bluuebunny/crossref_metadata_2025 huggingface dataset:
Epithelial to mesenchymal markers and clinical outcomes on erlotinib in stage IV non-small cell lung cancer patients.
Authors: Pool Mark , Fidler Mary J. , Basu Sanjib , Mahon Brett , Buckingham Lela , Walters Kelly Kaiser , Batus Marta , Hensing Thomas A. , Borgia Jeffrey A , Bonomi Philip D.
Published: March 2020

e19117

Background: An epithelial phenotype in NSCLC is associated with improved sensitivity to EGFR tyrosine kinase inhibitors (TKI). The best method to identify this subset is unknown (Richardson Anticancer Research 2012, Byers Clin Cancer Res 2012). This retrospective study correlates E-cadherin (Ecad) and vimentin (vim) immunohistochemistry (IHC) expression with outcomes in advanced NSCLC patients (pts) treated with erlotinib (E). Methods: Advanced NSCLC pts that received E were included if sufficient tumor was available from diagnosis. IHC scores for E-cad and vim were generated by multiplying frequency (0-4) by intensity (0-4). Log Rank was used to correlate IHC expression with progression free and overall survival (PFS, OS). Results were compared to a subset of pts with tissue from primary surgical NSCLC resection who later received E for recurrent disease. Results: 159 advanced NSCLC pts treated with E had tissue from diagnosis and IHC analysis. There was no correlation with PFS or OS on E and high/low vim or Ecad expression. Subtracting the IHC scores (vim minus ecad) created a difference score. A low difference score (n = 62) correlated with prolonged PFS (2.6 vs 1.9 months, p = .014 HR 1.52) compared with a high score, n = 97. Low difference score trended toward prolonged OS (p=.46) 33 of the patients had tissue available from primary surgical resection. The invasive front was examined for membranous E-cad and cytoplasmic vim (Allred score 0-8). Patients with low vim (< 4) and Ecad (>5), n= 19, trended toward prolonged PFS and OS on E compared with patients with high vim (>5) and low Ecad (<6), n=10 (4.2 vs 1.6 months and 15.5 vs 6.5 months, respectively, p=NS). Conclusions: In this retrospective analysis, using unselected, frequently small tissue specimens, the expression of ecad or vim alone by IHC did not correlate with outcomes for E treated patients. A complicated difference score (vimentin score minus ecadherin score) did correlate with PFS on E. Examining EMT markers at the invasive edge of resected NSCLC tumors might more accurately assess EMT activity and its relationship to outcomes when these pts are recommended EGFR-TKIs.
Clinical experience of oxaliplatin-based regimen for patients with relapsed or refractory B-cell lymphoma: A Bangladesh perspective.
Authors: Hoque Ehteshamul
Published: March 2020

e19501

Background: We performed a clinical study to evaluate the efficacy and toxicity of R-GemOx in the treatment of patients with relapsed or refractory B-cell lymphoma in Bangladeshi patient population. Methods: A total number of twenty (male 13, female 7, average age 60) patients with recurrent or refractory CD20 positive lymphoma, previously treated with CHOP of any performance status were eligible for inclusion. No primary and new cases were included. Treatment regimen consisting of rituximub 375 mg/m2, Gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2on day 1. Cycle was repeated every 3 weekly for six cycles. The patients were enrolled at our institution between December 2009 and December 2011. The primary endpoint was overall response rate and toxicity, assessed by Response Evaluation Criteria, secondary endpoints included both event free survival (EFS), and overall survival (OS). Results: A total of 20 patients were evaluable for efficacy and toxicity. The overall response rate was 75%. The EFS and OS under follow-up. No fatal toxicity was observed. Treatment was generally well tolerated. 13% patients complained about GIT upset (nausea, vomiting). Grade 3/4 neutropenia occurred in 8% of patients. Grade 2 neurotoxicity occurred in 5% of patients. No renal toxicity was observed. No other grade ¾ non hematological toxicity was observed. Conclusions: The combination of R-GemOx was effective in Bangladeshi patient population with Refractory B-cell lymphoma, with a predictable and manageable safety profile similar to that observed in Western patients.
Clinicopathologic features and treatment outcome of primary intestinal non-Hodgkin lymphoma: A single center experience.
Authors: Hsu Wei-Hsun , Yeh Kun-Huei , Lin Chung-Wu , Hsu Chih-Hung , Cheng Ann-Lii , Kuo Sung Hsin
Published: March 2020

e19523

Background: Primary intestinal non-Hodgkin lymphoma (NHL) is a rare but heterogeneous disease in East Asia. However, the benefit of multidisciplinary treatment is still in debate. We characterized the clinicopathologic features, and treatment outcome in a single institute database. Methods: Patients with NHL primarily involving the intestine and treated during 1992 to 2008 were selected from the Cancer Registry of National Taiwan University Hospital. The medical charts and pathology records were carefully reviewed. Results: There were 64 men and 17 women with a median age of 51.5 years. Sites involved were colon/rectum (53.2%), small intestine (30.9%), and duodenum (13%). Histopathology subclassification included diffuse large B-cell lymphoma (DLBCL) (61.7%), mucosa-associated lymphoid tissue lymphoma (11.1%), Burkitt’s lymphoma (8.6%), T cell lymphoma (6.2%), follicular lymphoma (2.5%), mantle cell lymphoma (1.2 %) and others (8.6%). Ann Arbor stage IE to IIE accounted for 61.7%, whereas lower IPI score (1-2) were 54.8%. Among them, 27 patients received surgery plus chemotherapy, 60 received chemotherapy, and 4 had radiotherapy. At average follow-up of 48.7 months, 5 year survival rate were 59%, 43% and 51% for colon/rectum, small intestine, and duodenal NHL, respectively (p=0.45). Surgery plus chemotherapy versus chemotherapy alone showed no survival benefit in lower IPI group (p=0.682) nor in higher IPI (3-5) group (p=0.939). A trend of better median overall survival (mOS) was seen in rituximab group than in non-rituximab group in DLBCL subtypes (not reach vs. 39.8mo, p=0.075). In univariate analysis, stage III/IV (p=0.008), IPI score greater than 2 (p=0.011), and T cell histology (p<0.001) were significant prognostic factors for poor OS. In multivariate analysis, T cell histology remained the independent prognostic factor for inferior OS (p<0.001, HR: 20.3, 95% CI: 5.1-80.4). Conclusions: Although B cell NHL was the majority of primary intestinal NHL in our institute, T cell histology has significant inferior survival. Chemotherapy is still the backbone of treatment for primary intestinal NHL. The benefit of rituximab to intestinal DLBCL needs further confirmation.
Clinical features and outcome of follicular lymphoma: 17 years experience from All-India Institute of Medical Sciences (AIIMS), New Delhi, India.
Authors: Gogia Ajay , Raina Vinod , Sharma Atul , Kumar Lalit , Sharma Mehar C , Gupta Ritu , Das Prasenjit
Published: March 2020

