bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival, surgical resectability, and late effects in the hepatoblastoma patients treated by cisplatin plus pirarubicin (CITA) chemotherapy.
Authors: Hiyama Eiso , Kamimatsuse Arata , Onitake Yoshiyuku , Ueda Yuka , Watanabe Kenichiro , Hishiki Tomoro , Tajiri Tatsuro , Ida Kohmei , Yano Michihiro , Kondo Satoshi , Oue Takaharu 
Published: March 2020

10038 Background: The Japanese Study Group for Pediatric Liver Tumor(JPLT) is running cooperative treatment studies on hepatoblastoma (HB) since 1991. The main aim in JPLT-2 study was to evaluate the efficacy of cisplatin/pirarubicin. JPLT-2 protocol was launched in 1999 to evaluate the cure rate of risk-stratified HB: standard risk HB (a tumor involving three or fewer sectors of the liver), intermediate risk HB (a tumor involving all sectors of the liver or invasion into portal or hepatic vein) and high risk HB (a tumor involving all sectors of the liver or with metastasis). Methods: Until 2011, 313 children with hepatic tumors who were younger than 15 years of age were eligible for inclusion in the JPLT2 study. The cisplatin/pirarubicin regimen (CITA) is kept as the first line in 254 cases. In this study, we examined the outcome and late effects of the HB patients by the risk-stratified three groups (standard, intermediate and high risk groups). Results: Until 2011, 254 cases underwent the CITA protocol including 78 cases (18%) with metastatic tumors. The 3-year OS of the cases with standard risk HB were 94%, while that of the cases with Intermediate and high risk HB was 64% and 34%, respectively. Except for23 cases who underwent primary resection, complete resection of primary after CITA was performed 86% of standard risk, 66% of intermediate risk and 56% of high risk patients. And the late phase complications were 4 cases with maldevelopment, 15 with cardiac complications, 24 with ototoxicity and 5 with second malignancies. Conclusions: As compared with other regimens, CITA regimens achieved similar or superior rates of survival and resectability in standard risk patients. More promising strategies including adequate liver transplantation and new targeting drugs should be developed for intermediate and high risk HBs. Clinical trial information: UMIN000001116.
Comparison of standard immunohistochemistry and automated quantitative immunohistochemistry for quantification of signaling proteins in archival Ewing sarcoma samples.
Authors: Applebaum Mark A. , Thomas Dafydd G. , Horvai Andrew , Lawlor Elizabeth R , DuBois Steven G. 
Published: March 2020

10045 Background: Targeted therapies are increasingly being evaluated for patients with Ewing sarcoma (EWS). Optimal strategies for quantifying key signaling proteins from paraffin-embedded material remain unclear. We sought to quantify tumor expression of IGF-1R, EGFR, and PTEN in EWS using two different methodologies. Methods: Decalcified paraffin-embedded tissue was obtained from 40 patients with EWS. 28 samples were obtained at time of diagnosis, 6 after initial chemotherapy, and 6 at time of relapse. Tumor was evaluated for the expression of IGF-1R, PTEN, and EGFR using standard immunohistochemistry (IHC) and automated quantitative analysis (AQUA) immunohistochemistry. Standard IHC results were categorized as low, medium and high expression based on a pathologist’s review. Expression by AQUA was measured as a continuous variable in arbitrary units. One sided ANOVA analysis was used to compare the mean AQUA expression for each analyte between categories of expression by IHC. Results: The mean age of patients was 15 years (range 1-49 yrs) at time of diagnosis. 68% were male and 66% had localized disease. Samples displayed a wide range of expression by AQUA: mean IGF-1R = 10702 (range 393 - 14424); EGFR = 2750 (range 672 – 9798); and PTEN = 2250 (range 251 – 6557). Mean IGF-1R expression by AQUA did not differ significantly between standard IHC expression categories (mean IGF-1R expression by AQUA for low IHC = 11255, medium IHC = 11070, high IHC = 11023; p = 0.98). Mean PTEN expression by AQUA was higher in the medium and high IHC categories (mean PTEN expression by AQUA for low IHC = 1229, medium IHC = 2715, high IHC = 2940; p = 0.064). Only two samples expressed EGFR by standard IHC. These samples qualitatively had higher AQUA expression levels, but there were too few samples for a reliable determination of statistical significance. Conclusions: AQUA provides a more dynamic range for each marker, though there was poor correlation with standard IHC results. Larger sample sets are needed to determine the optimal approach for quantifying signaling proteins in Ewing sarcoma.
Targeting apoptosis and autophagy by a novel bcl-2 inhibitor, GX15-070, in neuroblastoma.
Authors: Sartelet Herve , Cournoyer Sonia , Addioui Anissa , Belounis Assila , Beaunoyer Mona , Nyalendo Carine , Teira Pierre , Vassal Gilles , Haddad Elie 
Published: March 2020

