toxicity and 1.4% of mild renal dysfunction. Conclusions: This long follow-up series shows a good overall survival rate with chemoradiation therapy in locally advanced stages of cervical cancer, with a low rate of acute and, especially, chronic toxicity, indicating a good quality of life for these patients.
Ovarian cancer stem cells (OCSCs): Therapy for advanced chemoresistant ovarian cancer.
Authors: Sengupta Prattusha , Gangopadhyay Sudeshna , Sengupta Saubhik , Ray Ujjal Kanti , Mukhopadhyay Ashis
Published: March 2020

e16542

Background: Invasive and mesenchymal property of Ovarian Cancer Stem Cells (OCSCs)with CD44+/CD133+has made them promising target for targeted treatment. Chemotherapy treatment uses medicine to weaken and destroy cancer cells in body, including cells at original cancer site and any cancer cells that may have spread to another part of body. Chemotherapeutic drugs for advanced chemo-resistant ovarian cancer are yet to be well defined. Combination of drugs is also not fully known. Our objective is to define chemotherapeutic drugs and its action in OCSC which is the major reason for chemo resistance in case of advanced chemo-resistant ovarian cancer patients. Methods: A total of twenty biopsy proven advanced chemo-resistant ovarian cancer patients in the age group of 22-36 years were selected randomly and tested for CD44/CD133 via flow cytometry. Isolated OCSCs were cultured for ex vivo drug sensitivity towards platinum, anthracyclin, docetaxel, rapamycin, sunitinib, sorafenib and gefitinib. Correlation was drawn between cell differentiations, % of stem cells and drug response. Accordingly chemotherapy was designed for a particular patient. Results: We detected OCSCs in 90% of cases. Among positive samples ex vivo drug sensitivity was seen in 4(20%) to rapamycin, 1(5%) to sunitinib, 1(5%) to sorafenib, 1(5%) to gefitinib, 3(15%) to platinum, 1(5%) to anthracyclin, 1(5%) to docetaxel and rest showed no sensitivity to any drug. Conclusions: Thus primary aim to target OCSCs at onset of tumors in ovarian cancer patients to control metastasis and relapse of disease was somewhat obtained. Most interestingly, we found that the chemotherapeutic drugs which were less prescribed for ovarian cancer showed greater sensitivity in comparison to the widely used ones. We like to do animal model study followed by phase I, II and III human clinical trial to establish our hypothesis for better management of chemo-resistant ovarian cancer.
The impact of multimodality treatment on outcomes of patients with type II endometrial carcinoma: A single institution experience.
Authors: Talukdar Shobhana , Jankowski Michelle , Hanna Rabbie Kriakoss , Elshaikh Mohamed A.
Published: March 2020

e16552

Background: To determine the impact of different adjuvant treatment modalities on relapse-free (RFS), disease-specific (DSS) and overall survival (OS) of patients with type II endometrial carcinoma after hysterectomy. Methods: Our prospectively-maintained database of 1605 uterine cancer patients was reviewed for this IRB-approved study. We identified 167 consecutive patients with type II endometrial carcinoma 2009 FIGO stages IA-IIIC2 who underwent hysterectomy between 1991-2012. Recurrence-free survival (RFS), DSS and OS was calculated from the date of hysterectomy using the Kaplan Meier method. Cox regression modeling was used to explore the risks of various factors on recurrence. Results: Median follow-up was 5.4 years. Median age was 65 years. All patients underwent hysterectomy and salpingo-oophorectomy. 95% had peritoneal cytology and 87% underwent lymphadenectomy. 61% were stage I, 11% with stage II and 28% with stage III (including 33 patients with lymph node involvement). There were 60% of patients with uterine serous carcinoma, 22% with clear cell and 18% with a mixed histology. 29% of patients received adjuvant chemoradiotherapy, 25% received either chemotherapy or radiothereapy alone and 21% were managed with close surveillance. 5-year OS, DSS and RFS was 54%, 64% and 54%, respectively. On multivariate analysis and after adjusting for other prognostic factors, multimodality treatment, (p = 0.0076) presence of LVSI (p = 0.0443), lower uterine segment involvement (p = 0.0003) and involvement of lymph nodes (p = 0.001) were the only independent predictors of RFS. These factors in addition to positive peritoneal cytology were also significant predictors of DSS. Age at diagnosis, the presence of LVSI, positive lymph nodes, positive peritoneal cytology and adjuvant multimodality treatment were the only predictors of OS with p = 0.0251, 0.0178, 0.003, 0.0019 and 0.046, respectively. Conclusions: In this hospital-based study, adjuvant radiation treatment combined with chemotherapy was independent predictor of RFS, DSS and OS compared to single modality treatment. These findings need validation from a prospective randomized study.
Synchronous primary ovarian and endometrial cancer in recent years: Changes in recent years.
Authors: deLeon Maria Creselda , Del Priore Giuseppe , Gudipudi Deleep
Published: March 2020

