bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late side effects of osteosarcoma neoadjuvant chemotherapy: The experience at Rizzoli institute
Authors: Longhi A. , Ferrari S. , Ferrari C. , Cesari M. , Palmerini E. , Bacci G. 
Published: March 2020

9508 Background: Good cure rate has been reached in osteosarcoma treatment with chemotherapy, but there are late side effects. Methods: We reviewed charts of 755 patients (pts) with localized osteosarcoma of the extremity treated in 6 subsequent protocols (1983–2000) with Doxorubicin (300–480 mg/m2), Cisplatin (300–600 mg/m2), Methotrexate (3.7–75 g/m2), Ifosfamide (30–75 g/m2). Etoposide was employed only in 47 pts. Results: With a median follow up of 8 yrs (5–20), the median 10-yrs EFS was 58%. 13 patients (1.7%), 9 females and 4 males, had a symptomatic cardiopathy with two cardiopathy-related deaths, and 3 patients needed a heart transplant. The median age of these pts was 13 yrs (4–28). Median Doxorubicine dose = 480 mg/m2. Median interval from chemotherapy completion to cardiopathy onset was 3 months; 7 patients are alive, and 6 died: 4 for cardiopathy, 2 for metastatic disease. 17 second malignant neoplasms (SMN) occurred in 16 pts (2.1%) after a median interval of 7 yrs. One patient had both a breast and ovarian cancer. SMN were: 2 AML, 3 ALL, 1 CML, 3 breast cancer, 1 CNS tumor, 1 lung tumor, 1 parotid tumor, 2 soft tissue sarcoma, 1 skin cancer, 1 ovary cancer, 1 Ewing sarcoma. Eight of these 16 pts died of the second tumor. Infertility related to chemotherapy affected mostly males. Amenorrhea affected 69% of postpubertal females during chemotherapy but only two pts had permanent amenorrhea (39 and 43 yrs). No delay in pubertal maturation was seen in both gender. The incidence of infertility in male was related to Ifosfamide and was dose-dependent. Permanent azoospermia was 100% in males who received 60–75g/m2 Ifosfamide. No congenital defects were observed in the offsprings of both gender. The incidence of chronic renal failure was negligible in pts who received <60g/m2 Ifosfamide; in those who received >60 g/m2 a subclinical tubular impairment was observed in 48%, but only 1pt required dialysis. In the last protocol, a mild hearing impairment due to Cisplatin was evident in 40% of pts. Conclusions: Late toxicities are relevant and prolonged follow-ups are recommended as well as less toxic protocols. No significant financial relationships to disclose.
Gefitinib in second line treatment of metastatic or locally advanced synovial sarcoma expressing HER1: A phase II trial of EORTC Soft Tissue and Bone Sarcoma Group
Authors: Blay J. , Le Cesne A. , Whelan J. , Van Oosterom A. , Ray-Coquard I. , Judson L. , Hogendorn P. , Marreaud S. , Hermans C. , Van Glabbeke M. 
Published: March 2020

9517 Background: Synovial sarcomas (SyS) have been reported to overexpress HER1 in gene expression profile experiments and immunohistochemistry. Gefitinib, a specific inhibitor of HER1, was therefore tested in advanced or metastatic SyS failing doxorubicin (Doxo) ± ifosfamide (Ifo). Methods: Patients (pts) with advanced or metastatic SyS expressing HER1 using IHC were included. The principal inclusion criterias were: disease not curable with surgery and/or radiation, presence of a measurable progressive lesion(s), pretreatment with 1–3 line of chemotherapy in metastatic phase, ECOG PS 0 to 2, age ≥18 years. Gefitinib was given at 500mg/day until progression or intolerance. Primary endpoint was the rate of progression free survival at 3 months. A two step Simon design was used with a p0 of 25% and a p1 of 45%, with α and β of 0.1. 44 patients were scheduled to be recruited. Results: Between 10/02 and 10/05, 48 pts were included in 12 EORTC STBSG centers, 27 (56%) males and 21 (44%) females. Median age was 42 years (range 19–66). Metastatic sites were lung in 92% and soft tissue or lymph nodes in 42%, of the patients. Respectively 42, 40 and 18% of the patients had received 1, 2 and >2 lines of CT. As of December 2005, 37 pts are evaluable for toxicity and 39 for the primary endpoint. Median treatment duration was 11 weeks (range 2–25). Toxicity (G1–4) reported included fatigue (43%), diarrhea (54%), cough (35%), dyspnea (43%), cutaneous (73%). G3–4 toxicities were dyspnea (9), fatigue (4), cutaneous (2), cough (1), neurological (2), thombosis (2), hypoxia (1), infection (1). There was no drug related death. No dose reduction has been reported so far, but treatment had to be temporarily interrupted in 23% of the patients. As of December 2005, there were no objective response reported. Seven (18%) pts achieved stable disease as best response. At 3 months, 5 of the 39 (13%) evaluable patients achieved PFS; 6 and 12 months PFS were 10% and 3% respectively. Conclusions: 13% of SyS expressing HER1 achieved prolonged progression free survival at least 12 weeks) with gefitinib. Gene expression profiling and protein expression were not accurate predictors of gefitinib activity in this model. No significant financial relationships to disclose.
Sunitinib treatment of pediatric metastatic GIST after failure of imatinib
Authors: Janeway K. A. , Matthews D. C. , Butrynski J. E. , D’Amato G. Z. , Agresta S. , Garrett C. , Corless C. L. , Albritton K. H. , Demetri G. D. 
Published: March 2020