10048 Background: Neuroblastoma (NB) is a frequent pediatric tumor with poor prognosis. The disregulation of the anti-apoptotic protein Bcl-2 is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate the in vitro and in vivo therapeutic efficiency of GX 15-070, a Bcl-2 inhibitor, used alone and in combination with conventional drugs used in the treatment of NB and hydroxychloroquine (HCQ), a known autophagy inhibitor. Methods: Using 6 NB cell lines, cell viability (MTT) assays were done at progressively increased concentrations of GX 15-070 alone or in combination with cisplatin or with Z-VAD-FMK, a broad-spectrum caspase inhibitor. Apoptosis was tested by evaluating the cleavage of caspase 3 by western blots (WB) and the Annexin V/7-AAD staining studied by FACS. To assess if autophagy was modified by GX 15-070, the cleavage of LC3 protein was tested by WB and cell survival were tested with combination of GX 15-070 and HCQ. To verify the anti-tumor activity in vivo of GX 15-070, orthotopic injections were made on NSG mice treated with GX 15-070 alone and in combination with HCQ. Results: It was observed a high sensitivity of the NB cells to GX 15-070 with increase of cell death and a potential synergistic of this molecule when it’s combined with cisplatin or HCQ. This cell death was due to apoptosis and may also be inhibited by Z-VAD-FMK. GX 15-070 alone or associated to cisplatin increased the autophagy. The in vivo study showed that GX 15-070 treatment used alone or in combination with HCQ significantly decreased the size of the tumor. Conclusions: Our results support the interest of GX 15-070 in the treatment of NB alone or in combination with classical drugs. Our studies also support that activation of apoptosis associated with inhibition of autophagy have a synergistic potential against tumoral progression and must have to be considered in further mechanistic studies for the optimization of more efficient combined therapies in the treatment of NB.
Differential pathologic complete response rates after neoadjuvant chemotherapy among molecular subtypes of triple-negative breast cancer.
Authors: Masuda Hiroko , Baggerly Keith A. , Wang Ying , Zhang Ya , Gonzalez-Angulo Ana M. , Meric-Bernstam Funda , Valero Vicente , Lehmann Brian D. , Pietenpol Jennifer A. , Hortobagyi Gabriel N. , Symmans William Fraser , Ueno Naoto T. 
Published: March 2020

1005 Background: By gene profiling, Lehmann et al. (J Clin Invest 121:2750-2767, 2011) reported that triple-negative breast cancer (TNBC) can be classified into 6 clusters—basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR)—plus an unstable (UNS) cluster. While it is clear that patients with TNBC differently respond to chemotherapy, the clinical relevance of these molecular TNBC subtypes is unknown. Methods: We qualitatively reproduced the Lehmann et al. experiments using Affymetrix CEL files from the public datasets. We identified 130 TNBC gene expression microarrays obtained from 03/00 to 03/10. All patients had received neoadjuvant chemotherapy containing sequential taxane and anthracycline-based regimens and had evaluable pathological tumor response data. Median follow-up was 68.1 months. (5.1-147.5). We classified TNBC samples using Lehmann’s gene signatures, then performed Fisher's exact test to correlate TNBC subtype and pCR status. To assess the independent utility of TNBC subtype for predicting pCR status, we fit a logistic regression model to our data and used age, clinical stage, treatment regimens, and nuclear grade as potential explanatory factors. We also performed comparison of the subtypes with the PAM50 intrinsic subtypes and RCB index. Results: The BL1 subtype had the highest pCR rate (52%); BL2 and LAR the lowest (0% and 10%, respectively). TNBC subtype and pCR status were significantly associated (p = 0.044). TNBC subtype was an independent predictor of pCR status (p = 0.022) by a likelihood ratio test.The Lehmann’s subtype classification better predicted pCR status than did the PAM50 intrinsic subtypes (basal-like vs. non basal-like). Conclusions: Dividing TNBC into 7 subtypes predicts high vs. low pCR rate. The 7-subtype classification may lead to innovative personalized medicine strategies for patients with TNBC. There is a need for prospective validation of the hypothesis that pCR rates associated with the seven TNBC subtypes will predict long-term patient outcome.
Results with the intensive chemotherapy Mexican regimen in the treatment of pediatric high-grade osteosarcoma: Experience at the Instituto Nacional de Pediatria.
Authors: Castellanos-Toledo Araceli , Zapata-Tarres Marta , Peña-del-Castillo Humberto , Figueroa Carbajal Jose de Jesus 
Published: March 2020