e16554

Background: Patients with synchronous ovarian and endometrial cancer (SOEC) have been shown to have better prognosis when compared to patients with primary ovarian cancer alone; however with the increasing rate of obesity in the United States we hypothesize that this disease has significant characteristic changes compared to 20 years ago. Methods: This is retrospective study of patients with SOEC diagnosed between 1973-2009. We compared patients from 1973-1991 (n=962) to patients diagnosed between 1992-2009 (n=1800) when obesity became >10% of the US population starting in 1992. Using the Surveillance, Epidemiology, and End Results (SEER) registry, we obtained demographic information which included patient ID, primary site of tumor, year of diagnosis, sex, race, age group and survival months. SOEC was defined as diagnosis of ovarian and endometrial cancer within 0-12 months. Results: A query of SEOC yielded 2,762 women between the ages of 13-99 years. When we compared the stage of disease which was described as localized, regional, distant and unstaged, tumor grade and disease incidence, there was no difference found between the two groups. However when the age of diagnosis was compared, it was apparent that patients diagnosed between the years 1992-2009 were diagnosed at an earlier age 41-50 (28%) compared to patients diagnosed in 1973-1991 who were mostly diagnosed between ages 61-70 (31%) (p <0.001). Conclusions: We were able to demonstrate that women with SOEC in recent years are more likely to be diagnosed at an earlier age but that the disease stage, grade and incidence have stayed the same in the past 40 years. The hypothesis then that SOEC may have gone through some characteristic changes in the past 20 years seems plausible especially in the setting of increase incidence of obesity. [Table: see text]
Comparative analysis of DNA-cytometric indices of primary and relapsing ovarian cencer.
Authors: Novikova Inna Arnoldovna , Nerodo Galina , Mordan Anna Iurievna
Published: March 2020

e16558

Background: A ploidy of an average grade of aneuploidy cells and of proliferation index in ovarian tumor was studied. Methods: 21 patients with ovarian cancer of III-IV grades and 12 patients with acknowledged relapse of the disease aged from 46 to 67 to part in the research. We used CycleTEST PLUS DNA Reagent Kit (Becton Dickinson) for the analysis of DNA in the tumor’s tissues. Preparation of the tumor’s tissues was made with the use of disaggregating device BD Medimachine; after painting with propidium iodide (PI) we analyzed at flow cytofluorimeter BD Facs CantooII. Received data was processed with the help of computer program ModFit LT, allowing to analyze the ploidy and distribution of tumor’s cells according to phases of cellular cycle. Results: There was revealed the 2.5 times predominance of aneuploidy tumors over diploid in case of the relapse of the disease. The DNA index, different from 1.0, was registered in 83.3%, whereas there was noticed 33.3% primary ovarian tumors with aneuploidy content of DNA with predominance of diploidy tumors. There was noticed a tendency to the increase of aneuploidy cells during the relapse of the disease, where they made up 42.7±1.8%, whereas in primary ovarian tumors the share of aneuploidy cells was 40.4±1.6%. The index of proliferation of relapsing tumors was 1.8 times higher than this index of primary tumors, and made up 35.5±2.9 and 26.7±2.1 (p < 0.05). Conclusions: During the relapse of a tumor there is a predominance of aneuploidy tumors over diploid, the index of proliferation is higher in comparison with primary tumors.
Malignant sinonasal tumors in Stockholm, 2000-2005.
Authors: Jangard Mattias
Published: March 2020

