bluuebunny/crossref_metadata_2025 huggingface dataset:
Carboplatin hypersensitivity reaction in pediatric low grade glioma (LGG) patients: A national experience. On behalf of the Canadian Pediatric Brain Tumor Consortium
Authors: Lafay-Cousin L. , Hukin J. , Carret A. , Wilson B. , Zelcer S. , Strother D. , Odame I. , Silva M. , Johnson D. , Bouffet E.
Published: March 2020

9053

Background: Carboplatin based regimens are widely used in the treatment of unresectable pediatric LGG. Carboplatin hypersensitivity reaction (CHSR) represents a main limiting factor. Objective: To analyse the incidence, characteristics, management and impact on outcome of CHSR. Methods: National retrospective review of children diagnosed with LGG between 1988 and 2004. Inclusion criteria were age <18 years, pathology proven diagnosis of LGG except in NF1 patients, and no chemotherapy or radiotherapy prior to carboplatin chemotherapy. Results: 105 patients (61F/44M) from 10 Canadian centers were included in the study. Median age at diagnosis was 3.5y (0.3–16.8). 33 patients had NF1, 75 had diencephalic tumor. Carboplatin was given monthly or weekly respectively in 46 and 59 patients. 44 (41.9%) patients developed carboplatin HSR at a median time of 6.5 months (0.4–15.4), after a median number of 10.5 (3–39) injections. CHSR occurred significantly earlier with the weekly schedule (p=0.016). Cumulative incidence of CHSR increased with the number of injections with no plateau. Female had significant higher risk to develop CHSR (p=0.02) whereas age, NF1 status and schedule of administration were not significant risk factors. First allergic reaction was rated grade I, II in 36 patients (82%). 34 patients were reexposed to carboplatin with desensitization/premedication, allowing 14 patients (41.2%) to complete their treatment. But the majority (58.8%) had recurrent allergic reaction with a significant worsening of their symptoms (p=0.039). The median number of additional Carboplatin injections delivered was 4 (0.5–34). After Carboplatin discontinuation, 18 patients were switched to another chemotherapy regimen. 5 years PFS was not significantly different in allergic and non allergic patients (53.9% and 45.6%). Conclusions: In our experience, the incidence of CHSR is high (41.9%). Female have higher risk of CHSR. Desensitization/premedication has limited efficacy and does not prevent worsening of CHSR. CHSR did not impact the PFS. However many patients did switch to another chemotherapy regimen and the total duration of treatment was comparable in both groups.

No significant financial relationships to disclose.
Childhood nasopharyngeal carcinoma: A 4-year single institution experience
Authors: Patel A. A. , Shah P. M. , Patel K. M. , Shukla S. N. , Parikh B. J. , Anand A. S. , Shah S. A. , Talati S. S. , Panchal H. P. , Pandey R.
Published: March 2020

9069

Background: Pediatric nasopharyngeal carcinoma (PNC) represents a locally advanced undifferentiated tumor. In this study, clinical experience and therapeutic results of 24 children with newly diagnosed PNC, treated in a single oncology institution in India over a period of 5 years, are analyzed. Methods: 24 patients (23 males and 1 female) 7–14 years old (median = 12) from Jan 2000 to Sep 2005 with PNC were retrospectively evaluated. 18/24 patients were evaluable. 16 patients received induction chemotherapy followed by radiotherapy while 1 patient was offered concurrent chemoradiotherapy, 1 patient received radiotherapy alone. 15/16 patients received postradiation chemotherapy. The agents used in induction and adjuvant therapy were cisplatin (100 mg/m2) on day 1 and 5-fluorouracil 750 mg/m2 for 5 days. The dose of radiotherapy used was 60 gray in 30 fractions. Results: The time of onset of symptoms to diagnosis ranged from 1 month to 9 months with a median of 5.5 months. Histopathology was lymphoepithelioma in 5 patients (27.7%) while 13 patients (72.2%) had poorly differentiated carcinoma. Disease extent was T2 (n = 7), T3 (n = 6), and T4 (n = 5); N1 (n = 5), N2 (n = 7), and N3 (n = 5). 7 patients had intracranial invasion. None had metastatic disease on presentation. 13 patients (72.2%) achieved major response which included 7 (38.8%) complete remission and 6 (33.3%) partial remission after the induction chemotherapy and radiotherapy. 4 (22.2%) had progressive disease. Another 3 (16.6%) attained complete remission after post radiation chemotherapy which consisted of two cycles of cisplatin and 5-flourouracil. The follow up ranged from 5 months to 84 months with a median follow up of 35 months. The disease free survival ranged from 10 months to 53 months with a median of 33 months. The patients who had a better response to induction chemotherapy had a better disease free survival. Out of 7 patients who attained complete remission 2 relapsed with a median time to first relapse of 9.5 months. Toxicity to therapy was modest. Only one patient had grade 4 neutropenia and mucositis. There was no therapy related mortality. Conclusion: Chemoradiotherapy for nasopharyngeal carcinoma in children is an effective treatment modality with minimal toxicity.

