bluuebunny/crossref_metadata_2025 huggingface dataset:
Paraneoplastic dermatomyositis associated with metastatic leiomyosarcoma of unknown primary
Authors: Merry Eve , Smrke Alannah , Halai Kapil , Patel Gulam , Thway Khin , Jones Robin L. , Benson Charlotte
Published: August 2020

Background

Sarcomas are rare and heterogeneous tumours of mesenchymal origin, with over 100 histological subtypes. Paraneoplastic dermatomyositis has rarely been described in sarcoma. This is the first documented case of paraneoplastic dermatomyositis in a patient with metastatic leiomyosarcoma.

Case presentation

A 43-year-old female diagnosed with metastatic leiomyosarcoma of unknown primary presented with a mild rash in sun-exposed areas of her face and upper chest, with no other neuromuscular symptoms. This rash resolved with systemic treatment with doxorubicin for metastatic leiomyosarcoma. Imaging assessment confirmed overall stable disease after chemotherapy completion. She presented acutely 2 months later with new onset rash in a shawl-like distribution, periorbital oedema and proximal muscle weakness. Based on the characteristic cutaneous signs and symmetrical proximal muscle weakness, abnormal electromyography and raised skeletal muscle enzymes with a positive anti-transcription intermediary factor-1 gamma antibody result, a diagnosis of paraneoplastic dermatomyositis was made. Re-evaluation of her metastatic leiomyosarcoma revealed disease progression. Second-line chemotherapy was commenced once the dermatomyositis was controlled on steroid therapy. Systemic anti-cancer therapy was again associated with mild improvement in dermatomyositis symptoms.

Discussion

Paraneoplastic dermatomyositis heralded disease progression after first-line chemotherapy; however, in hindsight, subtle cutaneous features were present at sarcoma diagnosis. The temporal relationship between paraneoplastic dermatomyositis and metastatic leiomyosarcoma is key in this case, as fluctuations in dermatomyositis severity correlated with growth of metastatic disease. Understanding this relationship may provide clues for tumour progression and prompt timely initiation of anti-cancer therapy. It is important to recognise that in addition to the more common cancers associated with paraneoplastic dermatomyositis, it can also occur in rarer tumours such as leiomyosarcoma.
Distributed extended Kalman filtering for state-saturated nonlinear systems subject to randomly occurring cyberattacks with uncertain probabilities
Authors: Li Jiaxing , Hu Jun , Chen Dongyan , Wu Zhihui
Published: August 2020

In this paper, the extended Kalman filtering scheme in a distributed manner is presented for state-saturated nonlinear systems (SSNSs), where the randomly occurring cyberattacks (ROCAs) with uncertain occurring probabilities (UOPs) are taken into account. In particular, a novel cyberattack model is constructed by the consideration of false data-injection attacks (FDIAs) and denial-of-service attacks (DoSAs) simultaneously. The ROCAs are described by a series of Bernoulli distributed stochastic variables, where the so-called UOPs are considered and described by the nominal mathematical expectations and error bounds. The major effort is to develop a novel DEKF strategy for SSNSs with consideration of state delay and ROCAs with UOPs. In what follows, an upper bound with respect to the filtering error covariance is derived and minimized by selecting the suitable filter parameter. Besides, the concrete expression of the filter parameter is formed by solving matrix difference equations (MDEs). Meanwhile, a sufficient condition under certain constraints is proposed to testify the boundedness regarding the given upper bound. Finally, we use the experiments and corresponding comparisons to verify the feasibility of the designed extended Kalman filtering approach in a distributed way.
Role of partial splenic artery embolization in corpuscular correction in cirrhotic patients before anti-viral therapy: a recent update study among Egyptian patients
Authors: Mostafa Elian Mostafa Mohamed , Samea Mohamed Ahmed A. , Osman Nasr Mohamed M.
Published: August 2020

Background

To evaluate the role of partial splenic artery embolization in corpuscular correction in cirrhotic patients.

Results

Bleeding tendency was experienced in two thirds of patients (66.7%) and anemia in 63.3%. Splenic size ranged from 14.3 to 22 cm. PV diameter ranged from 11 to 18 mm. The mean platelet at the pre-operative laboratory was 34.9 ± 10.3 × 103, corrected to 137.6 ± 37.1 × 103 within 1 month follow-up, and then 140 × 103 after 6 months. The mean of RBCs was 3.6 ± 0.3 × 106, then 4 ± 0.5 × 106 at 1 month follow-up period. WBCs showed correction at the early post-operative period, 3.3 ± 0.4 × 103, compared to 5.4 ± 1.4 × 103 at 1 month. Reduction in splenic size was achieved by 3–6 months. All patients (100%) had post-embolization syndrome. Gelfoam was used in 20 patients, PVA was used in 5 patients, and microspheres were used in 5 patients. Antiviral treatment regimen was started after an adequate rise in corpuscular counts in all patients.