e17001

Background: Between2000-2005 58 patients developed malignant sinonasal tumours in the region of Stockholm that consist of 2.5 million people. Sinonasal malignant tumours are uncommon and account for approximately 3% to 5% of all upper respiratory tract malignancies and 0.2% of all malignancies. Because these tumours are rare and the treatment varies internationally and also in different parts of Sweden; our aim was to follow up these patients to get a better picture of this group and also find out which treatment modalities that had the best outcome. Methods: All the patients have been identified through a database that register all new malignant head and neck tumours in Stockholm. We identified the patients from 2000-2005 and studied all the medical charts for the patients. Results: 10-15 patients develop malignant sinonasal tumour per year in the region of Stockholm. The mean age at diagnosis was 67 year (21-95 year). The distribution between men and women where equal. We found that 50 % was squamous cell carcinoma, 20% was malignant melanoma, 10 % adenocarcinoma, 10 % SNUC (Sino Nasal Undifferentiated Carcinoma) and 10 % other tumours. The 3-year survival was 50 % between 2000-2005. The prognosis varies between differnet tumour types. Squamous cell cancer and adenocarcinoma has a better prognosis than malignant melanoma and SNUC. Conclusions: This study brings light to the distribution of the different tumour types and also we found that malignant melanoma has a tendency to increase if you compare to a study from Sweden 2003. We were not able to analyse which treatment modality to prefer in this study due to short follow up and a small material.
Investigating an orally available small-molecule inhibitor (vemurafenib) of BRAFV600E in a novel preclinical model of human papillary thyroid cancer.
Authors: Duquette Mark , Sadow Peter M. , Priolo Carmen , Fischer Andrew , Hodin Richard , Parangi Sareh , Lawler Jack , Nucera Carmelo
Published: March 2020

e17014

Background: Patients with BRAFV600E-positive human papillary thyroid cancer (PTC) have poorer prognosis, higher rates of metastases and mortality, and resistance to radioiodine treatment. The goal of this study was to assess the therapeutic efficacy of vemurafenib (a new orally available BRAFV600E selective inhibitor) in a translational therapeutic model of BRAFV600E human nonmetastatic or metastatic PTC. Methods: We have established in vitro cultures of human primary PTC cells with or without heterozygous BRAFWT/V600E, primary normal thyroid (NT) cells, and used previously established human PTC cell lines with BRAFV600E. Immunocytochemistry was used to characterize markers of differentiation. Genotyping (over 500 genes analyzed) by mass spectrometry was performed to determine genetic alterations. Cell viability assays were performed upon different concentrations of vemurafenib: 0.01, 0.1, 1, 5, and 10 µM. Phosphorylation (p) of ERK1/2 (downstream BRAFV600E) was used to measure BRAFV600E activity. Results: We have isolated 8 independent batches of primary human non-metastatic or metastatic PTC cells from total thyroidectomy patients with PTC >1.1 cm, and 4 independent batches of primary NT cells from normal matched thyroid tissue specimens. 62.5% of the isolated batches of PTC cells were heterozygous BRAFWT/V600E and expressed epithelial markers and thyroid differentiation markers (e.g. PAX8, TSH-receptor). The NT cells showed no mutations. BRAFWT/V600E nonmetastatic PTC cells showed decreased viability (IC50: 5 µM) and pERK1/2 levels (IC90: 10 µM) when exposed to vemarufenib, with no toxic effects. PTC cells with BRAFWT, or NT cells showed no change in viability and pERK1/2 levels when exposed to vemarufenib. Importantly, BRAFWT/V600E metastatic PTC cells showed a partial suppression of viability and inhibition of pERK1/2 but only at a higher dose (10 µM) of vemurafenib. Conclusions: We have established the first translational therapeutic model of heterozygous BRAFWT/V600E-PTC. Testing of PTC samples for BRAFWT/V600E and testing in vitro will help predict therapeutic efficacy of Vemurafenib in patients with BRAFWT/V600E-PTC.
A phase IB trial of 5-azacitidine (5AC) and suberoylanilide hydroxamic acid (SAHA) in patients with metastatic or locally recurrent nasopharyngeal carcinoma (NPC) and NK-T cell lymphoma.
Authors: Hsieh Wen Son , Tan Eng Huat , Lim Wan-Teck , Soo Ross A. , Chan Anthony T. C. , Hui Edwin P. , Lee Soo-Chin , Low John Soon Wah , Lim Pei Li , Loh Thomas Kwok Seng , Ames Matthew M. , Reid Joel M. , Murray Paul Gerard , Tao Qian , Goh Boon C. , Ambinder Richard F.
Published: March 2020