9519 Background: The genotype of most GIST in pediatric patients (pts) is “wild type” (WT-GIST), with no detectable KIT or PDGFR-α mutations. Adults with metastatic WT-GIST often have suboptimal results and primary resistance to imatinib (IM) therapy. Treatment with sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activities, results in significant clinical benefit, such as improved survival, for adult pts with IM-resistant GIST, including WT-GIST. We report here the treatment of 3 pediatric pts with IM-resistant, metastatic GIST using sunitinib. Methods and Patients: Pt 1 presented at age 17 with numerous abdominal and hepatic GIST metastases. Following surgical debulking and 6 wks of IM treatment, objective progression was noted due to growth of omental masses and a new hepatic lesion. Pt 2 presented at age 8 with an isolated gastric GIST, fully resected, followed by adjuvant IM that continued until resection of a local recurrence 14 mos later. She had 2 more local recurrences and developed lung metastases. Pt 3 presented at age 13 with a large gastric GIST and a retroperitoneal metastasis, both fully resected and followed by adjuvant IM for 18 mos. Six mos after discontinuing IM, recurrent metastatic GIST was noted in the liver and retroperitoneum; IM therapy was resumed with stable disease for 1 yr when new hepatic lesions appeared with progression of the retroperitoneal mass. Pts 1 and 2 had WT-GIST, while genotyping of Pt 3 is pending. Sunitinib, obtained via an expanded-access protocol, was administered in 6-wk cycles, orally QD for 4 wks followed by 2 wks off dosing. Results: All pts have received 5 cycles of sunitinib. All GIST lesions have stabilized or decreased in size by CT imaging, with complete regression of 2 lung nodules in Pt 2. 18FDG-PET imaging obtained in 2 pts showed significant decreases in tumor-associated activity at all disease sites. Side effects with sunitinib have been manageable, including grade 2 GI and hematologic toxicities in pt 1, grade 3 fatigue in pt 2 and grade 3 hematologic toxicity in pt 3. Conclusions: Sunitinib shows important antitumor activity in pediatric pts with IM-resistant GIST. An expanded phase I/II trial of sunitinib in pediatric GIST is warranted. [Table: see text]
Phase-1 study of isophosphoramide mustard (IPM)-lysine in advanced cancers
Authors: Gale R. , Van Vugt A. , Rosen L. , Chang L. , Lorusso P. , Valdivieso M. , Malburg L. , Struck R. , Morgan L. 
Published: March 2020