Conclusion

Partial splenic artery embolization is an effective alternative method to surgery in treatment of hypersplenism particularly in cirrhotic patients prepared for antiviral treatment with correction of the associated thrombocytopenia.
A singular case of massive urethrorrhagia solved by transarterial embolization
Authors: Francesco Pane , Milena Coppola , Antonio Borzelli , Francesco Giurazza , Fabio Corvino , Antonio Corvino , Mattia Silvestre , Raffaella Niola
Published: August 2020

Background

Urethrorrhagia is frequent in pelvic trauma, rarely due to traumatic injuries of internal pudendal artery branches.

Case presentation

Our aim is to underline the role of transarterial embolization in selected patients, as in this case in which a young man manifested urethral hemorrhage after high-energy motorcycle crash not associated with injuries of the inferior urinary tract. Multi-detector computed tomography (MDCT) showed pubic symphysis diastasis and perineal hematoma with pseudoaneurysm into the penis bulb. The first approach was conservative with perineal external compression and intravenous injection of tranexamic acid. Afterward, due to the decline of clinical conditions, we decided to perform a selective angiography, confirming the vascular injury of distal branches of both internal pudendal arteries with contrast agent extravasation into urethral bulb; endovascular embolization was performed with detachable micro-coils. The principal results were seen quickly, indeed urethrorrhagia arrested and hemoglobin values normalized. Erectile function was preserved at 6-months follow-up.

Conclusions

Endovascular embolization proved to be a minimally invasive therapeutic approach, clinically effective, with a low rate of complications and high probability to preserve erectile function.
Screening Patients With Cancer Admitted to Hanoi Medical University Hospital for Palliative Care Needs
Authors: Le Quang V. , Trinh Huy L. , Mai Kim Ngan T. , Pham Manh D. , Glare Paul A.
Published: August 2020

PURPOSE

To evaluate a screening tool for identifying which patients admitted to the oncology ward of a Vietnamese hospital should be referred to specialist palliative care (PC).

METHODS

We performed a cross-sectional survey of consecutive patients hospitalized in the Department of Oncology and Palliative Care at Hanoi Medical University Hospital between June 2019 and September 2019. We translated a validated 11-item screening tool into Vietnamese and used a total score of ≥ 5 as a positive screen.

RESULTS

One hundred participants were recruited. Forty-four patients (44%) screened positive. Of these, 37 (84%) had locally advanced or metastatic disease, 31 (70%) had uncontrolled symptoms, and 43 (98%) requested a PC consultation. A score ≥ 5 was significantly more common in patients with stage IV disease versus earlier stage, performance status of Eastern Cooperative Oncology Group (ECOG) 2 versus ECOG 0, and when life-limiting complications of cancer were present. Screening identified four patients overlooked by oncologists as needing referral, and 34% of patients requesting a referral had scores < 5.

CONCLUSION

This screening tool provided oncologists with easy-to-use criteria for referring patients for PC. At the same time, it relieved the work load for under-resourced PC physicians by screening out requests with low-level need. This tool should be part of routine assessment on admission in all oncology units in Vietnam.
Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin lymphoma (NHL)
Authors: Reiter A. , Meinhardt A. , Burkhardt B. , Zimmermann M. , Borkhardt A. , Kontny U. , Mann G. , Schrappe M.
Published: August 2020

10000

Background: Pediatric mature B-cell NHL differ from aggressive B-NHL of adults in terms of biology and treatment outcome. In contrast to adults, rituximab (Rx) is not established in the treatment of pediatric B-NHL has not be determined yet. Even the activity of Rx in pediatric B-NHL is not determined. We conducted a phase II window study to examine the activity of Rx in newly diagnosed pediatric B-NHL. Methods: Eligibility: age < 19 y, CD20 + B-NHL, ≥ 1 measurable lesion/s, informed consent. Exclusion: Lansky performance scale 5, pre-treatment, impaired renal-, heart-, liver-function, hepatitis B, pre-existing disease, pregnancy. Treatment: Rx 375 mg/m2 IV at day 1; concomitant therapy: Rasburicase, steroids only for anaphylaxis, intrathecal (IT) triple drug at days 1, 3 for CNS+ pts only. Begin of chemotherapy at day 5. Response evaluation: product of 2 perpendicular diameters of 1 - 3 index lesions/% blasts in BM/PB within 24 h prior to Rx and at day 5: responder (RP): at least 1 lesion with at least objective effect (decrease of ≥25%) and no progress (increase of ≥25 %) at other sites. Study plan: Simon 2-stage phase II with α and β = 5%. Response rate (RR) for poor activity was set to 45%, for good activity 65%. 33 pts entered the first stage, final evaluation after 79 pts. Results: One hundred thirty-six pts were enrolled from 04/04–08/08. NTC °3/4 toxicities: general condition 16%, fatigue 13%, anaphylaxis (chill/fever/bronchospasm) 6 (1/2/4)%, infection 3%, S-GOT/GPT 10%, acute tumor lysis (ATL) 7%, capillary leakage (0), toxic death (0). Forty-nine pts were not evaluable for response: Withdrawal (anaphylaxis 8, ATL 2, suspected progression, not verified 4, other 2), IT therapy in CNS- pts (8), corticosteroids (3), technical inadequacy of response evaluation (21), no index lesion (1). Of the 87 evaluable pts 37 were RPs (42.5%, 95%-CI 32% - 54%). RR by histology: BL/B-ALL 29/68, DLBCL 6/14, juvenile follicular lymphoma 1/2, PMBCL 1/1, B-NHL nfs 0/2. Fifty pts were non-RPs. Conclusions: Although the RR was lower than requested Rx as single agent is active in pediatric B-NHL.