e17017

Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/m2 and SAHA 100 mg b.i.d (dose level 3). Median number of previous treatment regimens was 3 (R:1-6). Dose limiting toxicities (DLT) were seen in 2/2 pts at dose level 1: grade 4 thrombocytopenia (1 pt), grade 3 nausea, vomiting and fatigue (2 pts), and grade 5 hepatic failure (1 pt). Two of six patients at dose level 2 experienced DLT: grade 3 fatigue (1 pt) and worsening of pre-existing Sweet’s Syndrome (1 pt). Common AEs (G1/2) included fatigue (73%), cough (64%), anorexia (55%), and injection site reaction (45%). One minor response was seen and 5 pt had prolonged stable disease (>16 weeks), including one patient for 88 weeks. Analysis of post-treatment tumor biopsies showed demethylation of EBV lytic cycle gene promoters after treatment. SAHA PK, IHC results for EBV gene expression in tumor tissue, EBV viral load and characterization of circulating EBV will be presented. Conclusions: 5AC/SAHA appears to be tolerable at dose level 3 with suggestion of clinical benefit. Analysis of post-treatment tumor and blood samples suggests that modulation of EBV gene expression may play a role in the mechanism underlying clinical benefit. Continued accrual at dose level 3 is ongoing. Clinical trial information: NCT00336063.
Acute toxicity of neoadjuvant chemotherapy in oral cavity cancers: Can it be predicted?
Authors: Poladia Bhavesh , Patil Vijay , Noronha Vanita , Joshi Amit , Bhosale Bharatsinha Baburao , Punatar Sachin , Sharama Vibhor , Prabhash Kumar
Published: March 2020

e17027

Background: Neoadjuvant chemotherapy administration is associated with significant amount of morbidity and around 2-3% mortality in the Western world protocol settings. In developing countries where malnourishment is prevalent, the same data might not apply. Methods: This analysis was performed on a database of patients undergoing NACT for oral cancers at our center from 2010- 2012. The toxicity was graded according to CTCAE version 4.02 scale. Descriptive analysis, univariate and multivariate analysis were performed to determine factors affecting toxicity. Results: There were 528 patients, the median age was 45 years (22-78 years). The regimens administered were TPF in 35 patients (6.6%) and taxane with platinum in the rest. At least one cycle of chemotherapy was taken at our center by 94.8% (494). The median number of cycles were 2. The any grade toxicity after 1st cycle of chemotherapy were vomiting, diarrhea, mucositis, fatigue, febrile neutropenia (FN), peripheral neuropathy, hyponatremia, hypokalemia, hperkalemia, transaminitis were in 41.3% (204), 43.9% (217), 44.3% (219), 47.2% (233), 7.2% (35), 3.0% (15), 33.8% (167), 14.4% (71), 4.9% (24) and 12.3% (61).Toxicity details of second cycle of chemotherapy were available for 390 patients. The any grade toxicity after 2nd cycle of chemotherapy were vomiting, diarrhea, mucositis, fatigue, febrile neutropenia, peripheral neuropathy, hyponatremia, hypokalemia, hyperkalemia, transaminitis were in 28.6% (113), 37.3% (108), 31.3% (124), 39.3% (116), 3.1 % (12), 3.2% (13), 19.7 % (74), 7.4% (30), 3.1% (12) and 4.9% (19). For diarrhoea, female sex, nutrition (BMI below 18.5 KG/m2) and use of 3 drug regimen were predictive. For development of mucositis only nutrition was predictive. Use of 3 drug regimen and overnourishment were predictive of FN. Use of 3 drug regimen and use of docetaxel were predictive for hyponatremia. On multivariate analysis for diarrhoea only nutrition was predictive (p=0.017), for FN both drug regimen (p=0.003) and over nutrition (p=0.035) were predictive and for hyponatremia only use of 3 drug regimen was significant (p=0.017). Conclusions: 3 drug regimen, malnourishment and use of docetaxel are important predictors of acute toxicity associated with NACT in oral cancers.
Highly sensitive C reactive protein (hsCRP) as a surrogate marker of head and neck cancer.
Authors: Lakshmangowda Preethi Bangalore , K Adarsh , Ponni T.R Arul
Published: March 2020