10058 Background: In Mexico, pediatric high-grade osteosarcoma (HGO) occupies the fifth place of all pediatrics cancers, representing the 4.4%. It presents with a high incidence of metastatic pulmonary disease and large primary tumor volume at diagnosis, resulting in poor survival. The results of the named 2005 Chemotherapy Regimen are very promising. Methods: A retrospective, longitudinal, clinical study was performed from January 2005 to January 2012, including 55 patients (<18 years old) with extremity HGO and no prior chemotherapy treatment. All patients received a 10-week neoadjuvant-chemotherapy regimen (6 curses), with cisplatino 120mg/m2 plus doxorrubicina 75mg/m2 and a 15-week adjuvant-treatment (5 curses) with ciclofosfamide 1800 mg/m2 plus etoposide 900 mg/m2. Results: Median age was 12 years, 51% boys and 49% girls. There were 51% distal femur, 11% proximal humerus, 18.2% proximal tibia, 7.3% distal tibia, 5.4% fibula and 5.5% proximal femur. Thirty-two patients (58.2%) had pulmonary metastases at diagnosis. There were 76.4% osteoblastic tumors, 16% chondroblastic and 7.3% telangiectatic. Twenty patients (36.4%) had an amputation procedure and 15 (27%) a limb desarticulation, 18 by a great tumor volume at diagnosis and two by eventual local relapse. Twelve patients (22%) had limb-sparing surgery. There were 10 (18.2%) good-responder patients and 38 (69%) bad-responders to neoadjuvant-chemotherapy. The overall survival (OS) for non-metastatic patients was 70% and 35% for metastatic patients (p 0.016). The event-free survival for non-metastatic patients was 65% and 30% for metastatic patients (p 0.032). OS for good-responders was 80% and 50% for bad-responders (p 0.009). No important toxicity and no second malignancies were reported. Conclusions: In spite of the presence of significant unfavorable prognostic factors in our patients, this intensive chemotherapy regimen showed improved results in overall survival as compared to other standard regimens, being short, inexpensive and with relatively few adverse events. This regimen can be useful in other developing countries.
Comparison of doxorubicin and cyclophosphamide (AC) versus single-agent paclitaxel (T) as adjuvant therapy for breast cancer in women with 0-3 positive axillary nodes: CALGB 40101.
Authors: Shulman Lawrence N. , Berry Donald A. , Cirrincione Constance T. , Becker Heather , Perez Edith A. , O'Regan Ruth , Martino Silvana , Shapiro Charles L. , Atkins James , Schneider Charles , Kimmick Gretchen Genevieve , Burstein Harold J. , Norton Larry , Muss Hyman Bernard , Hudis Clifford , Winer Eric P. ,   Cancer and Leukemia Group B
Published: March 2020