No significant financial relationships to disclose.
Final results of a randomized trial on the role of maintenance chemotherapy with weekly paclitaxel for patients with metastatic breast cancer
Authors: Mayordomo J. I. , Baena J. M. , Cirera L. , Sanchez-Rovira P. , Godes M. J. , Galan A. , Jimenez-Orozco E. , Muñoz M. , Tusquets I. , Sanchez M. J.
Published: August 2020

1001

Background: Chemotherapy for patients with metastatic breast cancer is not curative. Anthracyclines and taxanes are among the most active drugs. Optimal duration of chemotherapy in women with metastatic breast cancer is an open issue. Should they receive chemotherapy to progression or should chemotherapy be stopped after a fixed number of courses? The excellent safety profile of weekly paclitaxel prompted us to evaluate its role as maintenance treatment in this setting. The primary objective was to determine if addition of maintenance weekly paclitaxel prolongs progression-free survival in women with metastatic breast cancer on first-line chemotherapy. Secondary objectives included overall survival and toxicity. Methods: Following Ethical Committee approval and informed consent, from 2002 to 2006 180 women with metastatic breast cancer and no prior chemotherapy for metastatic disease were randomized 1:1 in the TASMAN phase III trial to: 3 courses of epirubicin 100 mg/m2 day 1 q 21 days, followed by 3 courses of paclitaxel 225 mg/m2 day 1 q 21 days, without further chemotherapy or hormonal therapy until progression (arm A), or 3 courses of epirubicin followed by 3 courses of paclitaxel and then maintenance with paclitaxel 60 mg/m2 day 1 q 7 days until progression or unacceptable toxicity (arm B). Results: Median age: 51 years (range: 30–73). Median performance status (ECOG): 0 (0–2). Sites of metastases: bone (36%), liver (20%), pleura and/or lung (19%), skin and/or lymph nodes (18%). No grade 3–4 toxicities were seen with maintenance chemotherapy. As of January 1, 2009, 18 patients remained progression-free and 48 were alive, with a minimum follow-up of 2 years. Median progression-free survival was 8 months for arm A versus 12 months for arm B (p = 0.1, logrank). Median overall survival was 24 months for each arm (p = 0.7). Conclusions: Maintenance chemotherapy with weekly paclitaxel following first-line chemotherapy with anthracycline and taxane is well tolerated but does not significantly increase progression-free survival.

No significant financial relationships to disclose.
Phase II single-arm study of irinotecan in combination with temozolomide in children with recurrent or refractory medulloblastoma
Authors: Grill J. , Perek D. , Sanchez de Toledo-Codina J. , Madero L. , Estlin E. , Cañete A. , Icher C. , Breazna A. , Geoerger B. , Cisar L. , Hargrave D.
Published: August 2020

10018

Background: Irinotecan and temozolomide have demonstrated moderate single agent activity in childhood medulloblastoma (MB). Using the recommended dose established from a prior pediatric phase I study, the combination of irinotecan and temozolomide was investigated in relapsed MB. Methods: Patients aged 6 months to 18 years with radiological measurable relapsed/refractory MB were treated with temozolomide 100–125 mg/m2/day on days 1–5 orally and irinotecan 10 mg/m2/day on days 1–5 and days 8–12 intravenously. After cycle 5, patients who did not progress could receive irinotecan 125 mg/m2 once weekly on days 1 and 8 of the 3-week cycle. The primary objective was confirmed tumor response (partial or complete) after 4 cycles of treatment. According to a two-stage Optimum Simon design, at least 6 of the first 15 evaluable subjects were to have a confirmed objective response, to proceed to stage 2; a total of 19 responses in 46 subjects are required for success. A central radiological review determined tumor response in all patients. Results: Preliminary results are reported on 33 patients entered from May 2007 through to November 2008 in 19 treatment centers. The median age was 9 years (range 2 to 17 years); 23 male and 10 female. The number of relapsed patients with M3:M2:M1:M0 (Chang M stage) were 10:15:2:6, and 17 had more than 1 prior therapy. Previous treatment included chemotherapy, 7 with high-dose regimens, and craniospinal (CSI) (n=30) or posterior fossa irradiation (n=2). Central radiological review is ongoing: 16/26 reviewed patients were evaluable for response. Six patients had confirmed PR, 3 had SD, and 7 had PD. To date, 10 patients have been excluded after central review (8, poor imaging; 2, no measurable disease). Toxicity has been manageable with dose reduction required in 11/33 MB patients, all of these had received prior CSI. The study is ongoing in stage 2 and centrally verified results will be reported at the Meeting. Conclusions: This multi-centre international study is the largest phase II trial of the irinotecan and temozolomide combination in pediatric central nervous system tumors. The activity of the combination in heavily pre-treated recurrent MB patients is promising.