e17034

Background: High-sensitivity C-reactive protein (hsCRP) an acute phase inflamatory reactant protein, has been used to predict the risk of cardiovascular disease healthy individuals and to monitor treatment responses. Epidemiological evidence also points to link between inflammation and development of cancer, i.e. long-term inflammation and dysplasia. Worldwide ~ 15 % of the cancer incidence is associated with microbial infection. NSAIDs have been used for cancer preventionin familial adenomatous polyposis. The objective of study is to evaluate the association between hs-CRP and head and neck cancer (SCCHN). Methods: Prospective, cross sectional case-control study was under taken involving 36 SCCHN (cases) and 36 normal volunteers age matched (controls). Cases staged as per UICC TNM. The study subjects 4ml clotted blood, centrifuged, serum stored at -20°C. hsCRP (mg/L) determined using Quantitative Immunoturbidimetric method. Statistical analysis was performed using SPSS. Results: Evaluable subjects = 72, Cases (Cancer patients) = 36 & Control = 36. Age group range 18 to 80 yrs. Mean Age Cases 59.5+9.9 v/s Control 59+96. M: F Cases- 25:9 v/s Control 27:9. In Cases Oral Ca – 22(61.1%) & Oropharynx - 14 (38.9%).T4 – 20(55.6%), T3-8(22.2%) & T2-8(22.2%). N3-3(8.3%), N2-14(38.9%), N1-5(13.9%) & N0-14(38.9%). The hsCRP of Control group v/s Cancer Case group = 3.03 ± 2.61 v/s19.23 ± 19.003 respectively (P < 0.0001). hsCRP for Oral Cancer – 15.07+7.66 & OPX – 25.77+28.31. In the case group, the mean hsCRP levels with tumor size T2 was 119.36 ± 7.0, T3 was 21.32 ± 23.27 , T4 was 18.3350 ± 21.0915 and with Node size N0- 20.3 ± 35.07, N1- 13.8 ± 5.37, N2 -21.6 ± 25.022, N3 - 122.1 ± 1.7. Conclusions: Inflammatory responses play decisive roles at different stages of tumor development, initiation, promotion, malignant conversion, invasion, and metastasis. This study shows serum hsCRP levels were significantly elevated in SCCHN cases compared to age matched normal control subjects. hsCRP Can be used as a surrogate marker of SCCHN. Measuring and charting hsCRP values can prove useful in determining disease progress or the effectiveness of treatments, Furthers studies are contemplated.
A discrete choice experiment to examine preferences and willingness to pay for prophylactic granulocyte colony-stimulating factors (G-CSF) in previously treated breast cancer patients.
Authors: Johnson Phaedra , Bancroft Tim , Barron Richard L. , Legg Jason C. , Li Xiaoyan , Watson Holly , Naeim Arash , Marshall Deborah
Published: March 2020

e17509

Background: As patient-centered care becomes more prominent, a better understanding of patient preferences and tradeoffs amongst treatment alternatives and outcomes is needed. This study used a discrete choice experiment to examine the preferences and willingness to pay for prophylactic G-CSF to decrease the incidence of chemotherapy (CT)-induced febrile neutropenia in breast cancer patients who previously received CT. Methods: An online survey was developed with 16 paired treatment choice scenarios comparing 3 alternative G-CSF options (11 versus 1 or 6 versus 1 injections per CT cycle) with a follow-up “no treatment” option. Each scenario had 4 attributes: risk of disruption to CT schedule due to neutropenia, risk of infection requiring hospitalization, frequency of G-CSF administration, and total out-of-pocket (OOP) cost for G-CSF during a CT cycle. Patients’ preferences and willingness to pay (as OOP cost) were estimated using logistic regression. Results: Patients’ (n = 296) preferred G-CSF options with the lowest OOP costs, the fewest injections, and improved outcomes (lowest risk of disruption to CT schedule and lowest risk of infection requiring hospitalization). In the context of this discrete choice experiment, OOP costs and risk of disruption to CT schedule were the most important attributes to patients; risk of infection requiring hospitalization and frequency of G-CSF administration affected patients’ choice of G-CSF option to a smaller but similar degree. Patients were willing to pay OOP $1,076 per cycle to reduce the risk of disrupting the CT schedule from high to low, $884 per cycle to reduce the risk of developing an infection requiring hospitalization from 24% (high) to 7% (low), and $851 and $667 per cycle to decrease the number of G-CSF injections per cycle from 11 to 1 and 6 to 1, respectively. Conclusions: With a current focus on patient-centered approaches in decision-making, physicians need to consider patient preferences when making decisions about therapy, including supportive care agents.
Prevalence, risk factors, treatment and outcomes of catheter-related thrombosis in patients with malignancies.
Authors: Cote Julie , Dumas Olivier , Demers Christine , Lemieux Julie
Published: March 2020