9524 Background: IPM is a bi-functional alkylator which cross-links DNA through G:C base-pairs resulting in irreparable 7-atom inter-strand cross-links. IPM is the active moiety of ifosfamide (IFOS), a pro-drug of IPM. IPM is active in diverse cancer models but is unstable. We stabilized IPM with lysine (IPM-lysine; ZIO-201). ZIO-201 was active in pre-clinical models including human cancer cell lines, human-mouse xenografts and cancers resistant to cyclophosphamide (CPA) and IFOS. Because ZIO-201 is not metabolized to acrolein or chloroacetaldehyde, bladder and CNS toxicities are unlikely. Methods: Phase-1 trial in subjects with advanced cancers. ZIO-201 was given daily for 3 consecutive d at a starting dose of 30 mg/me2/d every 3 w. Neither mesna nor IV hydration were given. 11 dose levels were studied in 18 subjects up to 795 mg/me2/d; dose-escalation continues. Data on the 1st 15 subjects are available for analysis. Results: Median age was 59 y (range, 18–70 y); 10 subjects were male. Diagnoses included colorectal cancer (N=5), sarcoma (N=3) and 1 subject each with gastric, lung, bladder, prostate, ovary and thyroid cancers and mesothelioma. 7 had extensive and 8, limited disease. All subjects received extensive prior therapy. Median N cycles was 2 (range, 1–13). Toxicities ≥ grade-2 occurring in > 20% of subjects included anemia (N subjects=4) and diverse GI complaints (N=4). 4 of 8 subjects receiving doses > 445 mg/me2/d had transient proximal renal tubular acidosis. There was no hemorrhagic cystitis or CNS toxicity. 1 subject with mesothelioma had stable disease > 13 mo. Pharmacokinetic studies at 595 mg/me2/d showed a tmax = 13 min (SD ± 9 min), Cmax = 44.7 μg/mL (SD ± 34.1 μg/mL), t1/2 = 35 min (SD ± 7 min) and AUC0-∞ = 1.68 mg·min/ml (SD ± 1.26 mg·min/ml). Conclusions: These data suggest a possible role for ZIO-201 in IFOS-sensitive cancers (especially sarcoma and lymphoma). ZIO-201 may also be active in CPA and IFOS-resistant cancers. Comparable or greater efficacy with less toxicity is expected. [Table: see text]
A non-comparative phase II study of bendamustine hydrochloride in patients with pretreated soft tissue sarcoma (German Sarcoma Group-AIO 001)
Authors: Mayer F. , Schleicher J. , Huober J. , Meisinger I. , Pintoffl J. , Kaefer G. , Gruenwald V. , Burkart C. , Kanz L. , Hartmann J. T. 
Published: March 2020

9525 Background: To assess the efficacy and safety of bendamustine hydrochloride, a nucleoside analogue with alkylating activity, in patients with adult type soft tissue sarcoma (STS) who have failed anthracyline-based chemotherapy. Methods: Pts with a ECOG performance status 0–2, measurable disease and adequate organ functions were eligible. All patients had inoperable locally advanced or metastatic disease and had progressive disease during or after first-line chemotherapy prior to study entry. Bendamustine was administered at a dose of 100 mg/sqm on day 1 and 2 every four weeks for a maximum of 6 cycles with tumour assessment every two cycles. The primary endpoint was overall response rate as defined by RECIST. The secondary endpoint was toxicity. A two-stage design was used (1st step: 14 pts, at least 1 PR in order to succeed with 2nd step; p0 = 5%, p1 = 25%, alpha = beta = 0.1). Results: 32 patients, median age 56 yrs (range, 18–74) with STS were recruited (3 pts not evaluable for efficacy analysis). In general the drug was well tolerated. Grade 3 toxicity was granulocytopenia in 9% and febrile neutropenia/fever in 3% of pts. No toxic death was seen in a total of 89 cycles administered. A single pt experienced a clinically significant allergic reaction (3%). Anti-tumour activity: 1 confirmed partial response (3%). A further 10 patients had progression arrest by cycle two (34%). Conclusions: The confirmed objective response rate is low. However, the incidence of progression arrest in pretreated adult type STS is in the range of other agents considered active in STS. The observed toxicity profile is favorable. Further investigation in STS appears warranted. No significant financial relationships to disclose.
Loss of heterozygosity with acquisition of homozygous KIT-activating mutation promotes gastrointestinal stromal tumor progression
Authors: Chen L. L. , Prieto V. G. , Sabripour M. , Wu E. F. , Raymond A. K. , Sang H. , Frazier M. L. 
Published: March 2020

