bluuebunny/crossref_metadata_2025 huggingface dataset:
Malignant hemangiopericytoma: A study of long-term outcomes
Authors: Yadav S. K. , Dwernychuk L. , Yadav A. S. , Alvi R. , Ahmad I. , Ahmed S. , Haider K. , Sami A.
Published: March 2020

9560

Background: Malignant hemangiopericytoma (MH) is a rare disease with limited data on long term clinical outcomes. We presented a poster at ASCO 2005 annual meeting, outlining the long term follow up of 14 patients. We reviewed the data from 10 additional patients from our affiliated center and present here a combined analysis. Methods: Clinical characteristics, pathologic and treatment data of 24 patients diagnosed with MH between 1972 and 1995 was reviewed. All cases were histologically proven. Survival was determined by using Kaplan-Meier curve. Results: The median age was 52 yrs. (range 28 - 74). Male: female ratio was 1: 2.4. Patients presented with involvement of following primary sites: cranial/meningeal 8 (33.34%), extremities 4 (16.7%), uterus 3 (12.5%), metastatic 2 (8.3%), retroperitoneal 2 (8.3%), pelvis 2 (8.3%), sinonasal, middle ear and thyroid 1 each (4.2% each). 20 patients had definitive surgical resection at initial presentation. 4 patients received post operative radiation therapy (RT). No patient received adjuvant chemotherapy. 7 out of 8 patients who recurred died of disease. One patient who was alive 5 years after recurrence got stereotactic RT to localized recurrence. At disease recurrence, 2 patients received chemotherapy and RT, while 5 were treated with surgery and/or RT. 4 out of 8 patients with cranial/meningeal disease at diagnosis recurred. Two of them recurred after 6 years. Only one of the 4 recurred patients had post operative adjuvant RT. Median recurrence free survival was 5.25 years. Median survival after recurrence was 3.28 years. Fourteen year cause specific survival was 55%. Conclusions: Combined analysis of 24 patients shows that complete surgical resection is the main treatment with 55% of patients living at 14 years (median is not reached). Compared to our prior report, female preponderance was less marked. Radiation may play some part in adjuvant setting, but its role is not clearly defined. Role of systemic treatment is not clear. In our series 40% recurred after definitive treatment. Recurrences can occur several years after the initial diagnosis and definitive treatment. There is a need to develop effective adjuvant systemic treatments.

No significant financial relationships to disclose.
Chemo-response biomarker discovery via expression profiling using soft-tissue sarcoma xenografts
Authors: Bruheim S. , Xi Y. , Ju J. , Fodstad O.
Published: March 2020

9569

Background: Soft-tissue sarcoma (STS) constitute a heterogeneous group of tumours of mesenchymal origin. Whereas the mainstay of treatment has been surgery and radiation, these tumours are generally considered as quite chemoresistant. However, it is well known that subgroups of patients benefit from chemotherapy. Markers that could predict drug response would therefore be beneficial for the management of this malignancy. We have previously established panel of 17 unique human soft tissue xenografts, representing 7 different histological subgroups and assessed their responsiveness to doxorubicin, ifosfamide, etoposide, and cisplatin. We wanted to utilize these xenografts as a model system to discover for novel candidate marker genes for STS chemo-response. Methods: GE Uniset Human 20K microarrays were used to obtain gene expression profiles from the each xenografts. One-way ANOVA test with a Benjamini-Hochberg multiple test correction allowing a false discovery rate of 5% was used to identify genes with significantly differential expression. Results: Doxorubicin, ifosfamide, etoposide and cisplatin were efficient in 6/17, 10/17, 1/17 and 7/17 xenografts respectively. However, in the expression profiles obtained none of the genes showed significantly correlation with chemo-responsiveness to any of the drugs. Two of the xenografts, TAX 1 and TAX 2, both originate from a malignant fibrous histiocytoma (MFH) in the same patient, but show strikingly different sensitivity to ifosfamide (TAX1 resistant, TAX2 sensitive). When triplicate hybridizations of TAX1 and 2 were compared, 294 genes met the above criteria. In addition we identified a subset of 122 genes that were flagged absent in one of the specimens, present in the other. Among genes with an already described role in mediating drug resistance are GST-pi and glutathione peroxidase. Taken together, these results indicate that discovery of general response markers in STSs may be difficult due to the heterogeneity of the different subgroups constituting this malignancy. Conclusions: Gene expression profiling of the TAX 1 and TAX 2 xenografts revealed a number of interesting candidate marker genes for ifosfamide sensitivity of MFH. This list of genes will be further refined by validation in clinical samples.

No significant financial relationships to disclose.
Phase II trial of temozolomide as first-line treatment for patients with advanced gynecological sarcoma: A Spanish Group for Research on Sarcomas (GEIS) and Spanish Ovarian Cancer Research Group (GEICO) study
Authors: Garcia Del Muro X. , Poveda A. , Buesa J. M. , Martinez Trufero J. , De Sande L. M. , Calvo E. , Escudero P. , Lopez Pousa A. , Fabregat X. , Casado A.
Published: March 2020