e19524

Background: Follicular lymphoma (FL) is second most common lymphoma in adult, constituted 20% of all lymphoma cases in the west. There is limited information is available on FL from India. Methods: The clinic-pathological profile, treatment outcome and prognostic factors for survival were assessed in 181 patients of FL seen at AIIMS, New Delhi, a large tertiary referral centre, over a period of 17 years (1996-2012). Results: There were 120 males and 61 females. The median age was 51 years (24-80 years). The common presenting features were lymphadenopathy 71%, fatigue 23% and fever 20%. Ann Arbor Rai stage distribution was: stage I - 9%, stage II - 11%, stage III -22 % and stage IV - 58%. Thirty six patients (20%) had ECOG performance status III/IV. Extra nodal involvement and bulky disease were present in 40 (22%) and 31 (19%) patients respectively. Follicular Lymphoma International Prognostic Index (FLIPI) 1 score : Low -25%, Intermediate-45% and high risk in 30% of cases. FL grade 1, 2 and 3 were seen in 63 ( 35%), 63 (35%) and 55 (30%) patients respectively. One forty five patients (80%) received treatment at presentation. Chemotherapeutic regimen used were: CHOP-45 , CVP-51, chlorambuil and prednisolone -7 , BR ( bendamustine and rituximab)-12, RCHOP- 14 and RCVP in 7 cases. The overall response (ORR) and complete remission (CR) rates were 70% and 35% respectively. Relapse occurred in 54 patients, 50 patients died and progression was observed in 63(35%) patients. Median overall survival (OS) and event free survival (EFS) was 5.5 years and 3.5 years respectively, with median follow up period of 3 years. Grade 3 histology, failure to attain CR, low serum albumin, PS III/IV, bulky disease and high risk FLIPI were significantly associated with lower event free survival. High risk FLIPI (HR 1.46, 95% CI 1.03-2.10, p=0.003) and failure to attain CR (HR 2.64, CI 1.10-4.30, p=0.001) were predictors of poor OS. Conclusions: FL represents 9 % of all lymphoma in adult. This is the largest data from single institute from India. Eighty percentage of patients presented in stage III/IV disease. High risk FLIPI and failure to attain CR were important prognostic variables for OS.
Pediatric hepatic angiosarcoma treated with chemotherapy and partial hepatectomy: A case report.
Authors: Faria Flavia Watusi
Published: March 2020

e21001

Background: Hepatic angiosarcoma is a high-grade malignant neoplasm, extremely rare in children and associated with a poor prognosis. It is reported in English language less than fifty cases in children between 2 months and 15- year-old at presentation. Due to the rarity of this tumor type, little is known about effective systemic therapy. Many diferent schedules have been reported, comprising surgery only, neoadjuvant chemotherapy, surgery wih adjuvant radiotherapy and hepatic transplantation. The median survival rate stays between 10 to 48 months, independently of the treatment chosen, with inconsistent results. Methods: retrospective medical records review. Objective: We present our experience wih a female 3-year-old child presenting wih a huge unressectable liver angiosarcoma at diagnosis, treated with neoadjuvant intensive chemotherapy based on ifosfamide, carboplatine and etoposide and right hepatectomy. The child remained in complete remission for 5 years, after that presenting with local relapse treated again with the same intensive chemotherapy, resulting in a very good response. Conclusion: the children is alive after a relapsed hepatic angiosarcoma treated with neoadjuvant chemotherapy and partial hepatectomy. In this case, neoadjuvant chemotherapy based in carboplatine, ifofamide and etoposide was an effective strategy to treat pediatric hepatic angiosarcoma.
Prognostic factor and outcome of 32 patients with classic and iatrogenic Kaposi sarcoma: A monoinstitutional experience.
Authors: Rescigno Pasquale , Palmieri Giovannella , Nappi Lucia , Buonerba Carlo , Federico Piera , Ottaviano Margaret , Matano Elide , Bosso Davide , Policastro Tania , Izzo Michela , Di Lorenzo Giuseppe
Published: March 2020