[Table: see text]
Phase I study of vandetanib (ZD6474) administered during and after irradiation (RT) in children with diffuse intrinsic pontine glioma (DIPG)
Authors: Broniscer A. , Merchant T. E. , Hillenbrand C. , Patay Z. , Chin T. K. , Onar A. , Kaste S. C. , Gilbertson R. J. , Gajjar A.
Published: August 2020

10020

Background: Children with DIPG have a dismal prognosis despite use of RT, which is the mainstay of therapy. All chemotherapy regimens used so far demonstrated no benefit. EGFR and VEGFR pathways are considered important in tumorigenesis of DIPG. Methods: We conducted a traditional phase I study combining oral vandetanib (VEGFR-2 and EGFR inhibitor) during and after local RT in children with DIPG. Five dosage levels were tested (50, 65, 85, 110, and 145mg/m2 per day). Vandetanib and RT started on the same day. The first 6 weeks of therapy constituted the dose-limiting toxicity (DLT)-evaluation period. Correlative studies consisted of pharmacokinetic analysis (PK), pharmacodynamic studies in blood, and standard and investigational imaging (before and 1, 3, and 6 weeks after start of therapy). Results: Twenty-one patients were enrolled on study (50 [n = 3], 65 [n = 3], 85 [n = 3], 110 [n = 6], and 145mg/m2 [n = 6]). Two patients experienced DLT consisting of rash/mucositis (level 4) and diarrhea (level 5). The maximum-tolerated dose (MTD) of vandetanib was not reached. Other significant toxicities included lymphopenia grade 3/4 (n = 10), grade 3 neutropenia and hypophosphatemia (one each), grade 2 proteinuria (n = 2), grade 2 hypertension (n = 4), and mild QTc prolongation (n = 7) .Once the phase I component was completed, two extra patients were enrolled at dosage level 5; one of them developed grade 4 seizure secondary to posterior reversible encephalopathy syndrome. PK (n = 21) showed similar drug clearance and volume of distribution compared to adults. However, drug exposure at steady state normalized by dose seemed higher in children. Increased tumor perfusion during the first 6 weeks of therapy was observed in the first 12 patients analyzed. Conclusions: Although MTD was not reached, we recommend administration of vandetanib at a dose of 110mg/m2 per day during and after local RT in children. Further combination studies of vandetanib in children with DIPG are planned.

No significant financial relationships to disclose.
Pulmonary function after whole lung radiation in pediatric patients with malignant solid tumors
Authors: Inaba H. , Zhu L. , Srivastava K. , Hudson M. M. , Motosue M. S. , Stokes D. C. , McPherson V. , Srinivasan S. , Krasin M. J. , Green D. M. , Spunt S. L.
Published: August 2020

10025

Background: Pediatric malignant solid tumors are increasingly curable; whole lung irradiation (WLI) may be used to treat pulmonary tumor involvement. Few studies have addressed long-term pulmonary function after WLI during childhood. Methods: We conducted a retrospective review of pulmonary function tests (PFTs) in 1 year survivors of pediatric malignant solid tumors treated with WLI. We assessed PFT changes over time and the relationship of abnormal values to clinical parameters (diagnosis, radiation dose, and presence or absence of boost lung irradiation or surgical resection). Results: We evaluated 164 PFTs performed on 49 patients with the diagnoses of Wilms tumor (38), rhabdomyosarcoma (5), Ewing sarcoma (3), synovial sarcoma (2), and thymoma (1). Median age at radiation was 6.3 years (range, 0.5–20.2 years); median WLI dose was 12 Gy (range, 10.5–18 Gy). Seventeen (34.7%) had focal pulmonary boost irradiation and 21 (42.9%) had partial lung resection. Across the entire population, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) declined after irradiation with a median follow-up of 9.3 years. The odds of having a normal FEV1 and FVC decreased by a factor of 0.90 (p = 0.0387) and 0.91 (p = 0.0445), respectively, every year, indicating that the proportion of patients with normal values of FEV1 and FVC decreases over time. FEV1/FVC ratio and forced expiratory flow (FEF25%-75%) remained stable. Abnormal FEV1/FVC and FEF25%-75% were more likely in patients who received boost irradiation than in patients who did not (p = 0.0034 and 0.0233, respectively). Conclusions: Pulmonary function worsened over time in this cohort of childhood cancer survivors treated with WLI. Boost irradiation further impaired pulmonary function. Further studies are planned to assess the clinical consequences of these progressive PFT abnormalities and to identify risk factors associated with clinically significant pulmonary dysfunction after WLI.