9570

Background: Temozolomide (TMZ) as an extended schedule showed activity in the subgroup of patients (pts) with pretreated gynecological sarcoma (GS) in a prior phase II study (Cancer 2005;104:1706) as well as in a series of GS pts treated in a compassionate use program (Proc ASCO 2005;9030). The purpose of the present study was to assess the activity of TMZ as first-line chemotherapy in pts with GS. Methods: Pts with non-previously treated advanced GS and non-irradiated measurable lesions were eligible for this phase II study. TMZ was administered orally at a dose of 75 mg/m2/day continuously for 6 weeks, every 9 weeks. The study was conducted using a Simon’s two-stage design. The initial planned sample size was 25, but after an amendment, this was increased to include 25 pts with leiomyosarcoma (LMS) histology. Primary endpoint was response rate (RECIST). Results: From October 02 to September 05, 33 pts were included at 16 centers. At present, 32 pts are evaluable (1 too early). Median age was 59 (39–75). Primary tumor sites were uterus (31) and ovary (2). Histologic types were: LMS (28), mixed mullerian tumor (3), endometrial stromal sarcoma (ESS) (2). Histologic grade: III:16, II:6, I:2, unknown:9 pts. PS: 0:12, 1:15, 2:6 pts. A total of 57 cycles were administered (median 2, range 1–3). Toxicity (pts): thrombocytopenia G-IV:2, GIII:1; neutropenia G-IV:1; nausea G-III:2, G-II:5; vomiting G-III:2, G-II:6; stomatitis G-III:1, G-II:2; asthenia G-III:1, G II:5. There were 3 CR, 3 PR and 6 SD, giving an overall response rate of 19% (95% CI, 5–32%). Responses were seen in LMS (5) and ESS (1) and lasted 4+, 6, 7+, 7+, 9+ and 17+ months. Median time to progression was 3.3 months (95% CI, 1.7–4.9). Conclusions: TMZ at this extended schedule was active against GS, producing in some pts long-lasting responses, and might be a well-tolerated alternative in selected pts, warranting further investigation.

No significant financial relationships to disclose.
Gene expression identifies heterogeneity of soft tissue sarcomas
Authors: Skubitz K. M. , Pambuccian S. , Skubitz A. P.
Published: March 2020

9574

Background: Soft tissue sarcomas (STS) exhibit heterogeneity in their clinical behavior, even within histological subtypes. Histological appearance is determined by gene expression. However, metastatic propensity, tumor growth, and response to chemotherapy may be determined by gene expression patterns that do not correlate well with morphology. One approach to identify heterogeneity is to search for markers that correlate with differences in tumor behavior. Alternatively, subsets may be identified based on gene expression patterns independent of knowledge of clinical outcome. We have reported gene expression patterns that distinguish two broad classes of clear cell renal carcinoma (ccRCC) independent of histological appearance, and other patterns that can distinguish heterogeneity of serous ovarian carcinoma (OVCA). Methods: In this study, gene expression in 41 samples of STS (including malignant fibrous histiocytoma (MFH), leiomyosarcoma, liposarcoma, and synovial sarcoma), 12 samples of fibromatosis, and 17 normal tissues was determined at Gene Logic Inc. (Gaithersburg, MD) using Affymetrix GeneChip U_133 arrays containing approximately 40,000 genes/ESTs. Gene expression analysis was performed with the Gene Logic Genesis Enterprise System Software. Results: Hierarchical clustering using two gene sets, one that distinguished two subsets of ccRCC, and a second set that distinguished two subsets of OVCA, both generated subgroups within the STS that for some, but not all, subtypes correlated with histology, and also suggested the existence of subsets of MFH. Both gene sets also identified the same two subsets of the fibromatosis samples. In addition, genes expressed uniquely in MFH, leiomyosarcomas, and liposarcomas among these and 512 samples from 17 other normal tissue types were identified. Conclusions: The ability to sub-classify histological subtypes of STS, including identifying possible subsets of MFH, using gene sets derived from studies of two different carcinomas suggests that these subgroups may have biological significance. Some of the genes identified as over-expressed in particular subsets of STS compared with a variety of normal tissues may reflect possible targets to which anti-tumor therapy could be directed, and may also be useful for sub-classification of STS.

No significant financial relationships to disclose.
Phase 3 study of atamestane + toremifene vs. letrozole in advanced breast cancer
Authors: Goss P. E. , Bondarenko I. N. , Manikhas G. N. , Pendergrass K. B. , Miller W. H. , Blanchett D. , Lang W. , Langecker P.
Published: March 2020

LBA525

Background: This study addresses the principle of “complete estrogen blockade” by combining atamestane, an investigational steroidal aromatase inhibitor (AI) with toremifene, an approved first line therapy. The primary objective was to assess whether atamestane + toremifene could improve on the time to disease progression achieved with letrozole alone. Methods: This was a multinational randomized, double blind, double dummy phase 3 clinical trial. Eligible women were postmenopausal with advanced breast cancer (ABC), estrogen and/or progesterone receptor positive. Prior adjuvant hormonal therapy was permitted only if completed >12 months prior to enrollment. Subjects received either atamestane 500 mg per day with toremifene 60 mg per day (A+T), or letrozole 2.5 mg per day (L). The primary endpoint was time to progression (TTP), log-rank test comparison on all randomized patients. Secondary objectives included objective response (OR), overall survival, and time to treatment failure (TTF). The study had 80% power to detect a 25% increase in TTP assuming a TTP of 9.4 months in the L population. Results: 865 patients with locally advanced (9%) or metastatic disease (91%) were randomized: 434 to A+T and 431 to L. Baseline characteristics were: mean age 64 years (S.D. = 9); ECOG Status 0 = 30%, 1 = 60%, 2 = 10%; prior adjuvant hormonal therapy 13%; prior adjuvant chemotherapy 20%. Sites of metastases and number of sites were well balanced between arms. The median TTP was identical in the two arms: 11.2 months (p < .92, log-rank chi square). The hazard ratio (L/A+T) for TTP was 1.00 (0.92–1.08, Cox proportional hazards 95% CI); for TTF was 0.99 (0.92–1.06) and for overall survival was 0.98 (0.87–1.11). OR occurred in 30% of patients on A+T and 36% of patients on L (p < 0.1, likelihood ratio chi square). Most frequent AEs (A+T vs L) were asthenia (11% vs 12%), increased weight (12% vs 10%), and hot flushes (10% vs 11%). Serious AEs were 10% vs 11%. Conclusions: While our study did not demonstrate increased TTP for A+T compared with L, this is the first endocrine therapy to be equally effective as letrozole as first line therapy in ABC. Both treatments were equally well tolerated. Unlike the ATAC trial, addition of an anti-estrogen did not decrease the efficacy of the AI. Further study of combination AI + SERM is warranted.