e21500

Background: Classic Kaposi Sarcoma (CKS) is a rare and mild form of the disease that primarily affects men, older than 50 years in the endemic areas. Iatrogenic KS (IKS) is associated with the use of steroids, immunosuppressive agents in patients with autoimmune diseases, inflammatory disorders, or organ transplantation. We have conducted a retrospective analysis from January 2008 to December 2012 for CKS and IKS to evaluated outcomes and potential prognostic factors in this rare disease. Methods: Patients with histologically proven KS lesions of the skin and negative HIV-1/2 were enrolled. In some cases diagnosis was completed by immunohistochemical tests for HHV-8 staining. Eligible patients received different systemic chemotherapy for disease at stage IIb and in all variants of stage III and IV, according Mediterranean KS staging. Results: 32 cases of non-AIDS KS were identified in this study. Mean age at diagnosis of the group was 70 year-old. Approximate male/female ratio was 2:1. 78.2% of cases was classic KS. All patients received systemic chemotherapy containing one of this agent: alkaloid of vinca, taxane, pegylated lyposomial doxorubicin. Ten patients (31.5%) experienced a partial response, a complete response was achieved in 4 patients (12.4%) and stability in 16 cases (50%). Two patients (6.2%) developed multiple local recurrences. PFS was 11.7 months while OS resulted 28.5 months. At multivariate analysis nodular lesions were related to lower PFS compared to macular lesions (HR: 2,5817, 95% CI 1,2911 to 5,1624; p: 0,0049), and HHV8 status (positive vs. negative) had a statistically significant correlation with a worse response to treatment (HR: 5,0289 95% CI 1,6540 to 15,2901; p: 0,0046). Conclusions: Classic and iatrogenic KS patients appears less aggressive, mostly limited to the skin and well-responsive on local or systemic therapeutic strategies. Our data show as positivity to HHV8 and nodular lesions correlate with a worse response to treatment.
Predictive and prognostic factors in locally advanced and metastatic sarcomas: A single institution experience.
Authors: El Mekkeoui Zineb Benbrahim , Arifi Samia , Boudahna Lamiae , Mellas Nawfel , El Mesbahi Omar
Published: March 2020

e21513

Background: Ifosfamide is frequently applied in first line systemic therapy in sarcoma. Several, and sometimes, contradictory data have been reported in the literature regarding predictive factors of response and prognostic factors. The aim of this study was to assess predictive factors and factors associated with PFS and OS in patients with locally advanced and metastatic sarcoma treated with ifosfamide. Methods: We reviewed retrospectively 50 cases of sarcomas treated between January 2007 to June 2012 at the Medical Oncology Department at Hassan II University Hospital. Clinical, histopathologic and prognostic features were evaluated. Results: Median age was 30.9 ± 13 years. 56 % of patients were men. Synovialosarcoma was the predominant histologic type (23%). In 85% of cases, Ifosfamide was associated with Doxorubicine. The total dose of ifosfamide was 9g/m2 in 96% of cases. After A median duration of follow up of 15 months [3-26], the overall response rate was 57.7%. The median PFS was 6.1 months [3-13] and median OS was 10.04 months [3-23]. The Predictive factor of response was high grade (78% vs 41%; p=0.03). For PFS, the prognostic factor was high LDH level (5 vs 12 months p=0.01). For OS, prognostic factors were localization in upper extremity (8.5 vs 13 months ; p=0.03) presence of metastasis (7 vs 11 months; p=0.02) and high LDH level (7 vs 13 months; p=0.02). Conclusions: In patients with sarcoma treated with ifosfamide, the response rate is influenced by tumour grade. High LDH level was prognostic for both PFS and OS whereas upper extetermity site and presence of metastases were prognostic for OS only.
The use of new diagnostic tests for the monitoring of new and existing therapies for breast cancer patients.
Authors: Rotmann Andre
Published: March 2020

e22006^

Background: Impaired glucose metabolism and elevated blood glucose levels have been linked with increased cancer risk and cancer mortality. Furthermore a diet with a high glycemic load and carbohydrate intake is positively associated with an increased cancer risk in a subgroup of breast cancer patients. New therapies have been established addressing new targets controlling glucose metabolism. Upregulation of glucose metabolism in cancer can be in vivo visualized by the imaging technique FDG-PET. Recently it has been shown that the detection of the biomarker transketolase-like-1 (TKTL1) in macrophages allows the non-invasive detection of upregulated glucose metabolism in cancer patients. The epitope detection in macrophages (EDIM) has been established as a new technology for a non-invasive biomarker based detection and characterization of tumors as well as early detection of recurrence and/or metastasis. The biomarker Apo10 is highly specifically expressed in tumor cells irrespective of the tumor entity. Apo10 and TKTL1 offers the possibility to detect abnormal cell proliferation and up-regulated glucose metabolism, indicating neoplasias and the degree of malignancy. This new technology could be used to identify patients that will benefit from existing and new approved therapies. Recently the mTOR inhibitor everolimus has been approved for a subgroup of advanced breast cancer. Metformin, a drug addressing glucose metabolism, has been shown to reduce the incidence of invasive breast cancer in postmenopausal women. Methods: We use the EDIM-tests for early detection, monitoring and in aftercare. Additional we use the test to monitor new therapies. The results where compared to clinical observations and laboratory data. Results: Up to now we have tested more than 100 women with breast cancer for a period up to 4 years. Our results show a good concordance between the EDIM-tests and the clinical observations. Conclusions: Our data from patients with breast cancer are promising results worth to be further validated. The combination of the biomarkers Apo10 and TKTL1 with EDIM-technology could be a useful tool to identify and monitor cancer patients and the use of new therapies.
Treatment implications for immunohistochemistry-based diagnoses with low positive predictive value.
Authors: Pillai Raji , Handorf Charles , Henner William David
Published: March 2020