No significant financial relationships to disclose.
Outcome in stage IV Wilms tumor treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) trials
Authors: Gandola L. , Nantron M. , Marchianò A. , Pession A. , Indolfi P. , Di Cataldo A. , Collini P. , Arcamone G. , Fossati Bellani F. , Spreafico F.
Published: August 2020

10031

Background: Children with metastases at diagnosis for Wilms tumor (WT) still display a worse prognosis compared to localized disease. Methods: We analyzed survival results in patients with stage IV WT enrolled in the AIEOP CNR92 and TW2003 clinical trials (3/1992–3/2008). Treatment strategy across these trials evolved in terms of sparing whole lung radiotherapy (RT) in case of complete disappearance of lung metastases after primary chemotherapy and a doxorubicin cumulative dose reduction from 360 mg/m2 to 240 mg/m2 in TW2003. Results: Of 553 in-study patients aged less than 18 years, 68 (12%) were classified as stage IV (38 patients in CNR92, 30 in TW2003; median age 58 months). Children displaying millimetric nodules visible only on computed tomography scan were excluded. Initial treatment consisted of 6-week 3-drug (vincristine, dactinomycin, doxorubicin) phase in 60 cases, while 8 had up-front nephrectomy. Adjuvant therapy included 8-month 3-drug chemotherapy for non anaplastic “local” tumor stage I to III (flank RT for stage III), or an intensified regimen for anaplastic histology, adding etoposide, carboplatinum and ifosfamide (6 patients). Overall 19 tumor failure occurred (3 in anaplastic tumors): metastases progression 9, abdominal relapse 5 (combined to liver and mediastinum in 1 case each), lung 4, liver 1. After a median follow-up of 53 months 5-yr RFS and OS were 71% ±6 and 77% ±5 for the whole cohort of children, respectively. Overall, RFS was 86% in patients who achieved a complete metastases remission (in 2 cases by surgery) compared to 55% in patients who did not (Logrank p<.05). Noteworthy the omission of lung RT in TW2003 trial for complete responders evaluated at week 6 did not jeopardize survival (85% RFS, vs 58% for those children with persistence of metastases and lung RT). There was a trend toward a worse outcome for patients with at least liver metastases (n 13) compared to those with other site (4-yr RFS 49% vs 74%, p=.1). Conclusions: Failure to obtain metastases complete remission, and maybe site other than lung, should be considered for chemotherapy intensification for metastatic WT. The impact of metastatic tumor burden deserves further analysis. Withholding RT in rapidly complete responders patients did not compromise outcome.

No significant financial relationships to disclose.
Correlatoin of apoptosis signaling in primary pediatric BCP-ALL xenograft cells with the kinetics of engraftment in vivo in a NOD/SCID model and patient outcome
Authors: Queudeville M. , Eckhoff S. M. , Debatin K. , Meyer L. H.
Published: August 2020

10043

Background: We previously identified the importance of intact apoptosis signaling for treatment response in pediatric ALL and AML by analyzing two key apoptogenic events, caspase-3 activation and cytochrome c release. A correlation of both events was exclusively found in the groups of patients with good response to treatment, showing that intact apoptosis signaling is a critical feature for favorable outcome. Using a NOD/SCID mouse model for pediatric BCP-ALL we found that short time from transplant to overt leukemia in the recipient mice (short time to leukemia, TTLshort) determines poor patient outcome. Methods: In this study we investigated the importance of deficient apoptosis signaling for leukemia engraftment in this model. The apoptosis signaling parameters cytochrome c release and caspase-3 activation were analyzed in 17 ALL xenografts (TTLshort n = 5, TTLlong n = 12) by flowcytometry in relation to TTL. Results: A significant correlation of both apoptosis parameters was found in the TTLlong group only (P = .017). Importantly, patients showing TTLlong revealed a superior outcome compared to TTLshort patients. Proficient apoptosis signaling was only found in blast cells from recipients where the corresponding patient had favorable prognostic factors such as TEL/AML1-positivity (P = .023), no hyperleucocytosis (P = .012), no relapse (P = .038), and no early relapse (P = .017). In contrast, the correlation of cytochrome c release and caspase-3 activation was absent in the groups with poor prognosis. We also found a direct positive correlation between TTL and cytochrome c (P = .022) and caspase-3 activation (P = .048), indicating that short engraftment may be due to deficient apoptosis signaling. Conclusions: Our finding in the NOD/SCID/huALL model matches our results in pediatric ALL and AML to conclude that the functional integrity of a downstream apoptotic checkpoint is an important feature regulating leukemia biology. Thus, deficient apoptosis signaling appears to determine rapid engraftment of leukemia cells in the NOD/SCID model in vivo and consequently poor patient outcome.

No significant financial relationships to disclose.
Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukemia
Authors: Te Loo D. M. , van Schie R. M. , Hoogerbrugge P. M.
Published: August 2020