No significant financial relationships to disclose.
Indication and results of surgery following imatinib treatment of locally advanced or metastatic GI stromal tumors (GIST)
Authors: Hohenberger P. , Langer C. , Pistorius S. , Iesalnieks I. , Wardelmann E. , Reichardt P.
Published: March 2020

9500

Background: Imatinib mesylate efficiently induces tumor remission in advanced GIST however the curve of progression-free survival (PFS) in the large randomised trials does not reach a plateau. Surgery after achieving a PR is often recommended to remove tumor remnants or seems to be the treatment of choice to control tumor progression not or no longer controlled by drugs. The true impact of surgery is unclear and we analysed the indication and outcome of resective procedures including patients treated outside randomised trials. Patients: In a multi-institutional setting, we collected data from 113 patients after surgery for histologically confirmed GIST after imatinib treatment since April 2002. Primary tumor location: esophagus 3, stomach 23, small bowel 46, rectum 21, extraintestinal 20 pts. Indication for resection: to remove remnants of tumor sites responding well to imatinib 44 pts, resection of progressive lesions 55 pts, resection of a primary tumor after intended neadjuvant treatment 14 pts. Median duration of imatinib treatment prior to surgery was 11 (7–30) months for responding tumors, 14 months (4–28) for progressive lesions and 7 months (3–14) in the neoadjuvant group. Results: Median follow-up postoperatively is 16 months. Operative procedures: hepatic resection 13 pts., abdomino-perineal excision/anterior resection 27 pts, multivisceral resection 73 pts, peritoneal debulking 31 pts. An R0 resection could be achieved in 72% in the PR group, 86% in the neoadjuvant group, but only 26% in the progression group, postop. mortality was 1.7%. Median PFS in the R0 group is 16 (7-39) months and 7 months (2-25±) in the progressive group. In 14 pts imatinib treatment was not continued after R0 resection, 8 pts developed a recurrence. Conclusion: Progression-free survival after R0 resection of responding GIST is encouraging and the data could be used for planning a randomized trial of delayed vs. immediate resection in responding lesions after criteria ‘best response’ are agreed upon. Outside a trial, GIST patients developing a good PR with imatinib should be evaluated for resection as early as possible. However, even patients with a limited number of progressive lesions may benefit from surgery for a longer duration of time.

[Table: see text]
A putative tumor suppressor role for Wnt-signaling in sarcomagenesis
Authors: Matushansky I. , Socci N. , Hernando E. , Singer S. , Schwartz G. , Cordon-Cardo C. , Maki R.
Published: March 2020