e22033

Background: In a recent study (Handorf, C. et al., Am. J. Surg. Pathol., in press), the accuracy of tumor diagnoses using immunohistochemistry (IHC) (83%) was directly compared to accuracy of gene expression profiling (GEP) (89%). However, in clinical practice, IHC is more commonly used initially and GEP is used secondarily in difficult-to-diagnose cases. For this reason, it is important to identify which IHC-based diagnoses have a low positive predictive value (PPV) and therefore might benefit from the addition of GEP or other diagnostic procedures. Methods: The direct comparison study included 157 metastatic tumors of known origin that represented 15 possible tumor types. A panel of four board-certified anatomic pathologists was blinded to the primary site and each pathologist used IHC to render final tumor diagnoses. 472 specimen reviews and diagnoses were performed. The fraction correct (PPV) for the diagnoses rendered for each of the 15 tumor types in the study were compared. Results: The PPV for each of the 15 tissue types diagnoses was either: low (gastric, 29%; pancreatic, 31%; non-small cell lung, 55%), moderate (prostate, renal, hepatocellular, ovarian and colorectal, 85-90%) or high (bladder, breast, testicular germ cell, non-Hodgkin’s lymphoma, melanoma, sarcoma and thyroid, 94-100%). Among the 90 diagnoses of tissues with low PPVs (gastric, pancreatic and non-small lung cancer) there were 59 incorrect diagnoses. For 23 of those 59 diagnoses, the actual tumor type is treatable for prolonged survival including: breast (N=11), colorectal (N=6), ovarian (N=3) and prostate (N=3) cancer. Conclusions: The PPV for IHC-based diagnoses of primary site varies substantially depending of the type of tissue diagnosed. Pathologists should consider the likely PPV of their IHC-based diagnoses of primary site when considering the use of GEP or other methods to refine their diagnosis. For many of the IHC-based primary site diagnoses with low PPVs, the correct primary site diagnosis may allow treatment for prolonged survival.
ALK-immunohistochemistry (IHC) standardization with D5F3 antibody in non-small cell lung carcinoma (NSCLC): An international consensus study.
Authors: Hirsch Fred R. , Yatabe Yasushi , Dietel Manfred , Sholl Lynette M. , Tsao Ming Sound , Schuuring Ed , Tubbs Raymond R.
Published: March 2020

e22042

Background: The outcome of patients with advanced NSCLC with ALK fusions detected by ALK FISH has improved significantly when treated with crizotinib. ALK IHC*, which is a relatively inexpensive assay, correlates well with ALK FISH. An international ALK IHC project was initiated to formulate scoring standardization and assess reproducibility of an ALK IHC assay. Methods: Using ALK FISH status (Abbott, Des Plaines, IL) as the enrollment criteria, formalin-fixed paraffin-embedded tumors from 103 NSCLC patients from 6 different institutes were stained and analyzed for ALK protein expression using a recently developed fully automated ALK IHC assay (Ventana, Tucson, AZ). Seven international observers blindly assessed the specimens as “positive” or “negative” after two training sessions and the use of an assessment manual. Results: The agreement between ALK IHC and ALK FISH for evaluable cases where 4/7 or 6/7 readers agreed on ALK status was 92/98 cases (93.9%, 95%CI 87.3-97.2) and 90/96 cases (93.8%, 95%CI 87.0-97.1) overall; positive IHC agreement was 39/43 cases (90.7%, 95%CI 78.4-96.3) for both methods; negative IHC agreement was 53/55 cases (96.4%, 95%CI 87.7-99.0) and 51/53 cases (96.2%, 95%CI 87.2-99.0), respectively. Average inter-observer agreement was 1987/2032 reads (97.8%, 95%CI 95.9-99.1) overall; average positive agreement was 1,710/1,755 reads (97.4%, 95%CI 95.0-99.1); average negative agreement was 2,264/2,309 reads (98.1%, 95%CI 96.4-99.3). Of the 6 discrepant cases, 4 were unanimously scored as ALK IHC negative with ALK FISH being positive. Two were confirmed by chromogenic ISH to be ALK rearranged, one was unevaluable, and one was genomically heterogeneous. The remaining 2 discrepant cases were discordant among scorers relating to ALK IHC cellular compartment staining in one case and a minute sample size showing ALK IHC staining in the other. Conclusions: ALK IHC standardized assessment achieved high inter-observer reproducibility among an international panel of participants and high correlation with ALK FISH. A screening strategy using ALK IHC should be considered.*ALK IHC has not been approved for use in the US as a diagnostic for crizotinib.
Recognizing seromadesis to prevent false-positive PET-CT interpretations.
Authors: Bhatt Geetika , Li Xiao-Feng , Jain Angita , Stephens Matthew , Civelek Ali Cahid
Published: March 2020

e22084

Background: Seromas are the result of a local inflammatory response to a mechanical injury incurred by tissue aggression either during surgery or the presence of foreign bodies. Unfortunately, the common practice of using of percutaneous or surgical drains, does not decrease the frequency of seroma formation and is associated with an increased risk of infection. Methods: Since first introduced in 1935 for pleurodesis, talcum powder has been used extensively as a simple, effective, and economic procedure for the treatment and prophylaxis of recurrent pleural effusions. It induces a strong fibrotic reaction due to the activation of polymorphonuclear neutrophils, interleukin 8 and fibroblast growth factor. One of the earliest documented uses was by Coons et al., in 1993 utilizing an experimental dog model. In 2006, Saeb-Parsy et al. described its use in recurrent seroma after breast surgery. More recently in 2012, Klima et al. reported that a prophylactic application of subcutaneous talc after axillary dissection in a porcine model safely reduces drain duration and prevents seromas without local or systemic side effects. More recently, it has also been used in superficial soft tissue excisions for melanomas and large metastatic lymphadenopathy excisions. Currently, F-18 FDG PET-CT is widely used in the diagnosis and management of patients with malignancies. However, the imaging tracer F-18 FDG is utilized not only by malignant cells but by infectious, inflammatory cells as well resulting in false ‘positive’ findings. Results: When a patient undergoes pleurodesis using talc, the local inflammatory process is seen as intense increased F18 FDG activity on PET-CT scan. This can be perceived and misinterpreted as initial or recurrent malignant foci or infection. Thus it is imperative that interpreting physicians be aware of the wide range of application of talcum powder to any site with a potential of seroma development. Conclusions: Presence of intense F-18 FDG activity corresponding to somewhat linear irregular area of hyperdensity seen in the CT portion of PET-CT in previous surgical bed should alert the interpreting physician on strong probability of talc induced exuberant inflammatory reaction and associated F-18 FDG activity.
First results of the prospective Neoadjuvant Breast Registry Symphony Trial (NBRST).
Authors: Whitworth Pat W. , Gittleman Mark , Akbari Stephanie , Stork Lisette , De Snoo Femke , Gibson Jessica , Beitsch Peter D.
Published: March 2020