1007 Background: Determining optimal adjuvant chemotherapy for early stage breast cancer depends on efficacy and toxicity. We sought to determine if T is equivalent to AC but with reduced toxicity. Methods: Pts with operable breast cancer with 0-3 positive nodes were enrolled on a 2x2 factorial design study which addressed (1) superiority of 6 vs. 4 cycles of therapy (previously reported, Shulman, JCO 2012) and (2) equivalence of single-agent T to standard AC, defined as upper bound of 95% confidence interval (CI) of hazard ratio (HR) of T vs. AC < 1.30 for the primary endpoint of relapse-free survival (RFS). A planned target of 567 RFS events required 4,646 pts with 4 yrs FU. At activation in 2002, T (80mg/m2) was q1wk for 12 or 18 wks and AC (60/600 mg/m2) was q3wk for 4 or 6 cycles. In 2003 (570 pts enrolled) schedules were revised to 4 or 6 cycles q2wk for both T (175 mg/m2) and AC. The 6-cycle arms were dropped in 2008 (3,171 pts enrolled) due to slow accrual. Relative effectiveness of T to AC is shown by hazard ratio (HR). Logrank p-values are measures of discordance but are not relevant for the equivalence question and are not adjusted for multiple comparisons. Results: After enrolling 3,871 pts, the study closed in 2010 due to slowing accrual. With a median follow-up of 6.1 yrs there are 437 RFS events. The HR of 1.26 (95% CI: 1.05-1.53; p = 0.02) does not allow a conclusion of equivalence of T with AC. With 266 deaths the HR for overall survival (OS) is 1.27 (95% CI=1.00-1.62; p = 0.05), favoring AC. The estimated absolute advantage of AC at 5 yrs is 3% (91 vs. 88%) for RFS and 1% (95 vs. 94%) for OS. All 9 treatment-related deaths were in pts receiving AC and are included in the survival analysis. The incidence of Grade 3+ toxicity for AC vs T was 33% vs. 4% for hematologic toxicity and 36% vs 22% for non-hematologic toxicity. Conclusions: This trial did not show equivalence of T to AC, a conclusion that is very unlikely to change with additional follow-up. T was less toxic than AC. Clinical trial information: CDR0000069444/NCT00041119.
Screening with whole-body MRI (WB-MRI) in pediatric patients with Li Fraumeni syndrome (LFS).
Authors: O'Neill Allison Frances , Steinberger Allie , Voss Stephan D. , Root Elizabeth J. , Garber Judy Ellen , Diller Lisa 
Published: March 2020

10071 Background: LFS is a rare hereditary cancer syndrome characterized by a high risk of developing a wide range of malignancies. Germline mutations in the tp53 gene confer approximately a 12-fold risk of developing cancer by age 20. Given the potential for diverse malignancies, cancer surveillance in LFS patients is challenging. We piloted the use of WB-MRI for pediatric LFS patients as a cancer screening tool. Methods: Eligibility included: documented tp53 mutation, or obligate carrier status based upon family history/genetic testing, and no recent cancer diagnosis. WB-MRI was performed as a research test, in conjunction with recommended clinical screening based upon family history and clinician recommendation. Our primary aim was to determine the feasibility (defined as 87% completion rate) of obtaining two planned annual MRI scans in 15 pediatric LFS patients. Our secondary aim was to calculate the incidence and describe the characteristics of primary cancers detected. Results: Nine pediatric patients from 5 families have been enrolled and all have successfully completed one WB-MRI. Seven patients were known carriers, and 2 underwent genetic testing in order to enroll in the study. Median age was 12 years, range 6 to 15. Scan time was 60-90 minutes and 2 patients required anesthesia with propofol. There were no acute scan complications. Six of the 9 (67%) scans demonstrated incidental findings (T2 cerebral cortex abnormality, L5-S1 synovial cyst, thoracic syrinx, T12 hemangioma, 2 ovarian cysts, and degenerative disc disease). Only one patient underwent a dedicated follow-up imaging study for an abnormality on WB-MRI. None of the patients required biopsy. All patients had normal screening laboratory work. These results are being presented early to foster collaboration. Conclusions: All patients enrolled on our study tolerated WB-MRI; none were diagnosed with a new malignancy. Although preliminary, our results to date are in contrast to previous reports documenting a high incidence of cancers detected during screening of LFS patients. WB-MRI may be a promising approach to screening; a large multi-center trial will be needed to determine its efficacy in detecting incident cancers and true test characteristics.
Proliferation-, estrogen-, and T-cell-related metagenes to predict outcome after adjuvant/neoadjuvant chemotherapy for operable breast cancer in the ECTO trial.
Authors: Bianchini Giampaolo , Cappelletti Vera , Callari Maurizio , Carcangiu Maria Luisa , Eiermann Wolfgang , Semiglazov Vladimir , Guillem Vicente , Lluch Ana , Mansutti Mauro , Zambetti Milvia , Mariani Gabriella , Magazzu Domenico , Valagussa Pinuccia , Paolini Biagio , Musella Valeria , Di Buduo Eleonora , Miodini Patrizia , Scuro Manuela , Daidone Maria Grazia , Gianni Luca 
Published: March 2020