10049

Background: Vincristine is one of the corner stitches in the treatment of children with acute lymphoblastic leukemia (ALL). Constipation and other peripheral and central neurotoxicities are the most common side effects. Drugs interfering with the metabolism of vincristine might potentiate these side effects. A group of drugs that interact with the metabolism of vincristine are azoles. Several case reports suggest that co-administration of azoles and vincristine lead to increased toxicity. A comparative study exploring toxicity in patients receiving vincristine with and without azoles, is lacking. For this reason, we retrospectively analyzed neurotoxicity induced by vincristine with (n = 20) and without (n = 20) co-administration of azoles in the same patient group. Methods: In total, twenty pediatric patients with de novo ALL were included in this study. Vincristine toxicity was graded retrospectively according to the National Cancer Institute toxicity scale without information considering comedication. Statistical analysis was performed using the Wilcoxon Signed Rank test and McNemar test. Results: Patients receiving vincristine in combination with prophylactic azole treatment experienced significantly more complaints of constipation and peripheral neurotoxicity (P = 0.001 and P< 0.001, respectively). Three patients (15%) treated with azole therapy developed severe toxicity and needed treatment at the pediatric intensive care unit. Vincristine induced CNS toxicity (convulsions, toxic encephalopathy and SIADH) was seen in 6 patients (30%). All these patients were treated with vincristine in combination with an azole. CNS toxicity was not observed in patients receiving vincristine alone (P = 0 .014). Because of severe toxicities, vincristine treatment was significantly reduced (50% of normal dose) in several patients. Conclusions: This study shows that vincristine toxicity is significantly increased when combined with azole treatment and even can be life threatening. Therefore we advise to avoid the combination of azole and vincristine treatment in patients with ALL.

No significant financial relationships to disclose.
The role of 131-I-metaiodobenzylguanidine (13II-MIBG) therapy in irresectable and compromising localized neuroblastoma
Authors: Schoot R. A. , Bleeker G. , Heij H. A. , van Eck B. L. , Caron H. N. , de Kraker J.
Published: August 2020

10053

Background: According to current practice, observation only is justified in patients with localized, irresectable neuroblastoma with favorable biologic features. However, when organ or life threatening symptoms arise, therapy is required. Side effects of treatment should be minimal, since outcome is good. The aim of this study was to evaluate the response and outcome of neuroblastoma under these circumstances, when treated with 131-I-metaiodobenzylguanidine (131I-MIBG). Methods: Between 1989 and 2008, 21 patients (8 boys/13 girls) with localized neuroblastoma were included. Median age was 1.6 years (range of 0–5.5 years). Patients were eligible when the primary tumour was irresectable and organ or life threatening. Diagnosis and staging were performed according to the International Neuroblastoma Staging System (INSS). Fixed dosages of 131I-MIBG (50–200 mCi) were given with an interval of four weeks. The median number of infusions was two (range 1 to 7).131I-MIBG was given according to standard directions for targeted therapy. Response was graded according to the International Neuroblastoma Response Criteria (INRC). Results: Four patients were classified as stage I, three as stage II, and fourteen as stage III. Three tumors were NMYC amplified and two had loss of heterozygosity of 1p. Minimal pretreatment was given to nine patients, because of organ or life threatening symptoms. These patients responded insufficiently or showed return of tumor growth. After 131I-MIBG treatment, 8/21 regressed. Resection became possible in 13/21 patients. In 10/13 patients resection was macroscopically complete. Three other patients had incomplete resection of their tumor. They had longterm progression free survival. At the end of treatment 16/21 patients achieved complete response (CR) and 3/21 had stable disease (2 very good partial response (VGPR), 1 partial response (PR)). Two patients died, one of progressive disease, one due to complications of surgery (CR). One patient was lost to follow-up. Ten years OS was 90.5%, 10 years EFS was 72.4%. Median follow-up was 7.5 years (range 1 to 17.4). Conclusions: 131I-MIBG treatment is an effective treatment modality in irresectable, localized neuroblastoma, in case of organ or life threatening situations.

No significant financial relationships to disclose.
Resistance of stem-like cells from neuroblastoma cell lines to commonly used anticancer drugs
Authors: Vangipuram S. D. , Wang Z. J. , Lyman W. D.
Published: August 2020

10054

Background: Neuroblastoma is the most common extra-cranial solid tumor of childhood. Recent studies have shown that most cancers contain a small number of stem-like cells which may be responsible for cancer progression and relapse. For this study, we investigated the cytotoxicity of 4 commonly used anti-cancer drugs on stem-like cells isolated from neuroblastoma cell lines. Methods: Cell surface marker CD133 positivity was used to define stem-like cells. Three neuroblastoma lines were screened for the expression of stem cell marker CD133 by FACS analysis. CD 133+ cells were isolated by positive selection using magnetic micro-beads. The cytotoxicity of four cancer drugs Cisplatin (0–50μg/ml), Etopside (0–200μg/ml), Doxorubicin (0–200ng/ml), and Carboplatin (0–200μMl) was studied on CD133+ and CD133- populations, by MTT and PI/Annexin binding assays. Results: Neuroblastoma lines SK-N-BE and SK-N-SH had 2% and 8% cells expressing CD133 respectively, while SH-SY-5Y had no CD133 expressing cells. CD133 + cells showed significant resistance to all four drugs in the MTT assay as well as the PI/Annexin binding assay compared to CD 133 - cells. Conclusions: This study suggests that CD133+ cells in neuroblastoma cell lines are more resistant to conventional anti-cancer drugs compared to CD133- cells. Targeting these stem-like cell populations could lead to development of more effective treatment for neuroblastoma. [Table: see text]