e22117

Background: Classification into molecular subtypes may be important for the selection of therapy for patients with early breast cancer. Previous analyses had shown that breast cancer subtypes have distinct clinical outcome (Sorlie, PNAS 2001; Esserman, BCRT 2011). The aim of the prospective NBRST study is to measure chemosensitivity as defined by pathological Complete Response (pCR), or endocrine sensitivity as defined by partial response (PR) and metastasis-free survival in molecular subgroups. Methods: The study includes women aged 18–90 with histologically proven breast cancer, who are scheduled to start neo-adjuvant chemotherapy (CT) or neo-adjuvant endocrine therapy (ET), and who provide written informed consent. Additional inclusion criteria include no excision biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for breast cancer. Treatment is at the discretion of the physician adhering to NCCN approved regimens. 500 Patients will be enrolled. Results: 128 Patients (median age 52, range 22-79), T1-4 N0-3, had definitive surgery and the overall pCR rate was 22%.14 (11%) patients are classified as Luminal A-type (BluePrint Luminal/MammaPrint Low Risk) of whom 11 received neo-adjuvant CT; none of these patients had a pCR. While 3 patients received neo-adjuvant ET and all 3 had a PR. 47 (37%) Patients are classified as Luminal B-type (BluePrint Luminal/MammaPrint High Risk). All but 1 patient received neo-adjuvant CT and 4 (9%) had a pCR. 20 (16%) Patients are classified as BluePrint HER2-type and received neo-adjuvant CT plus Trastuzumab; 8 (40%) had a pCR. 47 (37%) Patients are classified as BluePrint Basal-type and received neo-adjuvant CT; 15 (32%) had a pCR. Of the patients with IHC/FISH HER2+ cancer 13/39 (33%) had a pCR and 6/21 (29%) of the patients with IHC/FISH triple negative breast cancer. Conclusions: We observed differences in pCR to neo-adjuvant treatment in groups stratified by BluePrint and MammaPrint. Patients with Luminal A-type breast cancer have a high response to neo-adjuvant endocrine therapy (100% PR) and no pCR to neo-adjuvant CT. While patients with BluePrint HER2-type and Basal-type breast cancer have a high pCR rate to neo-adjuvant CT. Clinical trial information: NCT01479101.
Dynamics of T-cell infiltration during the course of ovarian cancer: The gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T cells.
Authors: Partlova Simona , Fialova Anna , Sojka Ludek , Rob Lukas , Bartunkova Jirina , Spisek Radek
Published: March 2020

e22129

Background: Ovarian cancer is diagnosed in more than 190,000 new patients every year and is known to have the highest mortality rate among gynaecologic cancers. The type of immune cells that are present within the tumor microenvironment can play a crucial role in the survival of patients. However, little is known about the dynamics of the tumor-infiltrating immune cells during disease progression. Methods: We studied the immune cells infiltrating the tumor tissue of ovarian cancer patients at different stages of disease. We analysed the patterns of T lymphocytes in fresh tumor tissue as well as blood samples of 44 newly diagnosed ovarian cancer patients by flow cytometry. To evaluate whether regulatory T cells (Tregs) develop in situ or migrate to tumor tissue, we measured a concentration of chemokine CCL22 in tumor cell culture supernatants. We also determined the expression of CCR4 on circulating as well as tumor-infiltrating Tregs by flow cytometry. Results: The early stages of development of ovarian carcinomas were characterized by a strong Th17 immune response, whereas in stage II patients, recruitment of high numbers of Th1 cells was observed. In disseminated tumors (stage III-IV), we detected a dominant population of Helios+ activated regulatory T cells along with high numbers of macrophages and immature myeloid dendritic cells. Tumor-infiltrating Tregs had markedly lower expression of CCR4 than circulating Tregs, and the numbers of tumor-infiltrating Tregs significantly correlated with the levels of CCL22 in ovarian tumor cell culture supernatants, suggesting their recruitment via a CCR4/CCL22 interaction. CCL22 was mainly produced by tumor cells, macrophages and mDCs in the primary ovarian tumors, and its expression markedly increased in response to IFNgamma. Conclusions: Taken together, the specific recruitment of Tregs, probably triggered by inflammatory stimuli, leads to a significant immune suppression in the advanced stages of ovarian cancer.
Deciphering Treg accumulation in melanoma.
Authors: Tobin Vealey Kristen E. , Le Poole I. Caroline , Klarquist Jared S. , Eby Jonathan M.
Published: March 2020