9530 Background: Gastrointestinal stromal tumors (GISTs) originate from interstitial cells of Cajal and represent the most common mesenchymal tumor of GI tract. The activating mutations of KIT and platelet-derived growth factor receptor α (PDGFRA) have been demonstrated in 88% and 6% of GISTs respectively. Multiple genetic events are involved in tumor initiation and progression. Activation of an oncogene can result from a single hit of gain-of-function mutation, but two hits leading to loss of heterozygosity (LOH) are necessary for inactivation of a tumor suppressor gene for the initiation of neoplasia. Little is known about the significance and mechanism of LOH of oncogenes in tumor progression. The LOH of activating-oncogenes is not infrequent, i.e. in more than 8% of GIST. These GIST clones with LOH prevail and dominate, strongly suggestive of proliferative and metastatic advantages. However, the significance and mechanisms of LOH acquiring homozygous activating-oncogene mutation remain unknown. Methods: Genomic DNA and cDNA sequencing analysis of KIT, single-nucleotide polymorphisms (SNPs), immunohistochemistry of GISTs clones, and 3D structural analysis of the mutated KIT. Results: Real-time genetic studies in GIST show initial development of overexpression of KIT without mutation, to coexistence of various heterozygous-activating mutations; eventually, one clone dominates. Comparisons within the same patient show that clonal evolution from heterozygous to LOH acquiring homozygous (diploid) KIT-activating mutation results in dominance of the latter, with augmented KIT signaling and doubling of mitotic figures. Using SNPs for allelotyping, we found that mitotic nondisjunction, rather than mitotic recombination, represents an important mechanism of the second hit. Conclusion: GIST clones with LOH acquiring homozygous KIT-activating mutation gain a selective advantage over the heterozygous counterpart. Mitotic nondisjunction, in addition to the commonly recognized mitotic recombination, is an important and perhaps the primary mechanism of LOH acquiring homozygous KIT-activating mutation during GIST progression. No significant financial relationships to disclose.
Phase II study of sunitinib administered in a continuous daily dosing regimen in patients (pts) with advanced GIST
Authors: George S. , Casali P. G. , Blay J. , Le Cesne A. , Tyler A. R. , Quigley M. T. , Tassell V. , Baum C. M. , Demetri G. D. 
Published: March 2020

9532 Background: Sunitinib malate (SU11248) is an oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities due to inhibition of KIT, VEGFRs, PDGFRs, RET, and FLT3. In previous phase I/II and III trials in pts with imatinib-resistant GIST, sunitinib demonstrated efficacy and favorable clinical tolerability when administered in 6-week treatment cycles consisting of 4 weeks sunitinib (50 mg QD), followed by 2 weeks off treatment. The current study examined continuous sunitinib dosing as a way to avoid potential reactivation of tumor cells during the off-treatment period. Methods: This open-label, multicenter, phase II trial was designed to evaluate the efficacy, safety, and tolerability of sunitinib administered once daily using a continuous-treatment regimen in pts with imatinib-resistant GIST. Treatment is initiated with 37.5 mg sunitinib daily, with the option to titrate dosing on an individual basis depending on tolerability. The primary study endpoint is clinical benefit rate, defined as percent of evaluable pts with confirmed CR, PR, or SD ≥24 weeks using RECIST. Secondary endpoints included ORR, TTP, PFS, OS, and safety/tolerability measures. Results: Of 28 pts who had started treatment at the time of this analysis, early results were available for 17 pts from two centers. The most commonly occurring treatment-related adverse events were stomatitis, hand-foot syndrome, gastroesophageal reflex, and fatigue, which were generally grade 1. Two pts experienced treatment-related grade 3 hypertension, and another exhibited grade 3 asymptomatic neutropenia. Five pts have been evaluated for benefit after 8 weeks of treatment. Stable disease (which is the clinical benefit typically observed in GIST pts treated with sunitinib) was demonstrated in all five pts. Expanded safety/tolerability and efficacy results will be available for presentation. Conclusions: Continuous dosing of sunitinib is feasible and appears to be associated with acceptable tolerability in pts with imatinib-refractory GIST, similar to the extensive experience documented with intermittent sunitinib dosing. It is possible that continuous daily dosing of sunitinib may further improve the outcomes of pts with GIST. [Table: see text]
Clinical, serum cardiac troponin T and echocardiographic evaluation for prediction of late doxorubicin cardiotoxicity
Authors: Benites E. C. , Paiva M. G. , Cappellano A. M. , Felix O. M. , Marinelli S. B. , Malheiros R. C. , Petrilli A. S. 
Published: March 2020