[Table: see text]
SWOG 0012, a randomized phase III comparison of standard doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T) versus weekly doxorubicin and daily oral cyclophosphamide plus G-CSF (G) followed by weekly paclitaxel as neoadjuvant therapy for inflammatory and locally advanced breast cancer
Authors: Ellis G. K. , Barlow W. E. , Russell C. A. , Royce M. E. , Perez E. A. , Livingston R. B.
Published: March 2020

LBA537

Background: Between 10-1-02 and 12-01-05, SWOG 0012 accrued patients to a two-arm randomized trial, with formal participation from NCCTG and CTSU participation by other cooperative groups. Arm 1 gave A at 60 mg/m2 and C at 600 mg/m2 q 3 wk IV for 5 cycles, arm 2 A at 24 mg/m2/wk × 15 IV and C at 60 mg/m2/day PO for 15 wk with G at 5 mcg/kg/day × 6/7 weekly. Both groups then received T at 80 mg/m2/wk × 12, and proceeded to surgery with pCR by NSABP criteria at the primary site as the endpoint. A total of 372 were randomized, and we report here on 265 patients (pts) evaluable for outcome, including those who did not proceed to surgery. In arm 1, pCR was seen in 17% vs 27% in arm 2 (p = .06); when adjusted for hormone receptor status (ER-PR- in 49% on arm 1, 41% on arm 2) and disease type (locally advanced vs inflammatory), the odds ratio in favor of arm 2 is 1.98 (95% CI 1.05–3.74, p = .034). For ER- PR- pts, pCR rates for Arm 1 vs 2 were 26 vs 43%, while for those with ER or PR+, pCR rates were 9 vs 14%. Inflammatory pts showed a striking difference in pCR rates for arm 1 vs arm 2 (12 vs 33%, p = .033). HER 2 status (+ in 29%) did not predict response or interact with treatment. Grade 3/4 toxicities (arm 1 vs 2, %) were as follows: hand-foot syndrome (0 vs 13), neutropenia (47 vs 16), neutropenic infection (1.8 vs 0.6), stomatitis (2 vs 11), and nausea/vomiting (11 vs 5). Toxicity from T was grade 3 neuropathy in 10%, with grade 3 or 4 neutropenia in 12%. There were no treatment-related deaths. Continuous or “metronomic” chemotherapy with AC is superior to standard intermittent AC, and the pCR rate reported for the continuous arm is the highest reported in a cooperative group experience for this patient population.

[Table: see text]
In vivo proton magnetic resonance spectroscopic (PMRS) evaluation: Emerging tool to solve the diagnostic dilemma in soft tissue sarcoma management
Authors: Kar M. , Deo S. S. , Kumar V. , Sharma U. , Jagannathan N. R. , Dannishad K. A. , Deo V. , Shukla N. K. , Datta Gupta S. , Thulkar S.
Published: March 2020

10020

Objective: Presently grade is the most important factor used to decide the soft tissue sarcoma management. But it is always very difficult to assign a pathologic grade because of discordance rate is 30–40%, even among experienced sarcoma oncopathologists. Again histopathology has the disadvantages of being invasive, subjective and insensitive to tumour heterogeneity. This emphasizes the need for an objective and accurate assessment of histologic type and grade of sarcoma. The aim of this study is to evaluate the correlation of in vivo proton magnetic resonance spectroscopic findings with histopathological features and validate its diagnostic efficacy in management of different types of soft tissue sarcomas. Methods: PMRS Study was performed at 1.5Tesla MRI machine with a surface coil appropriate for the location of the lesions in 25 patients. Single-voxel (SVS) study has been done in 10 cases and chemical shift imaging (CSI) study characterised the heterogeneity of the tumor in 15 cases by using point - resolved spectroscopic sequence (PRESS) with echo time TR=2,000 / TE = 30, 135 & 270 msec. The choline peak, identified at 3.2 ppm in spectra was considered as significant which shows the activity of the tumour. MRS results and histopathologic findings were correlated and P < 0.001, considered being significant. Results: Choline peak was found in 17 out of 17 patients with malignant soft tissue tumours where as three patient with benign and five treated malignant soft tissue tumour patients with no residual disease did not show any choline. In vivo spectroscopy here shows sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 100% each. Conclusion: Choline peak in MRS study can predict the grade, margin status (especially CSI) and tumour activity in recurrent and / or residual soft tissue sarcoma. Most important findings here was that without using any contrast medium in study the choline peak in CSI spectroscopic evaluation could show the tumor activity at the margin of the tumor which is very important point for evaluation of residual or recurrent or completion of the surgical excision of the tumor A major study should be done to validate its efficacy for routine use in oncology.

[Table: see text]
Female patients with soft tissue sarcoma are at a higher risk for developing breast cancer
Authors: Jiveliouk I. , Geva R. , Inbar M. , Merimsky O.
Published: March 2020