e17517

Background: Tunnelled catheters (Leonard, BARD) and peripherally inserted central catheters (Piccline, BARD) are used for intravenous therapies in patients with malignancies. Thrombosis is a well known complication, but risk factors are not clearly established. The objective the incidence, risk factors, therapeutic approaches and complications of catheter-related thrombosis among patients with malignancies. Methods: Medical charts of patients with malignancies and Leonard or Piccline inserted, from August 2002 to December 2006 at Hôpital de l’Enfant-Jésus (Québec City, Canada), were retrospectively reviewed. Results: A total of 618 catheters were inserted in 361 patients. Eighty-six percent of the catheters were placed in patients with hematologic malignancies and most were Piccline (70%). Sixty-one thromboses were identified (incidence of 10%). Fourteen percent of the patients had more than one episode of catheter-related thrombosis. The majority of thromboses was related to a Piccline (93%) and occurred at a mean time of 34 days after the insertion. At the time of thrombosis, the mean platelet count was 169 x 109/L. Previous history of a catheter-related thrombosis (OR = 4.30 (1.48-12.50); p = 0.0075) as well as lymphoma (OR = 3.29 (1.22-8.87); p = 0.0185) were associated with superficial thromboses. The Piccline was associated with both types of thromboses (OR = 5.78 (1.69-19.74); p = 0.0051), especially with superficial thromboses. Most of the catheters (88%) were removed once a thrombosis was identified. The management of anticoagulation varied considerably. No complication associated with thromboses was reported. Conclusions: The incidence of central venous catheter-related thrombosis was 10%. The thrombosis occurred on average 34 days after the insertion. The Piccline was associated with all types of thromboses, especially the superficial ones. A previous history of catheter-related thrombosis and lymphoma were risk factors for superficial thromboses. Further studies are necessary to better define characteristics and optimal management of central catheter-related thrombosis.
Awareness and attitude of cancer patients about participation in clinical research (CR) in Saudi Arabia.
Authors: Sheblaq Nagham Ramzi , Traifi Sara , Al Sakiani Moahmmed , Gasmelseed Ahmed , Abolfotouh Mostafa A , Jazieh Abdul Rahman
Published: March 2020

e17528

Background: Enrollment of patients in CR may be impacted by their levels of awareness and attitude toward participation. Our study aims at assessing the awareness and willingness to participate in CR and identifying the barriers and influencing factors for participation. Methods: A cross-sectional study was performed using an interview-based questionnaire composed of close-ended questions conducted by trained research coordinators. Descriptive statistics, univariate and multivariate analyses were applied. Results: A total of 300 patients were enrolled in the study with a median age of 53.6 (42.2 - 64.0), and 188 patients (62.67%) were females. The majority of patients 289 (97.31%) were not aware of what is institutional review board. On the other hand, 226 (75.33%) showed interest in CR participation, if offered. The trust in treating physician (88.33 %) and the belief that participation in CR offers a better chance of cure (73.14%) were the two most important influencing factors to participate, while the preference of receiving standard treatment (43.13%) and the unknown efficacy of treatment (40.32%) were the top two barriers to participate. In univarate analyses, patients younger than 45 years (p<0.015) and those with higher education (more than middle school) (p<0.022) were significantly more interested in CR participation. However; in a multivariate analysis, higher education was the only significant predictor of interest to participate (p<0.023). Conclusions: There is an apparent gap in cancer patients’ awareness about CR. However, there is an obvious interest in participation in CR especially in patients with higher education level. Enhancing public awareness is crucial to improve CR participation.
Insufficient involvement of the family physician (FP) in the care of chemotherapy-treated cancer patients: A barrier to comprehensive medical care.
Authors: Ben-Ami Eytan , Merom Hadar , Sikron Fabienne , Livneh Jessica , Sadetzki Siegal , Wolf Ido
Published: March 2020