9507

Background: We sought to elucidate the relationship between the human adult mesenchymal stem cell (hMSC), Wnt signaling and sarcomagenesis. Methods: In vitro hMSC differentiation, microarray gene expression analysis, distance correlation analysis, and standard molecular biology techniques were used to explore the role of Wnt in controlling the differentiation of both hMSCs and high grade undifferentiated sarcoma (HGUS; MFH, malignant fibrous histiocytoma), a common form of adult soft tissue sarcoma. Results: We determined that 1) hMSCs appear to be the progenitor cells of HGUS/MFH; 2) Dickkopf-1 (Dkk1), a specific inhibitor of Wnt signaling, is overexpressed in MFH as compared to other sarcoma subtypes and is involved in the proliferation of hMSCs; 3) in hMSCs, Dkk1 levels decline and nuclear β-catenin accumulates as hMSCs reach confluence, a prerequisite for initiation of in vitro differentiation, while in an MFH cell line Dkk1 levels do not decline and there is no nuclear β-catenin accumulation; 3) MFH cells appear to be primed for differentiation and express early markers of mesenchymal differentiation, then undergo apoptosis, if nuclear β-catenin is manipulated to enter the nucleus; 4) Wnt2 signals via the canonical β-catenin pathway and is responsible for “commitment” of hMSC and an MFH cell line to various differentiation pathways, while Wnt5a signals via the non-canonical JNK pathway in preventing apoptosis upon appropriate commitment toward differentiation. Conclusions: We identified the contribution of canonical and non-canonical Wnt signaling in the differentiation of hMSCs and showed that enhancing signaling via these pathways could be exploited as a potential target for therapy for high grade undifferentiated sarcomas. These data implicate Wnt-signaling as a mechanism of tumor suppression in early sarcomagenesis.

No significant financial relationships to disclose.
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]
Ifosfamide (IFO) and doxorubicin (DOX) dose-intensities seem related to overall survival in adult soft-tissue sarcoma (STS) patients
Authors: Almeida G. F. , Castro G. , Snitcovsky I. M. , Bassani A. C. , Diz M. E. , Federico M. H.
Published: March 2020

9581

Background: IFO/DOX dose intensities (DI) seem to impact on the outcome of STS. We explored retrospectively the relationship between DI and overall survival (OS) in STS. Methods: From Jan/00 to Jun/05, 70 untreated STS pts received IFO/DOX, 32 as neo/adjuvant and 38 in the palliative setting at our outpatient unit. Filgrastin was not mandatory. Median age 47 y (17–74 y), 44 male; mean tumor size 13.6 cm in the neo/adjuvant and 16.5 cm in the palliative group (p=0.202, t-test). Most frequent histologies: leiomyo (16 pts), synovial (13), malignant fibrous histiocytoma (8) and liposarcoma (8). 28 pts had lower/ 9 upper limb tumors, 9 retroperitoneal, 9 trunk, 6 mediastinal, 5 visceral and 4 head and neck. Kaplan-Meier survival curves were considered from diagnosis and compared by log-rank test. Results: For the 70 pts, the mean DI for IFO and DOX were 2.5±0.9 mg/m2/wk and 18.8±6.0 mg/m2/wk, respectively. There was no difference between neo/adjuvant and palliative IFO/DOX DI (p=0.314/p=0.247, respectively). With 19-mo median f-up, the median OS (mOS) was 43 mo in the neo/adjuvant group with an advantage for pts submitted to conservative surgeries (46.5 mo vs. 16.8 mo; HR 0.185, 95%CI 0.003–0.399, p=0.007) as well as in those diagnosed with tumors with less than 3 mitoses/10 HPF (48.3 mo vs. 18.8 mo; HR 0.272, 95%CI 0.058–0.871, p=0.031). No differences in mOS related to tumor size, margin status or primary sites were found. According to IFO DI, the mOS were 46.5 mo, not reached (NR), 14.5 mo and 43 mo for pts in the 1st and subsequent DI quartiles (chi-square test for trend, p=0.004). In the median f-up of 9.8 mo, pts in the palliative setting presented mOS 21.8 mo, superior in the lower grade subgroup (NR vs. 11.1 mo; HR 0.130, 95%CI 0.076–0.746, p=0.014) and in the STS not from extremities (40.9 mo vs. 10.8 mo; HR 2.152, 95%CI 0.959–5.137, p=0.063). According to IFO DI quartiles, we also found a direct correlation between mOS (11.3 mo, 19 mo, 45.1 mo, and NR) and DI (p=0.052), and similar trend was shown for DOX DI, with 11.3 mo, 10.3 mo, NR, and 40.9 mo mOS for the 1st, 2nd, 3rd and 4th quartiles (p=0.018). Conclusions: In these STS adult pts, we have found a relationship between IFO and DOX DI and OS. Further evaluations of more intensive chemotherapy schedules are warranted.