10071

Background: An increased incidence of MPM has been reported in association with STS. In a series of 1350 adults with STS almost 10% were diagnosed with additional primaries. The incidence of breast cancer (BC) in the general population is 97/105,(Israel-Cancer-Registry) and the incidence of STS is 1.5/105 (Enzinger&Weiss). It is expected that approx. 1.5/105 × 97/105 of the general population will have both BC and STS. Methods: A retrospective search of the database of approx. 1,350 adult STS patients, who were referred, diagnosed, or treated at our center between 1995- 2005. Results: A group of 132 patients (F=62) with STS had at least one additional malignancy. Twenty-five (25/62=40%) had BC, before or after STS. A family history of malignancy was reported by 8/25 patients (32%), 3 with a specific breast cancer family history. STS types varied. Sixteen (16/25) patients had breast cancer as their first primary, 9 as their second or third. Of 17 patients with first primary BC, the sarcoma appeared in the RT field in 2, and in 1 it appeared in a lymphedematous ipsilateral arm. Of eight patients with first primary sarcoma, only one got chemotherapy prior to the diagnosis of BC. Median interval between 1st to 2nd malignancy was 6.9 years (0.7–31y) when the BC was diagnosed first, and 3.8y (0–47y) when the BC was the second. Exposure to carcinogens, or therapeutic radiation and cytotoxics, given for the 1st tumor prior to the 2nd tumor, was recorded in 58%. The incidence of BC among all patients (females + males) with STS-first (in our database) followed by a second malignancy is 8/58 (14%), or 7/23 (30%) female patients with STS-first, or 25/890 (3%) of all female patients with STS in the registry of STS. The incidence of STS among the BC patients is rather low, and most of the cases in this series are not therapy related (14/17). The median survival of patients with BC-first was 312 months, versus 383 months for STS-first (p=NS). Among patients with BC-first, the median survival of patients with RT related sarcoma was 265 months, versus 312 months for RT unrelated STS (p= 0.6). Conclusions: Second primary BC in patients with STS-first is higher than the expected incidence of BC for this population. Screening for BC should be incorporated into the regular follow-up of patients with STS.

No significant financial relationships to disclose.
Hypoxia-inducible-factor 2 alpha mediates cisplatin resistance in the lung adenocarcinoma cell line A549
Authors: Rose F. , Eul B. , Kwapiszewska G. , Marsh L. , Kamlah F. , Seeger W. , Grimminger F. , Lohmeyer J. , Haenze J.
Published: March 2020

10573

Background: Hypoxia in solid tumors is associated with cancer progression, metastasis and resistance to chemotherapy. The hypoxia inducible factors (HIF-1a and HIF-2a) are key players in the response to hypoxia affecting angiogenesis, proliferation and apoptosis. Here we investigated the role of HIF-1a and HIF-2a in cellular resistance to cisplatin in non small lung cancer cells (A549). Results: Hypoxia reduced the efficiency of cisplatin treatment on A549 cells via enhancement of drug efflux activity. In addition, hypoxia induced the hypoxia-responsive-element (HRE) reporter gene assay, demonstrating the transcriptional activity of HIF-1a and HIF-2a. Administration of cisplatin further increased the reporter activity under both normoxic and hypoxic conditions. This correlated with the induction of HIF-2a protein expression upon cisplatin treatment in normoxia and hypoxia, whereas HIF-1a was suppressed. Additionally, cisplatin induced nuclear accumulation of HIF-2a. Suppression of HIF-2a by RNA interference potentiated the sensitivity to cisplatin treatment in hypoxic A549 cells. In vivo growth delay assay gave analogues results for subcutaneous A549 tumors treated with cisplatin and suppression of HIF-2a. In comparison, other cytostatic drugs such as doxorubicin and gemcitabine differed with respect to HIF signalling. Doxorubicin induced both HIF-1a and HIF- 2a. Cellular sensitivity to doxorubicin was increased via suppression of HIF-1a and HIF-2a. Gemcitabine appeared to act independent of HIF. The underlying mechanism of hypoxia-induced resistance was due to increased mRNA expression of drug resistance proteins such as MDR1, MRP1 and LRP. These were found to be HIF-2a but not HIF-1a dependent. Conclusion: This data identified HIF-2a as a key player in the hypoxia induced cisplatin resistance and show on the molecular level that HIF-2a is a credible target for therapeutic strategies.

No significant financial relationships to disclose.
The impact of waist-to-hip ratio (WHR) on survival in metastatic breast cancer patients treated with aromatase inhibitors (AIs)
Authors: Artac M. , Samur M. , Bozcuk H. , Afacan B. , Ozdogan M.
Published: March 2020

1070

Background: Aromatase inhibitors represent a novel hormonal therapy for breast cancer. Aromatase is expressed in the ovaries, brain, bone and, adipose and breast tissue. Elevated WHR, representing a higher abdominal fat distribution, has been associated with both the development of and mortality from breast cancer. Therefore, we aimed to identify whether abdominal fat distribution could affect the outcome in metastatic breast cancer patients treated with AIs. Methods: A total of 46 metastatic breast cancer patients treated with first line hormonal therapy were enrolled in this study. Pretreatment body weight, height, BMI and WHR were measured. Estrogen, progesteron and c- erb-B2 receptor status were also evaluated in analyses. Univariate and multivariate Cox regression analyses, and Kaplan Meier survival curves subjected to log rank testing were utilized for the survival analyses. Forward likelihood ratio was used for the multivariate selection process. A P value < 0.05 was considered to be significant. Results: Median age was 51 years (range 28 - 75). 36 patients were treated with letrozole and 10 patients with anastrozole. Median body weight, height, WHR and BMI were found to be 68.5 kg (range 46 - 115), 156 cm (range 137 - 167), 0.91 (range 0.7 - 1.2), and 28.7 (range 18 - 45), respectively. Factors associated with overall survival in the univariate analysis were age, c-erb-B2 expression intensity (+++ versus others by immunohistochemistry), and WHR, whereas only WHR retained significance in the multivariate analysis. Likewise, predictors of progression free survival were c-erb-B2 expression intensity and WHR. However, none of these factors was significant in the multivariate analysis. Median overall survival figures were 472 days versus unreached for patients with a WHR of <0.92 and =0.92 (Log rank statistic = 9.76, P = 0.002). Similarly, the corresponding progression free survival figures for patients with a WHR of <0.92 and =0.92 were 423 versus 1,004 days (Log rank statistic = 6.37, P = 0.012). Conclusions: This is the first report examining and suggesting the value of abdominal fat distribution in relation with benefit from AIs in metastatic breast cancer. Our results should be validated in larger series.