e17536

Background: Following advancement in the oncology field, increasing numbers of patients are receiving ambulatory active treatment for prolonged periods of time. Many of these patients suffer from additional comorbidities and require comprehensive medical care. We aimed to assess the perception of cancer patients regarding the role of the FP and the oncologist in their care during times of active cancer treatment. Methods: A survey was conducted among 265 consecutive chemotherapy-treated patients at the day care clinic of the Oncology Institute at Sheba Medical Center in Israel. Results: Median age was 60 years (range 22-86), 184 (69%) were woman and 147 (55%) were Israeli born. All patients belonged to one of four Israeli HMOs, 96% had a regular FP and 70% met with him during the prior month. While 78% of the patients evaluated that their FP had sufficient time to devote to them, only 32% and 27% thought their FP was trained to or wished to treat medical problems occurring while receiving chemotherapy. Yet, a majority of patients (76%) stated that involvement of the FP is important to them. Surprisingly, 85% perceived the oncologist as having enough time to devote to their care and 60% perceived him as being capable of dealing with non-oncological problems. However, only 30% stated that the oncologist communicates with the FP. Accordingly, 72% of the patients stated that in the case of an urgent problem they will turn first to the oncology institute and only 9% will turn to their FP. Indeed, 46% had unscheduled visits to the day care facilities during the prior month. Conclusions: Our data indicate lack communication between team members and inadequate medical training as major barriers for comprehensive medical care for chemotherapy-treated cancer patients. This may adversely affect medical care, decrease satisfaction among physicians and increase unnecessary workload. A change of the current situation requires collaboration between FPs and oncologists at the local and national levels and should include standardization of communication measures as well as implementation of required aspects in educational programs of both specialties.
The economic assessment of eribulin compared to treatment of physician's choice (TPC) in Australia.
Authors: Jones Trefor , Simons W. Robert
Published: March 2020

e17552

Background: The Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE) established clinical benefits. This study evaluates its translation into comparative economic value. Methods: Because of superior survival benefits and a non-inferior safety profile, we use a cost-effectiveness analysis. Costs include medication and administration costs, cost of toxicity management, and indirect cost. The primary endpoint is the ratio of incremental means of costs and quality adjusted life years (QALY) yielding an incremental cost effectiveness ratio (ICER). Partitioned survival analyses were evaluated using a log-logistic function for overall survival, progression free survival, response duration, and toxicity time. Health state utilities or quality weights are applied to each component and aggregated. Sensitivity analyses assessed the influence of variability in a number of parameters. Results: Overall survival based on the log-logistic extrapolation was 686 days in the eribulin group compared to 550 days in the TPC group for a difference of 136 days. Mean time without progressive disease was 214 days and 160 days, respectively, for a difference of 59 days. Time spent with Grade 3 and 4 toxicity were 3.62 and 2.25 days in the eribulin group versus 2.25 and 0.98 days in the TPC group. Response times were 15.62 and 9.64 days, 5.98 days longer in the eribulin group. After weight components of overall survival with corresponding utilities and converting to years, the QALY were 1.166 in the eribulin group compared to 0.926 in the TPC group for a mean incremental improvement of 0.24 years. Mean treatment costs were $14,302.80 AUD and $1,672.02 AUD for a difference of $12,630.78 AUD. Total incremental cost is $13,794.35 AUD. The ICER with and without discounting is $48,134.29 AUD and $45,770.97 AUD, respectively. Survival time and drug cost were the most influential variables on the ICER. Conclusions: At a threshold of $50,000 AUD per QALY, eribulin is good value at $48,134 AUD per QALY. Clinical trial information: NCT00388726.