No significant financial relationships to disclose.
Neuroblastoma: A spectrum of cells isolated from bone marrow of patients
Authors: Saulnier Sholler G. , Illenye S. , Warzynski M. , Brown R. E. , Lescault P. J. , Koto K. , Dorf L. , Bond J.
Published: August 2020

10055

Background: Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, portends a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant and radiation, long-term survival remains at 30%. Better detection of the 70% of patients who will relapse is essential. One possibility may be in the better detection of minimal residual disease and improved classification of the heterogeneous populations of cells present in the bone marrow with respect to risk. Methods: Bone marrow aspirates of patients with neuroblastoma were harvested and placed in neurobasal culture media and heparinized vacutainer tubes. They were analyzed by 6-color flow cytometry (CD56+, GD2+, CD81+, CD45−, CD9+, CD34+or−). Neuroblastoma cells and neurospheres were grown. mRNA expression analysis using U133 chips, immunofluorescence, and immunohistochemistry were performed. Mouse xenograft models were used to evaluate tumorigenicity of patient cells injected subcutaneously. Results: Flow cytometry can detect neuroblastoma cells as low as 0.001% within the heparinized samples and used to characterize the cultured cells. Cell culture showed a spectrum of neuronal morphology. Neurospheres express lower levels of GD2, TrkB, and CD56 compared to adherent neuroblastoma (consistent results were obtained using flow cytometry, immunofluoresence, immunohistochemistry, and mRNA expression analysis). Tumorigenicity was confirmed using mice injected subcutaneously with patient neurospheres tumors were present at the injection site and metastasized. Conclusions: Bone marrow aspirates of patients with neuroblastoma can be analyzed for the presence of neuroblastoma initiating cells which can be further characterized. This may play an important role in clinical decision making for therapeutic end points in a cancer that is likely to relapse.

No significant financial relationships to disclose.
A clinical trial to study the effect of adding cis-retinoic acid during and after conventional treatment for pediatric neuroblastoma patient
Authors: Arafat W. , Abdelghany A. , Awad N.
Published: August 2020

10057

Background: Neuroblastoma is predominantly a tumor of early childhood, with two thirds of the cases presenting in children younger than 5 years. Cis-retinoic acid has been used as maintenance therapy for treatment of advanced neuroblastoma after BMT. Patients who received cis-retinoic acid had significantly better 3-year event-free survival than patients receiving no maintenance therapy. However, there is no data available about usingcis-retinoic acid during induction phase of chemotherapy. The aim of this study is to evaluate the efficacy of cis-retinoic acid when used in combination with conventional chemotherapy in pediatric patient who is newly diagnosed with locally advanced neuroblastoma. Methods: Seventeen newly diagnosed children with locally advanced neuroblastoma who is candidate to receive chemotherapy were also received cis-retinoic acid starting at a dose of 160 /m2 day (day 2–15 of chemotherapy) first the 3 patients, 20% dose reduction were allowed if toxicity occurred in first cohort of patient. . Patients were giving the drugs for at least 4 cycles. RT-PCR analysis of several related genes was done from tumor, sample after treatment. Results: Median age 2.4. Male:Female ratio was 1.4:1. Patients were stage III, IV (70%), II (30%). 88% of patients were presented with abdominal mass .Most patient received at least 6 cycles of OPEC/OJEC regimen. N Myc was done to 12 of patients. Median follow up was 6 months. Maximum tolerated dose were 130mg/m2, response was seen as CR 30%VGR 40, PR 12%, and PD 18%. Median event free survival was 12 months. Toxicity: Hypercalcemia mucositis, rash, and elevated liver enzymes were the main dose limiting effect of cis-retinoic acid. Preliminary collaborative analysis showed that down regulation of N-MYC is related to response rate. Conclusions: Cis-retinoic acid at dose 130mg/m2 is a well tolerated drug with chemotherapy. Response to treatment is better than historical control. Randomized phase III trial is warranted.

No significant financial relationships to disclose.
ATM gene analysis in neuroblastoma: A report from the COG
Authors: Gumy-Pause F. , Ozsahin H. , Khoshbeen-Boudal M. , Pardo B. , Betts D. , Maillet P. , Sappino A.
Published: August 2020