No significant financial relationships to disclose.
Paradoxical effects of medical reassurance in patients with breast cancer
Authors: Shields C. G. , Corbin K. , Weiss M. , Lambert D. M. , Griggs J. J.
Published: March 2020

11018

Objective: The purpose of this study was to investigate the impact of medical reassurance on distress and fear of recurrence in women with ductal carcinoma in situ (DCIS) and early stage invasive breast cancer. Methods: We conducted an anonymous survey on the website of breastcancer.org, a non-profit organization. Recruitment to the survey was through a general invitation to “Tell us about your breast cancer experience.” The survey inquired about disease and treatment characteristics and contained the Positive and Negative Affect Scale (PANAS) and the Concerns about Recurrence Scale. Participants were also asked if they had been told by any of their medical providers that they had a “good cancer,” “favorable cancer,” or “better kind of cancer.” Analyses were performed to investigate the impact that being told one has or had a “good cancer” and feelings of reassurance, isolation, distress, and guilt. Results: A total of 362 participants with breast cancer completed the survey, 143 of whom had DCIS. Of these, 147 (41%) reported having been told that they had a “good cancer” by one or more of their medical providers, most often by their surgeon (83%) and/or their medical oncologist (61%). Among those told they had a good cancer, 67% reported that being told this led to their feeling moderately-to-extremely “reassured.” Many respondents, however, also reported moderate-to-severe negative responses to being told that they had a good or favorable cancer_feeling “isolated” (38%), “distressed” (43%), “scared” (61%), and “guilty” (30%). Conclusions: Although telling patients they have a “good” or “favorable” cancer leads to feelings of being reassured in the majority of women, such terms may also contribute to distress, feelings of isolation, and guilt among many patients who otherwise might enjoy a good prognosis quality of life. Providing reassurance is a complex process. Further research into effective ways of communicating reassurance is warranted in order to minimize distress and enhance quality of life.

No significant financial relationships to disclose.
Results of trastuzumab targeted therapy in metastatic breast cancer (MBC): The Sultanate of Oman experience 2002–2006
Authors: Khalifa A. , Faris M. , Al-Bahrani B.
Published: March 2020

11518

Background: The first random study of incidence of Her-2 over expression among Omani breast cancer patients was carried out by the Medical Oncology Department, the Royal Hospital in 2001. The incidence was reported as 40% (higher than international published figures). The Herceptest was routinely performed on all new patients for a whole year (2004) and the incidence was found to be 36%. Trastuzumab was approved for use in the Sultanate of Oman in 2002, since then a total of 26 patients with metastatic breast cancer received Trastuzumab, the results are presented. Methods: Prospective, single arm, single centre experience. Patients with confirmed metastatic breast cancer (at presentation or after adjuvant treatment), HER-2 positive (+++ by Herceptest, or FISH positive), age > 18, ECOG PS ≤ 2, LVEF = 50% and adequate renal & liver function, were included. Treatment consisted of trastuzumab as single agent or in combination with chemotherapy as indicated. A loading dose of 8mg/kg was followed by 6mg/kg q3 weeks. The endpoints were response rate (RR) progression free survival (PFS) and survival (OS). Results: a total of 26 patients were included between October 2002-October 2006, median age was 45.5years (27–60), 12 patients presented with metastasis at first presentation and 14 had metastatic disease 6 months or more after finishing adjuvant chemotherapy. The median number of received cycles was 10 (range 4–30), the overall response rate was 77% (54% CR and 23% PR), the median survival 15 months (range 4–36m), median Time to Progression 9m (range 4–33m). Six patients (23%) developed brain metastasis while on herceptin. There were 8 events (disease related deaths) during the study period. Conclusions: The incidence of Her-2 +ve breast cancer in Omani patients is slightly higher than the reported figures in international studies. The response to trastuzumab in metastatic disease is comparable to other similar studies.

No significant financial relationships to disclose.
Infectious complications associated with alemtuzumab treatment
Authors: Siddique S. A. , Fowler N. , Asatiani E. , Mavromatis B. , Cohen P. , Kessler C. M. , Cheson B. D.
Published: March 2020

13504

Introduction: We report our single institutional experience of ICs associated with alemtuzumab treatment. Methods: Patients (pts) who received alemtuzumab were identified by review of the GUH pharmacy database. All ICs occurring from initiation of alemtuzumab until death or end of follow up as of January 3, 2007 were reviewed and categorized as opportunistic (OI) or non- opportunistic (NOIs). Pts who received hematopoetic stem cell or solid organ transplantation subsequent to alemtuzumab (n=33) or who could not tolerate test doses of alemtuzumab (n=1) were excluded from analysis. Results: Data were reviewed for 16 pts treated with alemtuzumab from February 2003 to September 2006. Median age was 60 years (range 40–78); with 4 females and 12 males. Fifteen pts had chronic lymphocytic leukemia (CLL), and 1 had acute lymphoblastic leukemia (ALL). Median follow-up after starting alemtuzumab treatment was 462 days. Pts with CLL had an average of 2.4 prior treatments (range 1–6). The pt with ALL received alemtuzumab as part of multi-agent intensification chemotherapy regimen. Alemtuzumab was administered subcutaneously, 30 mg three times a week. Median of 29 doses (range 7- 45) were given. Among CLL pts there was 1CR, 8 PRs and 6 PDs (RR 60%). Pneumocystis jirovenci (PCP) and herpersvirus (HSV) prophylaxis was given to 15 (93%) pts. Cytomegalovirus (CMV) surveillance was performed for all. Absolute lymphocyte count (ALC) <1000/μL developed within 5 weeks in 12 (75%) pts. Median ALC at 8 weeks was 155/μL (range 0–18,612). Thirteen OIs were diagnosed in 9 (56%) pts including asymptomatic CMV viremia (n=5), PCP (n=2, one pt did not received PCP prophylaxis), invasive pulmonary aspergillosis (n=2), disseminated histoplasmosis (n=1), localized HSV (n=1), disseminated herpes zoster (n=1), and cerebral acanthamebiasis (n=1). Seven NOIs were noted in 6 pts including bacterial pneumonia, sinusitis, endocarditis and pseudo-membranous colitis. Mortality secondary to ICs was 31%. There was no correlation between ICs and age, duration of lymphoproliferative disorder, number of prior treatments, cumulative dose, response to alemtuzumab, or ALC. Conclusion: Despite adequate prophylaxis, ICs secondary to alemtuzumab are more frequent and diverse than previously reported in clinical trials.