No significant financial relationships to disclose.
A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferon-alpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC)
Authors: Hudes G. , Carducci M. , Tomczak P. , Dutcher J. , Figlin R. , Kapoor A. , Staroslawska E. , O’Toole T. , Kong S. , Moore L.
Published: March 2020

LBA4

Background: Temsirolimus (TEMSR, CCI-779) is a specific inhibitor of mTOR, a signaling protein that regulates cell growth and angiogenesis. In a single-agent, phase 2 study, TEMSR administration to heavily pretreated patients (pts, n = 111) with adv RCC resulted in a median overall survival (OS) of 15.0 mos (Atkins et al, J Clin Oncol 2004). Retrospectively, 49 pts were categorized in a poor-risk group (Motzer et al, J Clin Oncol 2002). The TEMSR-treated pts in this group had a 1.7-fold longer median OS than the first-line, IFN-treated, poor-risk group reported by Motzer et al. In a phase 1 study, the maximum tolerated dose of the combination of TEMSR + IFN in adv RCC pts was TEMSR 15 mg intravenously (IV) once/wk + IFN 6 million units (MU) subcutaneously (SC) 3 times weekly (TIW) (Smith et al, Proc ASCO 2004). Thus, this phase 3 study in first-line, poor-risk adv RCC pts was initiated in July 2003. Methods: Pts with adv RCC and no prior systemic therapy were enrolled in this open-label study if they had ≥3 of 6 risk factors (the 5 Motzer criteria and >1 metastatic disease site). Pts were randomized (1:1:1) to arm 1, IFN up to 18 MU SC TIW; arm 2, TEMSR 25 mg IV once/wk; or arm 3, TEMSR 15 mg IV once/wk + IFN 6 MU SC TIW. The primary study endpoint was OS; the study was powered to compare the TEMSR arms with the IFN arm. Results: We report 20 Mar 2006 preliminary data from an interim analysis performed by the IDMC. Of the 626 pts enrolled, 442 deaths occurred. Patients treated with TEMSR had a statistically longer survival than those treated with IFN (Table). OS of patients treated with IFN and TEMSR + IFN were not statistically different. The 3 most frequently occurring adverse events ≥gr 3 were asthenia (arm 1: arm 2: arm 3, 27%: 12%: 30% pts), anemia (24%: 21%: 39% pts), and dyspnea (8%: 9%: 11% pts). Conclusions: Single-agent TEMSR significantly increases the OS of first-line, poor-risk adv RCC pts compared with IFN, with an acceptable safety profile.

[Table: see text] [Table: see text]
The study of tamoxifen and raloxifene (STAR): Initial findings from the NSABP P-2 breast cancer prevention study
Authors: Wickerham D. L. , Costantino J. P. , Vogel V. , Cronin W. , Cecchini R. , Atkins J. , Bevers T. , Fehrenbacher L. , McCaskill-Stevens W. , Wolmark N.
Published: March 2020

LBA5

Background: The STAR trial was designed to compare raloxifene to tamoxifen in terms of relative effect on invasive breast cancer risk and on other beneficial and detrimental outcomes associated with the use of tamoxifen. Methods: The trial opened on 7-1-1999, and accrual was completed November 4, 2004, with 19,747 women enrolled. To be eligible, a woman had to be postmenopausal with a 5-year predicted breast cancer risk of 1.66% as determined by the modified Gail model. Women were randomized and treated in a double-blinded fashion to receive 5 yr of therapy with either 20 mg per day of tamoxifen or 60 mg per day of raloxifene. The protocol-defined monitoring plan called for a final analysis and release of findings when 327 invasive breast cancer cases had been diagnosed in the total population. The mean age of the population at the time of entry into this trial was 58 yr, and the mean 5-yr risk of breast cancer was 4.04%. 93.5% of the women were white; 51.5% had a hysterectomy before entry into the study; 9.2% had a history of LCIS; 71.1% had at least one first-degree relative with a history of breast cancer. The average time on the study is 47 months. Results: There was no difference between the treatment groups in terms of effect on invasive breast cancer: 163 cases in women assigned to tamoxifen and 167 in women assigned to raloxifene (RR = 1.02, 95% CI = 0.82–1.27). The risk of invasive uterine malignancies was 40% less in the raloxifene group (36 in women assigned tamoxifen and 23 in women assigned raloxifene [RR = 0.62, 95% CI = 0.35–1.08]). The risk of non invasive breast cancer was less in the tamoxifen group (57 cases in those assigned to tamoxifen and 81 in those assigned to raloxifene [RR = 1.41, 95% CI = 1.00–2.02]). There were no significant differences between the treatment groups for any of the other invasive cancer sites or for cardiac events, osteoporotic fractures, or deaths. There were fewer thromboembolic events in women taking raloxifene than in those taking tamoxifen. Conclusions: Raloxifene is an effective alternative to tamoxifen for reducing the incidence of invasive breast cancer in postmenopausal women at increased risk of developing the disease and is associated with fewer endometrial cancers, deep vein thromboses, and pulmonary emboli.