9536 Background: To evaluate whether clinical signs or symptoms of congestive heart failure, serial assessment of systolic and diastolic cardiac function by low dose dobutamine stress echo (LDSE) and serum cardiac troponin T (cTnT) can predict doxorubicin (DOXO) cardiotoxicity. Methods: Twenty five patients with osteosarcoma enrolled in the Brazilian osteosarcoma treatment group study 2000, from january 2000 to may 2004, were studied with LDSE (>5μg/kg/min) before chemotherapy, 160 mg/m2 DOXO and after 160 mg/m2 DOXO. cTnT were measured before and during DOXO infusion. Cardiotoxicity was defined as shortening fraction (SF) less than 30% assessed by rest echo 1 to 6 months off chemotherapy. Group A comprised those without cardiotoxicity (16 patients, 10 male, 14.3 ± 4.7 years) whereas group B included those with a SF < 30% (9 patients, 6 male, 15.4 ± 3 years). Elevated serum cTnT was defined as seric levels above 0.01ng/ml. Results: Patients were submitted to a mean 3.4 LDSE and a mean of 32.5 serum cTnT. One patient (group B) presented clinical manifestation of cardiotoxicity. There was no statistical difference of elevated serum cTnT between the group B and group A (87.5% vs 46.2%; p=0,06). Left ventricular dimensions by M- MODE and transmitral Doppler inflow diastolic parameters were not significantly different between the two groups. Resting SF showed comparable values in both groups until cumulative doses of DOXO reached 160mg/m2, then the resting SF in group B was significant lower than group A (27% ± 2 and 34.1% ± 2, p<0.01). During dobutamine infusion, SF and ΔSF (dobutamine-rest) were significantly lower in group B as compared to group A at a DOXO dose 160mg/m2 (SF 36.1%±3,4 and ΔSF 2.1±2.3 vs. SF 45.2%±4.9 and ΔSF 9.4±3; p< 0.01 and p < 0.01) as well as at a DOXO dose > 160mg/m2 (30.3%±3 and 3.1±1.9 vs. 40.8%±5.9 and 7.2±4.2;p<0.01 and p<0.01). Conclusions: This study suggests that LDSE is more reliable than cTnT and clinical evaluation for predicting future subclinical cardiotoxicity,even at lower doxorubicin dose. No significant financial relationships to disclose.
Imatinib mesylate as a preoperative therapy in dermatofibrosarcoma: Preliminary results of a multicentric phase II study
Authors: Kerob D. , Porcher R. , Verola O. , Dalle S. , Maubec E. , Servant J. M. , Calvo F. , Berthaud P. , Mathieu-Boue A. , Pedeutour F. , Lebbe C. 
Published: March 2020

9550 Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma of intermediate malignant potential. Treatment relies on a wide local excision with negative margin with frequent need of reconstructive surgery. A translocation between chromosomes 17 and 22 that places PDGFB under the control of the collagen 1A1 promoter is present in > 90% of the cases leading to an up regulation of PDGFB expression and activation of the tyrosinase kinase PDGFRβ. Anecdotal reports and a report on 8 patients suggest that Imatinib mesylate (IM) has a clinical interest in DFSP. The primary aim of this phase II multicentric study is to define the percentage of clinical responders (RECIST) to a preoperative 2 months 600mg IM daily before wide local excision. The secondary goals are to determine tolerance, imaging (ultrasound and MRI), pathological responses and to analyse PDGFRβ phosphorylation status and tumour cell apoptosis in sequential tissues specimen. Fifteen adults suffering from primary or recurrent DFSP have been included since July 2004. All tumors had a diameter ≥2cm. A flexible design with interim analysis after recruitment of 6 patients was used. 18 to 28 patients had to be enrolled to detect a 30% response rate with power 80%, using a one-sided test against 5%, at the 2.5% level. Three men and 3 women, median age 48.4 years [23; 72.5] have been evaluated. Tumour characteristics are as follows : primary (n=4), recurrence (n=2) all involved trunk, median size 5.75cm [2.5–12]. Tolerance was good apart from grade 1 facial oedema (n=6) grade 2 maculopapular rash (n=1), grade 1 asthenia (n=1), grade 1 pyrosis (n=2). Translocation t(17;22) was detected in all tumours. A partial response was achieved in 3 of 6 patients. The median relative decrease of tumor in the PR and non responder patients was of 21.9% [−3.3; 72.0]. Histological analysis revealed a global decrease of cellularity often accompanied with a CD34 loss of expression, a fibrosis and mild peripheral lymphoid infiltrates. No evidence of apoptosis on tissue specimen after surgery was observed using TUNEL. These encouraging interim results weresubmitted to an independent committee who allowed to continue the trial and to include a total of 24 patients in order to reduce the confidence interval of response rate. [Table: see text]