No significant financial relationships to disclose.
Is farnesyltransferase inhibitor effective as adjuvant or neoadjuvant therapy in orthotopic implantation of hamster pancreatic cancer
Authors: Lima E. M. , Morioka C. Y. , Costa F. P. , Saito S. , Huang C. C. , Watanabe A.
Published: March 2020

14153

Background: p21-Ras participates in signalling events from membrane tyrosine kinase receptors and a variety of intracellular biochemical pathways to downstream therapeutic strategy.Farnesyl transferase inhibitors (FTI) block the main post-translational plasma membrane and subsequent activation of downstream effector.A curative resection model in Syrian golden hamsters has been developed previously. Aim: To evaluate the effectiveness of FTI as adjuvant or neoadjuvant therapy in hamster experimental pancreatic cancer model. Materials and Methods: HaPT-1,a cell line derived from nitrosamine induced pancreatic cancer was used in these experiments.MTT and MTT agarose were performed.Subcutaneous implanted tumor was resected in exponential phase and tissue was implanted into the pancreas.At Day 7 or Day 14, partial pancreatectomy and splenectomy were performed.Hamsters were divided in 7 groups:1.Positive control (PC,n=5),2.Only FTI (FT,n=5),3.Neodjuvant therapy after surgical resection at Day 7 (NT-R7,n=10),4.Adjuvant therapy after resection at Day 7 (AT-S7,n=10),5.Neoadjuvant therapy after resection at Day 7 (NT-S14,n=10),6.Adjuvant therapy after resection at Day 14 (AT-S14,n=10), and 7.Only surgery at Day 14 (SR,n=5).FTI was administered for one week. In FT and NT groups, drug was administered 3 days after orthotopic implantation.Body weight and side effects were recorded.Fourteen days after the surgical resection, sacrifice was done.Four animals of each group were left to study the survival.After 180 days, living hamsters were sacrificed. Resected and necropsied specimens were sent to histopathological analysis. Results: Successful rate of implantation was 100%.PC,FT,NT-S7,AT-S7,NT-S14,AT-S14,and SR survived in average 82,103,119,134,123,132,and 139 days.Two hamsters of AT-S7 (20%),two of AT-S14 (20%),and two of SR (40%) were alive until 180 days.Intra operatory bleeding was higher in NT groups.Loss of body weight was present in all FTI treated groups. Conclusions: Farnesyltransferase inhibitor showed not to be effective in the curative treatment of orthotopically implanted tumors. It may be used to increase the survival time as adjuvant therapy.

No significant financial relationships to disclose.
Relevance of a medicosurgical strategy combining cetuximab and chronomodulated (Chrono) chemotherapy (chemo) with metastases resection as 3rd line treatment for patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Karaboue A. , Bouchahda M. , Adam R. , Innominato P. , Bralet M. P. , Moreau T. , Hauteville D. , Guettier C. , Levi F.
Published: March 2020

14505

Background: Metastases surgery offers long tem survival for pts with chemo-downstaged MCRC (Adam et al. Ann Surg 2004). The relevance of this medicosurgical strategy was investigated in pts given cetuximab (Cetux) and Chrono after chemo failure. Methods: 56 pts with progressive MCRC on prior chemo received Cetux (400 mg/m2 on 1st dose then 250 mg/m2/week) and q2w Chrono based on irinotecan (34 pts), oxaliplatin (14 pts) or both (8 pts). Toxicity grades (G) and response were assessed q2w and q8w, respectively. Tumour EGFR was determined by immunohistochemistry (all pts) and gene copies by fluorescence in situ hybridisation (27 pts). Metastases surgery was attempted whenever complete resection was foreseen. Results: Median of 3 prior chemo (1 to 8); median age: 61 years (35 to 79); M/F: 34/22; WHO PS 0/1/2/3: 37/14/4/1; colon/rectum: 32/24; M sites 1/2/=3: 15/22/19; liver/lung: 45/40. EGFR was detected in the tumor of 39 pts (69.6%). 3 pts had G4 allergy. 53 evaluable pts received a median of 5 courses of Cetux-Chrono (1–22). G2–3 acneiform rash occurred in 36 pts (67.8%; G3: 30.4%). Main G3–4 toxicities were diarrhea (26.5%), neutropenia (23.1%) and neuropathy (22.6%). The objective response rate (ORR) was 32% [95% CI, 19.4 to 44.6] (13 PR and 3 CR). ORR was correlated positively with acneiform rash (p= 0.019) but negatively with the detection of EGFR+ tumor cells (0%, ORR=54.5%; 1–10%, 33%; >10%, 16.7%; p = 0.044). No EGFR amplification was documented including 8 OR. Median progression-free survival (PFS) and overall survival were 5.1 [3.2–6.9] and 13.9 months [6.5–21.3] respectively. Metastases surgery was performed in 10 pts (8 R0, 2 R1) after 3–15 courses of Cetux-Chrono as 2nd-5th line. Median PFS in resected pts was 11.7 months [5.8–17.6], with a survival estimate of 80% at 21 months. Conclusions: Cetux-Chrono safely reverted MCRC resistance and allowed successful metastases resection in 17.8% of these pts, like 1st line chemo. This medicosurgical strategy impacted favourably on long term survival, despite its application as 3rd treatment line. Supported by ARTBC, Hôpital Paul Brousse, Villejuif, France