e22170

Background: A high density of regulatory T-cells (Tregs) at melanoma tumor sites correlates with poor prognosis due to immunosuppressive effects on the host immune system. While the concentration of circulating Tregs in patients with melanoma is not significantly different from that of healthy controls, Tregs tend to accumulate at tumor sites. We hypothesized that the influx of Tregs observed in melanoma tumors may be explained by enhanced tumor homing. Methods: To quantify the relative expression of chemokine receptors CCL4 and CCL8, and skin homing receptor CLA, blood was drawn from five metastatic melanoma patients and five healthy controls. Lymphocytes were ficolled and negatively sorted for CD3 expression. T-cells were subjected to 7-color FACS staining where Tregs were defined as CD4+CD25+CD127lowFoxP3+ and were simultaneously assessed for expression of CCR4, CCR8, and CLA. To further understand chemokine-receptor signaling involved in Treg homing in melanoma we analyzed the number of CCL22 producing cells in four human metastatic melanoma tissues and four healthy skin tissues obtained during surgery. Dermal CCL22+ cells were detected by indirect immunohistochemistry and quantified to a depth of three times the thickness of the epidermis. Results: Lymphocytes of melanoma patients were found to exhibit enhanced expression of CCR4 (mean of 65.9 versus 51.2%, p<0.01) and CCR8 (3.0 versus 1.5%, p<0.05), but not CLA (21.9 versus 23.9%) as compared with healthy controls. The mean fluorescence intensities of CCR4 and CCR8 were likewise elevated by 63 and 49% over controls (p<0.05 and p<0.01), respectively. A markedly increased number of CCL22 secreting cells were found in tumor samples (mean of 1063.1 versus 207.4, p= 0.02) as compared with healthy controls. Conclusions: These data strongly suggest that enhanced homing of CCR4+ Tregs towards the ligand CCL22 is likely involved in accumulating Tregs at melanoma tumor sites, ultimately impeding effective anti-tumor immune responses. Targeting chemokine-receptor signaling may thus be an effective intervention strategy in melanoma.
Serum chemokine CXCL7 activity after resection of breast cancer.
Authors: Kosir Mary Ann , Ju Donghong
Published: March 2020

e22182

Background: The chemokine CXCL7 is associated with tumor migration, invasion and angiogenesis and is a ligand for CXCR2. The purpose of the study is to measure changes in serum chemokine CXCL7 from resectable breast cancer patients between preoperative and postoperative blood samples. Methods: With IRB approval, we prospectively collected serum samples from patients undergoing breast cancer surgery immediately preoperatively and at least one week postoperatively. Serum CXCL7 protein concentrations were measured by enzyme-linked immunosorbent assay (ELISA) using human CXCL7/NAP-2 Duo set ELISA Development System (R and D Systems, Minneapolis, MN) according to manufacturer’s instructions. Measurements were performed in duplicate with three separate experiments. Results were analyzed using unpaired and paired Student’s t-Test. Demographic and clinical information were collected. Normal donor samples were from ProteoGenex. Results: Twenty-three matched serum samples were analyzed. The mean age was 52 years (range 36-67), 65.2% were African American, 56.5% underwent partial mastectomy. There were 5 in Stage I, 9 in Stage II, 2 in Stage III, and 7 in Stage 0. Only 4 of 16 with invasive cancer had nodal disease, 11 were ER positive, 6 were triple negative, and 5 of 7 with DCIS were ER positive. Matched serum samples showed greater CXCL7 serum levels in preoperative samples when compared to normal donor samples (9.10 ±0.45 vs 8.10 ± 0.22 ug/ml; mean±sem, p<0.05). The CXCL7 serum levels were significantly decreased in postoperative serum as compared to preoperative serum (8.40 ± 0.47 vs 9.10 ± 0.45 ug/ml; mean±sem, p<0.05) reaching normal donor serum levels. When individual matched pairs of serum were analyzed, 16 showed decrease in postoperative CXCL7 levels compared to preoperative. Conclusions: The chemokine CXCL7 found in serum is increased in breast cancer patients compared to normal donors, and significantly decreases postoperatively to normal levels. This supports translational research of the role of CXCL7 in breast cancer.
Urinary 8-oxoguanine as a predictor of survival in patients undergoing radiotherapy.
Authors: Roszkowski Krzysztof , Olinski Ryszard
Published: March 2020

e22197

Background: Despite several factors with prognostic value which are available for conventional cancer therapy, there is no test of the outcome of radiotherapy for individual prediction. Usually a certain dose level is prescribed for a whole group of cancer patients with similar diagnosis. This dose is set empirically taking into consideration the most sensitive patients. However, development of a prognostic test would allow to predict in advance which patients may be treated with even a higher dose while in the other case to find another more successful modality. The aim of this work was to investigate whether fractionated radiotherapy of cancer patients (n=99) is responsible for oxidative DNA damage on the level of the whole organism and whether the biomarkers of the damage such as 8-oxo-dG (8-oxo-7,8-dihydro-2’-deoxyguanosine) and its modified base (8-oxo-Gua) in urine and DNA may be used as a predictor of radiotherapy success. Methods: All the aforementioned modifications were analyzed using techniques which involve HPLC/EC or HPLC/GC/MS. Results: Of all analysed parameters only patients with significantly elevated urinary excretion of the 8-oxo-Gua with concomitant unchanged level of 8-oxo-dG in leukocytes DNA in the samples collected 24 h after the first fraction in comparison to the initial level have significantly increased survival time (60 mo. after the treatment, survival of 50% of the patients who fulfill the above mentioned criteria, in comparison with 10% of the patients who did not). Conclusions: Results of our work suggest that patients with higher urinary 8-oxo-Gua and concomitant stable level of 8-oxo-dG in leukocytes DNA, after 24h of the first dose should be regarded as better responder to radiotherapy as being at lower risk of mortality. Impact: The above mentioned statement could make it possible to use these parameters as a markers to predict the clinical success.
The study of in vivo acute effect of two different delivery modalities of iron oxide core with titanium dioxide shell nanoparticles in rabbits liver tumor.
Authors: Refaat Tamer , West Derek , Elachy Samar , Parimi Vamsi , May Jasmine , Harris Kathleen R. , Larson Andrew C. , Omary Reed A. , Paunesku Tatjana , Woloschak Gayle
Published: March 2020