[Table: see text]
Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)
Authors: Dharmaraj Poonam , Gorvin Caroline M , Soni Astha , Nelhans Nick D , Olesen Mie K , Boon Hannah , Cranston Treena , Thakker Rajesh V , Hannan Fadil M
Published: March 2020

Context

Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR) and is considered a benign condition associated with mild-to-moderate hypercalcemia. However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy.

Objective

The objective of this work is to characterize the range of calcitropic phenotypes in the children of a mother with FHH1.

Methods

A 3-generation FHH kindred was assessed by clinical, biochemical, and mutational analysis following informed consent.

Results

The FHH kindred comprised a hypercalcemic man and his daughter who had hypercalcemia and hypocalciuria, and her 4 children, 2 of whom had asymptomatic hypercalcemia, 1 was normocalcemic, and 1 suffered from transient neonatal hypocalcemia and seizures. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (6.28 mg/dL); normal, 2.0 to 2.8 mmol/L (8.0-11.2 mg/dL) and parathyroid hormone of 2.2 pmol/L; normal 1.0 to 9.3 pmol/L, and required treatment with intravenous calcium gluconate infusions. A novel heterozygous p.Ser448Pro CaSR variant was identified in the hypercalcemic individuals, but not the children with hypocalcemia or normocalcemia. Three-dimensional modeling predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction within the CaSR extracellular domain. The variant Pro448 CaSR, when expressed in HEK293 cells, significantly impaired CaSR-mediated intracellular calcium mobilization and mitogen-activated protein kinase responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation.

Conclusions

Thus, children of a mother with FHH1 can develop hypercalcemia or transient neonatal hypocalcemia, depending on the underlying inherited CaSR mutation, and require investigations for serum calcium and CaSR mutations in early childhood.
Poji: a Fiji-based tool for analysis of podosomes and associated proteins
Authors: Herzog Robert , van den Dries Koen , Cervero Pasquale , Linder Stefan
Published: March 2020

Podosomes are actin-based adhesion and invasion structures in a variety of cell types, with podosome-forming cells displaying up to several hundreds of these structures. Podosome number, distribution and composition can be affected by experimental treatments or during regular turnover, necessitating a tool that is able to detect even subtle differences in podosomal properties. Here, we present a Fiji-based macro code termed ‘Poji’ (‘podosome analysis by Fiji’), which serves as an easy-to-use tool to characterize a variety of cellular and podosomal parameters, including area, fluorescence intensity, relative enrichment of associated proteins and radial podosome intensity profiles. This tool should be useful to gain more detailed insight into the regulation, architecture and functions of podosomes. Moreover, we show that Poji is easily adaptable for the analysis of invadopodia and associated extracellular matrix degradation, and likely also of other micron-size punctate structures. This article describes the workflow of the Poji macro, presents several examples of its applications, and also points out limitations, as well as respective solutions, and adaptable features to streamline the analysis.

This article has an associated First Person interview with the first author of the paper.
Physical Activity across Retirement Transition by Occupation and Mode of Commute
Authors: PULAKKA ANNA , LESKINEN TUIJA , SUORSA KRISTIN , PENTTI JAANA , HALONEN JAANA I. , VAHTERA JUSSI , STENHOLM SARI
Published: March 2020

Purpose

Retirement induces changes in the composition of daily physical activity. Our aim was to examine changes in accelerometer-measured physical activity around transition to statutory retirement among men and women by occupational category and by preretirement modes of commuting.