No significant financial relationships to disclose.
Baseline and temporal patterns of fatigue predict pathological response in patients treated with preoperative chemoradiation therapy (CRT) for rectal cancer
Authors: Delclos M. , Krishnan S. , Mendoza T. , Lin E. , Vadhan-Raj S. , Das P. , Crane C. , Zhang Y. , Cleeland C. , Janjan N.
Published: March 2020

14522

Background: We investigated whether symptom burden before and during preoperative chemoradiation therapy (CRT) for rectal cancer predicts for pathological response, a surrogate for treatment outcome. Methods: Fifty-four patients with T3/T4/N+ rectal cancers were treated on a Phase II trial using preoperative capecitabine and concomitant boost radiotherapy. Most patients had T3 tumors (94%) and hemoglobin > 12 (85%). Symptom burden was prospectively assessed prior to (baseline) and weekly during CRT by a patient self-reported questionnaire, the MD Anderson Symptom Inventory (MDASI). Survival probabilities were estimated non-parametrically using Kaplan-Meier’s product limit method. Lowess curves were plotted for symptom burden across time. Logistic regression was used to determine whether symptom burden levels predicted for pathological response. Results: Among 51 patients evaluable for pathological response, 9 patients (18%) achieved pCR, and 26 patients (51%) had TDS. The actuarial rates of local control (LC), disease-free survival (DFS), and overall survival (OS) at 2 years were 93%, 76%, and 98%, respectively. Patients with TDS had lower levels of fatigue at baseline and at completion (week 5) of CRT compared to those without TDS (p = 0.03 for both). A similar trend was not observed for other symptom burden parameters of pain, sleep disturbance, appetite, nausea, or feeling of sadness. Evaluation of the potential effect of symptom burden on pCR, LC, DFS, or OS was not possible because of the low number of events during the 2-year median follow-up. Conclusions: Lower levels of fatigue at baseline and completion of CRT were significant predictors of pathological response, as gauged by TDS. Unlike studies that have documented improved quality of life among responders, our study demonstrates the converse, i.e. fatigue, a measure of symptom burden, independently predicted for tumor response. This provocative finding could potentially be used to stratify patients into prognostic groups, influence treatment decisions, and/or modify treatment. An evaluation of changes in cytokine profile during CRT is ongoing to determine the molecular basis of this phenomenon.

No significant financial relationships to disclose.
Serum REG4 protein in pancreatic cancer as a tumor marker: A prospective study
Authors: Sawaki A. , Takayama R. , Mizuno N. , Tajika M. , Hoki N. , Sayed Z. E. , Matsuo K. , Nakagawa H. , Nakamura Y. , Yamao K.
Published: March 2020

15063

Background: Pancreatic cancer (PC) shows the worst mortality rate in common malignancies, with 5-year survival rate of 4%. The only way to cure the disease is surgical resection of early stage PC. Establishment of a screening strategy to detect early stage PC is eagerly expected. REG4, a member of the regenerating islet-derived (REG) family, are secreted proteins that play a role in tissue regeneration and inflammation in digestive organs. We reported overexpression of REG4 in PC cells and serum, and preliminary data of the serum REG4 level of pancreatic disease patients including PC patients. We conducted a prospective study to evaluate the role of serum REG4 in PC. Methods: The series included 57 patients diagnosed pathologically as PC between November 2004 and December 2005. Serum REG4 was quantified by standard sandwich ELISA (Enzyme Linked Immunosorbent Assay) using original kit (MBL116: provided by Medical and Biological Laboratories Co., LTD, Japan) before treatment. The upper limit of the test was set at 3.52ng/ml and was based on studies of serum from 48 healthy control subjects. Results: With a specificity of 100%, the diagnostic sensitivity and accuracy were 63.2% and 80.0%, respectively. The ROC (receiver operating characteristic) analysis showed that area under the curve was 0.91. REG4 levels were a significant differences between PC and control (p<0.001), between each T stage and control (T1,T2, T3 or T4 v control), and between each TMN stage and control (stage 1, stage 2, stage 3 or stage 4 v control), but were not a statistical significance with T stage (T1 v T2 v T3 v T4), M stage (M0 v M1) or TNM stage (stage 1 v stage 2 v stage 3 v stage 4) in PC patients. The diagnostic sensitivity of carcinoembryonic antigen (CEA>5.0ng/ml) and carbohydrate antigen19–9 (CA19–9>50U/ml) was 56.5% and 68.4%, respectively. No significant correlation was demonstrated between REG4 and CA19–9 (coefficient of correlation [rs]=0.45). Conclusions: This study shows the potential of serum REG4 as a screening test for PC, especially for early PC. REG4 is considered to be a more useful marker in combination with CA19- 9.