e22204

Background: To compare intravenous (IV) versus fluoroscopy-guided transarterial intra-catheter (IC) delivery of iron oxide core with titanium dioxide shell nanoparticles (NPs) in vivo in VX2 model of liver cancer in rabbits and detect the NPs distribution and effect of NPs presence on the target tumor and other rabbit’s organs. Methods: After obtaining the IACUC approval, liver tumors were obtained by implantation of tumor tissue obtained from a hind limb VX2 tumor of donor rabbits. NPs were delivered either IV or IC. After rabbit termination, 2 hours post NPs injection, tumor, liver, kidney, lung and spleen were harvested, split in half and a part of it was frozen while the remainder was formalin fixed and paraffin embedded. To assess the NPs distribution in 2D we stained 5um thick paraffin tissue sections using Dopamine-Biotin-DHS histochemical (HC) staining followed by Nanozoomer microscopy analysis. H and E staining, TUNEL assay and Ki67 immunohistochemistry were also done. X-ray Fluorescence Microscopy (XFM) was used to quantify the NPs. Frozen tissue was used for bulk NPs concentration analysis using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Results: This study included ten rabbits; 3 rabbits had IV NPs injections, 3 had IC NPs injection, 2 control and 2 donors. ICP-MS analysis showed statistically significant higher NPs concentration in tumors of IC arm vs. IV arm (p= 0.0356), while there was higher concentration of NPs in liver (p=0.00077) and spleen (p = 0.01356) of IV vs. IC arms but no difference in kidneys or lungs. These findings were consistent with results from HC and XFM analyses. HC 2D analysis of NPs distribution showed that the RES have taken up the NPs non-specifically. There were no statistically significant differences between the treatment groups regarding the Ki67 proliferation or the TUNEL apoptosis indices or when control rabbits were compared to NPs treated rabbits. Conclusions: Both IV and IC NPs injection are feasible modalities for delivering NPs to tumors with acceptable acute systemic effects and comparable tumor effect. IV delivery increased sequestration of the NPs by RES and their accumulation in spleen and liver.
A pilot chemoprevention study of isopropanolic black cohosh extract in women with ductal carcinoma in situ.
Authors: Hofstatter Erin Wysong , Stavris Karen , Horowitz Nina Ruth , Killelea Brigid K. , Tsangaris Theodore , Lannin Donald R. , Andrejeva Liva , Cong Xiangyu , Yao Xiaopan , Rimm David , Chagpar Anees B.
Published: March 2020

TPS1609

Background: Recent evidence suggests that black cohosh (Cimicifuga racemosa) may be a potential agent for breast cancer prevention. The active ingredients in black cohosh preparations appear to be triterpene glycosides. Recent preclinical data suggest several mechanisms by which triterpenes may prevent and treat breast cancer, including anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. Epidemiologic data demonstrate a significant protective effect of black cohosh against the development of breast cancer in healthy women, and prolonged disease-free survival in breast cancer patients. There is also abundant evidence demonstrating the safety and tolerability of black cohosh in several clinical trials studying its use for treatment of hot flashes. We hypothesize that efficacy of black cohosh can be demonstrated in a pilot pre-operative window trial in a cohort of women with ductal carcinoma in situ (DCIS). Methods: In this trial, we treat women with a 2-5 week pre-operative course of commercial standardized isopropanolic black cohosh extract (20 mg orally twice per day). We aim to demonstrate a reduction in breast epithelial cell proliferation as measured by Ki-67 staining in regions of DCIS using traditional IHC staining and AQUA analysis. We also assess safety and tolerability of black cohosh through monitoring of patient adherence, liver function tests and serum hormone levels. 22 patients will be enrolled onto the trial. Sample size is based on power calculations for the specific study aim of determining the mean change in the levels of Ki67, using a targeted effect size. Assuming a 10% drop-out rate, a sample size of 20 patients will achieve 91% power to detect a 0.8 standard deviation of difference with a two-sided significance level at 0.05 using Wilcoxon signed-rank test. Eligible subjects are pre- and post-menopausal women ≥ 18 years of age newly diagnosed with DCIS histologically confirmed on breast core biopsy, prior to definitive excision. Women who have recently taken any agent known to affect Ki67 levels in the breast (e.g. hormone therapy) are excluded. Enrollment is currently ongoing with 10 of 22 patients accrued. Clinical trial registry number NCT01628536. Clinical trial information: NCT01628536.
Design of the AFFINITY study: A randomized phase III study of a novel clusterin inhibitor, custirsen, plus cabazitaxel/prednisone (CbzP) versus CbzP alone as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Beer Tomasz M. , Blumenstein Brent A. , Fizazi Karim , Hotte Sebastien J. , Jacobs Cindy , Stewart Patricia S.
Published: March 2020