Methods

We included 562 workers (mean [SD] age, 63.3 [1.1] yr; 85% women) from the Finnish Retirement and Aging study. The participants wore an accelerometer on their nondominant wrist for 1 wk before and 1 wk after retirement, with 1 yr between the measurements. We compared mean daily activity counts before and after retirement between manual and nonmanual occupations by gender and by preretirement commuting mode using linear models with generalized estimating equations.

Results

Before retirement, women were more active than men (2550 (95% confidence interval, 2500–2590) vs 2060 (1970–2140) mean daily activity counts), with the most active group being women in manual occupations. After retirement, physical activity decreased by 3.9% among women and increased, albeit nonsignificantly, by 3.1% in men. The decrease was most pronounced among women in manual and increase among men in nonmanual occupations. After retirement, women remained more active than men (2450 (95% confidence interval 2390–2500) vs 2120 (2010–2230) counts). Active commuting, especially cycling, before retirement was associated with higher physical activity both before and after retirement, and these people also maintained their total activity lever better than did those who commuted by public transportation.

Conclusions

Although women in manual occupations decreased and men in nonmanual occupations increased their activity after retirement, women were more active than men both before and after retirement. Those who engaged in active commuting before retirement maintained their activity level also after retirement.
OS 30 ANOS DA CONSTITUIÇÃO: O PAPEL DO DIREITO E DA JURISDIÇÃO CONSTITUCIONAL
Authors: Streck Lenio Luiz
Published: March 2020

Passados trinta anos da promulgação da sua Constituição, o Brasil se depara com uma grave crise institucional. Neste momento marcante, procuro refletir sobre o Direito (e sua teoria) em nosso país, desde a redemocratização, especialmente sobre o papel que se atribui à jurisdição constitucional e que ela efetivamente desempenha. Reafirmo o papel transformador do constitucionalismo — tanto mais necessário em países com graves problemas estruturais, como o nosso — argumentando que isso não deve ser confundido com ativismo judicial. Na sequência, discuto parâmetros para a jurisdição constitucional e a construção de uma adequada teoria da Constituição. Por fim, volto da teoria à prática, analisando criticamente algumas dificuldades na efetivação do constitucionalismo contemporâneo no Brasil.
Condiciones sociodemográficas y perfil de salud de los adultos mayores indígenas del departamento de Nariño
Authors: Paredes A. Yenny V. , Yarce P. Eunice , Aguirre A. Daniel C.
Published: March 2020

Introducción: en América Latina, la etnicidad es un determinante crítico de pobreza, desigualdad y exclusión social; además, puede constituir una situación doble de vulnerabilidad, pues los grupos poblacionales minoritarios requieren atención diferencial. El presente estudio determina los factores sociodemográficos y el perfil de salud de un grupo de adultos mayores indígenas. Materiales y métodos: estudio analítico de tipo descriptivo transversal, con una muestra por conveniencia de 518 adultos mayores ambulatorios indígenas de la exprovincia de Obando, Nariño, Colombia. Mediante una encuesta personal, se recogieron datos sociodemográficos y de antecedentes médicos. La valoración nutricional se realizó con el Mini Nutritional Assessment; la evaluación cognitiva, con el Mini-Mental State Examination; los síntomas depresivos, con la Escala de Depresión Geriátrica de Yesavage; y la capacidad funcional, con el índice de Barthel y la escala de Lawton y Brody. Finalmente, con respecto al análisis estadístico, se empleó el enfoque del análisis de clases latentes, con el objetivo de identificar subgrupos o clases, de acuerdo con los patrones de comorbilidad. Resultados: en cuanto a los datos sociodemográficos, el 44.6 % es de género femenino, el 40.2 % es analfabeta, el 63.5 % está casado, el 91.7 % reside en áreas rurales, y el 53.43 % no posee ingresos. En cuanto a los antecedentes médicos, el 47.7% tiene artritis, seguido por el 23%, que tiene cataratas. El 26 % presenta riesgo nutricional; el 65 %, sintomatología depresiva; el 54 %, deterioro cognitivo; y el 35%, dependencia funcional. El análisis de clases latentes mostró predominio de comorbilidad en un 55 %. Conclusión: en la población de adultos mayores indígenas prevalecen condiciones sociodemográficas y de salud precarias que tienen mayor incidencia que en otros grupos etáreos.