1014 Background: Predicting recurrence in operable breast cancer (BC) despite optimal chemotherapy would be relevant to new drug development and tailored treatments. Methods: A large series (n=3,154) of public Affymetrix gene-expression profiles (GEP) was used to define prognostic/predictive metagenes in different BC subtypes. In ER+/HER2- a proliferation and an ER-related metagene were combined to predict low, intermediate and high risk of recurrence. In TN and in HER2+ a T cell metagene was used to predict low, intermediate and high risk (higher expression associated with lower risk). The metagenes were validated in patients enrolled in the phase III ECTO trial (Gianni L. JCO 2009) and treated with the same taxane-anthracycline-CMF regimen as neoadjuvant or adjuvant therapy before endocrine therapy if indicated. The outcome was distant event free survival (DEFS). Results: 283 good quality GEPs were obtained (neoadjuvant n=121; adjuvant n=162) from 464 retrospectively collected samples. Median follow-up was 8.9 years. In ER+/HER2- tumors the 10-yrs DEFS was 92.3, 81.2 and 66.6% in low, intermediate and high risk groups, respectively [high vs low HR 4.38 (1.01-19.1) p=.048] according to proliferation and ER-related metagenes. In HER2+ and TN subgroup the 10-yrs DEFS was 97.2, 75.6 and 78.8% in low, intermediate and high risk groups, respectively [high vs low HR 8.73 (1.09-69.8) p=.041]. In TN tumors, the pCR rate was 20% in the high and 61.5% in the low risk group. By combining the predicted risk group in each molecular subtype the 10-yrs DEFS was 95.3, 79.2 and 71.5% in low (24.2%), intermediate (42.7%) and high (33.1%) risk group, respectively [logrank p=0.003; high vs low HR 6.22 (1.87-20.6) p=.002]. ER, PGR, Ki67 and lymphocyte infiltration (LI) by IHC underperformed compared to genomic predictors. Conclusions: BC patients at higher risk of relapse despite optimal standard treatment can be identified who should be spared ineffective and toxic therapy and considered for investigational new strategies. In TN and HER2+, high T cell metagene and to a lesser extent LI are prognostic/predictive and associated with an extremely low risk of DEFS after chemotherapy.
10-year outcomes of breast cancer patients with histologically confirmed axillary lymph node metastases and pathologic complete response after primary systemic chemotherapy.
Authors: Mougalian Sarah Schellhorn , Lei Xiudong , Hsu Limin , Hortobagyi Gabriel N. , Kuerer Henry Mark , Symmans William Fraser , Valero Vicente 
Published: March 2020

1017 Background: Pathologic complete response (pCR) of tumors in the breast and axillary lymph nodes (ALN) after primary systemic chemotherapy (PST) is associated with an excellent outcome. A previous analysis showed superior 5-year overall survival (OS) and relapse-free survival (RFS) for patients who achieved an ALN pCR after PST compared to those without a pCR in 5 prospective clinical trials. This study is an expanded analysis of all patients treated with PST at our institution examining the impact of ALN pCR on 10-year OS and RFS. Methods: Patients with clinical stage II/III and pathologically confirmed ALN metastases who underwent PST were categorized into 1 of 2 groups: ALN pCR and ALN residual disease. Additional data were collected, including breast cancer subtype, clinical tumor size, and lymph node staging, pathologic tumor (T) stage, and class of PST. RFS and OS were estimated by the Kaplan-Meier product limit method. Subset analyses were performed on patients with HER2-positive cancer. Results: 1,600 women diagnosed between 1989 and 2007 were identified. Median follow-up was 79 months (5-277); 454 (28.4%) achieved an ALN pCR. ALN pCR was associated with triple-negative and higher grade cancers, lower clinical stage, and lower pathologic breast T stage. 5-year OS and RFS estimates were similar to prior analysis. The 10-year OS was 85% and 58% and the 10-year RFS 83% and 55% (p < 0.001), for patients who achieved an ALN pCR and those with residual ALN disease. For HER2-positive breast cancers, 67.3% of patients who received HER2-targeted therapy achieved an ALN pCR vs. 32.3% without HER2-targeted therapy (p < 0.001). For patients receiving HER2-targeted therapy for HER2-positive breast cancer (n = 153), the 10-year OS was 92% and 52% (p = 0.006), and the 10-year RFS was 89% and 59% (p < 0.001) for those with and without an ALN pCR. Conclusions: ALN pCR is an excellent early surrogate marker for long-term outcome, 10-year RFS and OS. In HER2-positive breast cancers, HER2-targeted therapy is associated with high rates of pCR. Despite the aggressive nature of their disease, patients who achieve ALN pCR with PST have an excellent 10-year prognosis.