No significant financial relationships to disclose.
Significance of galectin-3 immunohistochemistry , clinical characteristics, and liver imaging in differentiating intrahepatic cholangiocarcinoma from adenocarcinoma liver metastasis
Authors: Thamrongwitsawa A. , Kanngurn S. , Tanutit P. , Khow-Ean U. , Sunpaweravong P.
Published: March 2020

15120

Background: Difficulties remain in distinguishing intrahepatic cholangiocarcinoma from adenocarcinoma liver metastasis , therefore specific immunohistochemistry markers are still needed. Galectin-3 is a beta-galactoside-binding protein and has been reported as a tissue marker in many neoplasms, including cholangiocarcinoma. Adding Galectin-3 to Cytokeratin immunohistochemistry may provide more definitive diagnosis to these conditions. Methods: Histological slides of intrahepatic cholangiocarcinoma and adenocarcinoma liver metastasis were reviewed independently by 2 pathologists to confirm diagnosis. Immunohistochemical staining was done with primary antibodies for Galectin-3 (NCL-GAL3), Cytokeratin-7 (CK-7) and Cytokeratin-20 (CK-20) in paraffin embedded tissues. The extent of Galectin-3 staining was categorized as 0% (none), 1–25% (weak), 26–65% (moderate), and > 65% (strong) positive of tumor cells. Clinical characteristics and liver imaging of all patients were also reviewed. Results: Thirty-three patients were evaluated , 17 cholangiocarcinoma and 16 adenocarcinoma liver metastasis. Seventy-five percent of cholangiocarcinoma strongly expressed Galectin-3 whereas 56% of adenocarcinoma liver metastasis did. CK-7 expression was found in 47% of cholangiocarcinoma and CK-20 41%. In colorectal liver metastasis, 6 of 7 patients (85%) were negative for CK-7 and positive for CK-20. When correlated with patient characteristics, cholangiocarcinoma tended to occur in patients who were older than 55 years. Regarding liver imaging, multiple liver masses without intrahepatic bile duct dilatation correlated with adenocarcinoma liver metastasis. Conclusion: Adding Galectin-3 immunohistochemistry may benefit for differentiating intrahepatic cholangiocarcinoma from adenocarcinoma liver metastasis. Further study in a larger series is encouraged to better define role of this protein in cholangiocarcinoma diagnosis.

No significant financial relationships to disclose.
A phase II multicentric trial of combined chemotherapy with gemcitabine plus S-1 in patients with advanced pancreatic cancer
Authors: Ohkawa S. , Amano A. , Ueno M. , Miyakawa K. , Sugimori K. , Tanaka K. , Kida M.
Published: March 2020

15129

Background: While gemcitabine (GEM) is the standard drug for chemotherapy against advanced pancreatic cancer, the development of multidrug therapies for improved outcome is important. We conducted multicentric combined chemotherapy with GEM and S-1 trial and reported the results of the phase I trial last year. And this phase II study evaluated the efficacy and feasibility. Methods: The subjects had unresectable pancreatic ductal cancer. Eligibility criteria were pathologically-proven, Karnofsky performance status 80 to 100%, age 20 to 74 years, adequate hematological, renal, and liver functions and written informed consent. The method of administration was single administration of GEM on the first day of the week 1000 mg/m2, with concurrent administration of S-1 at 80 (<1.5 m2) to 100 (=1.5 m2) mg/day × 7 days, repeated every other week until the progressive disease or life threatening adverse events. This administration dose was determined from the result of the phase I study. The primary endpoint was median survival time. And the secondary endpoints were the overall response rate and the toxicities. Results: 40 patients(pts) were enrolled. Average age was 62.9±8.3 years (34–73 years). Thirty nine pts were conducted this therapy except one who refused this study before the start of administration. Thirty eight pts were evaluable for response, partial response, stable disease, progressive disease were observed in 7 (17.5%), 21 (52.5%) and 10 pts (25.0%), respectively. The median survival time at this stage is 276±51 days in this ongoing study. Grade 3 and 4 toxicities were mainly leucocytes(10 pts), neutrophils(8 pts) and anorexia(6 pts). Conclusions: The GEM plus S-1 combined chemotherapy is effective and feasible in patients with advanced pancreatic cancer.

No significant financial relationships to disclose.
Induction cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy in locally advanced esophageal cancer: A single institution’s initial clinical experience
Authors: Harper J. L. , Shirai K. , Sharma A. K. , Montero A. J. , Hoffman B. J. , Reed C. E. , Sherman C. A.
Published: March 2020

15151

Background: Phase I and Phase II trials of induction Cisplatin (C) and Irinotecan (I) followed by concurrent C+I and radiotherapy (RT) have produced encouraging clinical and pathologic response rates in esophageal cancer. However, to date published data detailing clinical outcome with this regimen is limited. Methods: A retrospective review of 17 patients with locally advanced esophageal cancer was performed to characterize toxicity and outcomes for this regimen in our institutional experience. Patients were treated during the period from August 2003 to July 2006 and staged comprehensively with EUS, CT and PET. Induction therapy with weekly I (65mg/m2) and C (30mg/m2) was administered (wks1,2,4,5). Those without progression received weekly I (65mg/m2) and C (30mg/m2) (wks 8,9,11,12) concurrent with RT. Patients considered surgical candidates based on pre- treatment clinical stage, medical co-morbidities, and pre-operative re-staging were offered an esophagectomy. Results: The patient demographics were as follows: 15 men, 2 women, median age 63 (45–76), white 53%, black 47%, adenocarcinoma 59%, squamous cell carcinoma 41%, 47% stage T3N1, 94% node positive, 6% M1a, and 29% T4 primary tumors. The mean RT dose was 50.4 Gy and median number of elapsed days of RT was 43 days. All patients completed induction C+I. Grade 3–4 hematologic toxicity (CTC v3.0)neutropenia (47%), anemia (6%), thrombocytopenia(18%). One patient died of a TE fistula 22 days after completing therapy. Two patients (12%) progressed during therapy. An esophagectomy was performed on 41% (7/17) of patients; 6 of 7 were R0, 71% (5/7) were downstaged, 14% (1/7) pCR. At median follow-up of 15 months, 8/17 (47%) pt are alive NED, 3/17 are alive with disease, 3/17 dead of disease and 3/17 are dead of other causes. Median DFS is 7 months and median local RFS is 7 months. Median OS has not been reached at 15 months. Conclusions: In this population with very advanced disease, I+C+RT have produced promising OS and local control outcomes with greater toxicity than in previously reported experiences with this regimen.

No significant financial relationships to disclose.