TPS5103

Background: Custirsen enhances chemotherapeutic activity via inhibition of clusterin expression. Clusterin is a cytoprotective, antiapoptotic chaperone upregulated by anticancer therapies that confers treatment resistance. In a phase 2 study, mCRPC patients who had progressed within 6 mos of completing first-line docetaxel (DOC)/prednisone (P) and who were retreated with DOC/P and custirsen had a median overall survival of 15.8 mos. Lowering of serum clusterin level during second-line treatment was associated with significantly longer survival. CbzP has recently shown a survival advantage in patients with prostate cancer that has progressed after DOC therapy. The AFFINITY study was designed to evaluate in a larger study whether adding custirsen to CbzP will further improve survival in this patient population. Methods: AFFINITY was initiated in August 2012. Eligible patients in this phase 3, international, multicenter, open-label trial must have received ≥225 mg/m2 of DOC; have progressive disease as defined by RECIST 1.1, bone scan progression, and/or serum prostate-specific antigen level; have metastatic disease of the chest/abdomen/pelvis/bone; have adequate renal and liver function; and have a Karnofsky score ≥70%. Patients may have received up to 1 DOC regimen as well as abiraterone and/or enzalutamide. Approximately 630 patients will receive 21d cycles of Cbz (25 mg/m2IV q21d) + P (10 mg PO/d), either alone or with custirsen 640 mg IV given for 3 loading doses and then weekly until disease progression, unacceptable toxicity, or 10 cycles. The primary efficacy measure is overall survival. The secondary measure is proportion of patients alive without disease progression at Day 140 post-randomization. All efficacy analyses are intent to treat. Adverse events of all patients who receive ≥1 dose of custirsen or Cbz will be included in the safety analysis. This study is sponsored by Teva BPP R&D, Inc., in collaboration with OncoGenex Pharmaceuticals, Inc. Clinical trial information: NCT01578655.
MotHER: A registry for women with breast cancer who received trastuzumab (T) with or without pertuzumab (P) during pregnancy or within 6 months prior to conception.
Authors: Brown Vikki , Partridge Ann , Chu Laura , Szado Tania , Trudeau Caroline , Andrews Elizabeth B
Published: March 2020

TPS658

Background: T and P are monoclonal antibodies that target different HER2 epitopes. T is approved for treatment of early and metastatic HER2+ BC while P is approved in combination with T for previously untreated HER2+ MBC. Oligohydramnios has been reported in patients (pts) who received T during pregnancy, and also in P-treated pregnant monkeys. Although both antibodies are FDA Pregnancy Category D, indicating evidence of fetal harm, some physicians and pts accept this risk and continue treatment. The MotHER registry was established in 2008 as an FDA postmarketing commitment to evaluate the effects of T therapy on pregnancy outcome; P was included in the study following its approval in 2012. MotHER is the first prospective study of the effects of a targeted cancer therapy on pregnancy outcome. Methods: MotHER is a US registry study of women exposed to T±P during pregnancy or within 6 months prior to conception. Women enroll voluntarily and are followed until pregnancy outcome; infants are followed through the first year of life. Medical information is primarily collected from healthcare providers. Information on potential birth defects noted at birth or during the pediatric follow-up is classified by a birth defect evaluator/clinical geneticist. Enrollment must be initiated before pregnancy outcome. Pts with known prenatal testing results may enroll, but to reduce the potential for bias these pts will be analyzed as a subset. Primary outcomes: number and nature of pregnancy complications, including oligohydramnios, pregnancy outcomes, fetal/infant outcomes and fetal/infant functional deficits. Secondary outcomes: preterm births, elective/therapeutic abortions, miscarriages, fetal growth abnormalities and delivery complications. The study is descriptive and not for formal hypothesis testing; event proportions with CIs will be calculated. The registry will accrue in the US from 2009 to 2019 for T-treated pts and from 2012 to 2022 for P+T-treated pts. The number of potential pts is small therefore physicians are encouraged to refer any eligible pt to increase knowledge about the safety of T±P in pregnancy. herceptinpregnancyregistry.com. Clinical trial information: NCT00833963.
Phase I/II study of neoadjuvant carboplatin, eribulin mesylate, and trastuzumab (ECH) for operable HER2 positive (HER2+) breast cancer.
Authors: Schwartzberg Lee Steven , Tauer Kurt W. , Hermann Robert C. , Nikolinakos Petros G. , Houts Arthur C.
Published: March 2020

TPS659

Background: Carboplatin, docetaxel and trastuzumab (TCH) regimen yields substantial pathologic complete response (pCR) in operable HER2+ breast cancer. Eribulin mesylate (E) is a tubulin inhibitor recently shown to improve overall survival compared to taxanes and other agents in heavily pretreated metastatic breast cancer patients. This trial was designed to determine the maximum tolerated dose (MTD) of E in combination with CH (Phase I) and to determine efficacy and safety of the ECH regimen (Phase II) given as neoadjuvant therapy to early stage HER2+ breast cancer with pathologic complete response the primary endpoint. Methods: This is a multicenter prospective open label single arm trial. Eligible patients were operable stage IIA – IIIB HER2+ breast cancer, ECOG 0-1, normal LVEF, QTc < 480 msec, < grade 1 neuropathy and no history of invasive cancer within the past 3 years. Phase I planned up to 12 patients from 4 centers to 1 of 3 E dose cohorts, with pts treated at the MTD also evaluable for Phase II. Starting dose level 0 was 1.1 mg/m2 with escalation to dose level +1 at 1.4 mg/m2 and de-escalation to dose level -1 at 0.9 mg/m2 if necessary. ECH was given IV for six 3-week cycles with E d1 and d8; C AUC 6 d1; and H 8 mg/kg loading dose d1C1 and 6 mg/kg d1C2-C6. H is scheduled to continue after surgery to complete 1 year of treatment. C1 dose limiting toxicities (DLTs) were defined as: grade 4 thrombocytopenia, anemia, or neutropenia lasting > 5 days; any grade 3-4 non-hematologic toxicity attributable to E, C, H, or the combination; inability to deliver all three agents at assigned dose and schedule. Standard 3+3 dose escalation design was used. At present, 6 patients have been enrolled at dose 0 and 6 have been enrolled at dose +1. The MTD for E has not yet been determined. Phase II has planned enrollment of 44 additional patients from 8 centers with primary endpoint rate of pCR at surgery to be performed 4-8 weeks after completion of ECH and secondary endpoints of safety to include peripheral neuropathy and cardiac toxicity at treatment completion and 1 year follow up. Clinical trial information: NCT101388647.