10058

Background: Neuroblastoma (NB) is the most common malignant disease of infancy and accounts for approximately 8% of all childhood cancers. The clinical hallmark of this tumor is the marked variability in prognosis depending of the age, stage, and biological characteristics. There is evidence to suggest that the long arm of chromosome 11 (11q) plays a role in NB biology. The ATM gene is located at 11q22–23 and hereditary mutations of this gene cause ataxia-telangiectasia, a recessive disorder associated with a high incidence of neoplasia. The aim of this project was to determine the prevalence of ATM gene mutation and ATM methylation status in 50 NB samples. Methods: Following DNA extraction, PCR products of the 65 exons of the ATM gene and its promoter were screened by DHPLC. This screening was also performed on DNA from 60 blood donors. Alterations detected were analyzed by direct sequencing. Direct and indirect criteria were used to classify the observed nucleotide alterations as mutation (if pathogenic), rare variant (if the allelic frequency in controls was < or = 1%), variant (1.1–2.4%) or polymorphism (> or = 2.5%). The ATM methylation status was analyzed by MS-MLPA (Methylation-Specific Multiplex Ligation-dependent Probe Amplification). Results: Except polymorphisms, 17 different sequence alterations were found in 17 NB samples (34%). Ten of these 17 alterations, found in 11 NB (22%), were rare variants (RV). In 5 NB (10%), RV were found homozygous. At the same time, we found 20 different sequence alterations in 19 controls (32%). Sixteen of these 20 alterations were RV and one was a heterozygous pathogenic mutation. These 17 alterations concern 15 controls (25%). No homozygous RV was found in controls. We found no evidence of ATM promoter hypermethylation in the 48 NB samples analyzed. Conclusions: We found no difference in ATMvariant and RV frequency between NB and control samples. However, as ATM deletion is a frequent event in NB, we found a high frequency of homozygous RV (10%). At present, we are completing this study by screening ATMlarge genomic deletion/duplication using MLPA. Finally, our observations indicate that epigenetic ATM silencing by methylation is uncommon in neuroblastoma.

No significant financial relationships to disclose.
Multimodality treatment on long-term outcome of intracranial germ cell tumors in children: A single institution study
Authors: Kebudi R. , Darendeliler E. , Ayan I. , Gorgun O. , Yaman Agaoglu F. , Dizdar Y. , Darendeliler F. , Emiroglu H.
Published: August 2020

10063

Background: Intracranial germ cell tumors (iGCT) constitute 1% of all malignant neoplasms in children. The aim of this study is to evaluate the demographic characteristics, therapy, and long term outcome of children with iGCT in a single institution. Methods: 16 children (9 female, 7 male) with a median age of 11 years (10 months-18 yrs) treated for iGCT between 1990 and 2008 were evaluated retrospectively. They were treated according to our institutional protocol. Patients > 13 years old with germinomas recieved radiotherapy alone (2520 cGy craniospinal/1980 cGy local boost), patients <13 yrs old recieved 2 courses of etoposide, cisplatinum followed with cranial radiotherapy. Nongerminoma patients recieved 3 courses of bleomycine, etoposide, cisplatinum followed by 3600 cGy craniospinal / 1980 cGy local boost RT. Results: Presenting clinical features were diabetes insipidus (7), raised intracranial pressure (12), visual changes-oculomotor palsies (6), hypopituitarism (4). 8 had germinomas and 8 nongeminomatous GCT. Ten were suprasellar and 6 pineal. AFP and BHCG were evaluated at diagnosis and during therapy both in serum and CSF. Three had seeding in the spinal axis in MRI. One had widespead systemic metastasis. Three had a total resection, 12 had a biopsy, 1 was clinically/radiologically diagnosed, 5 had a shunt. Two nongerminamatous iGCT patients died: 1 of widespread disease in the intensive care unit at diagnosis, the other with progressive disease 18 months after diagnosis. Fourteen patients are alive at a median follow-up of 12 years (1–17 years) from diagnosis. One that had motor and mental retardation before diagnosis needs special care. All others have a moderate/good quality of life. One is married and has a child. Six are at school (2 in university). Five are employed. The patients are also followed up in the endocrinology clinic. One is recieving growth hormone. Conclusions: Cisplatin based chemotherapy and radiotherapy is successful and well tolerated in children with iGCT. The possibility of an early clinical diagnosis based on MRI and tumor markers and the use of modern neurosurgical techniques increases the chance of cure, gives a chance to reduce acute morbidity and further decrease late effects.

No significant financial relationships to disclose.
Preliminary safety and activity results of trabectedin in a phase II trial dedicated to triple-negative (ER-, PR-, HER2-), HER2+++, or BRCA1/2 germ-line-mutated metastatic breast cancer (MBC) patients (pts)
Authors: Delaloge S. , Tedesco K. L. , Blum J. , Gonçalves A. , Lubinski J. , Efrat N. , Osborne C. , Lebedinsky C. , Tercero J. C. , Holmes F. A.
Published: August 2020

1010

Background: Trabectedin ([T]; Yondelis) binds to the minor groove of DNA; its cytotoxicity is determined by the synergistic action of two DNA repair mechanisms, the efficient nucleotide excision repair (NER) and deficient homologous recombination repair (HRR) machinery. T has EMEA authorization in soft tissue sarcoma after failure of standard treatment. Preliminary data have shown activity of T as single agent in MBC. Clinical and preclinical data suggested T may display specific activity among certain NER-intact or HRR-deficient MBC, and prompted this phase II trial dedicated to 3 subgroups: triple-negative (TN), HER-2-overexpressed, and BRCA1/2 germline-mutated MBC. Methods: T was given at 1.3 mg/m2 as a 3- hour iv infusion every 3 weeks to pts with pretreated progressive MBC: Group A: TN; Group B: HER-2+++; Group C: BRCA1/2 mutation carriers. Endpoints were objective response (OR) rate by RECIST, duration of response, progression free survival (PFS), tumor volume changes, safety and exploratory pharmacogenomics (PGx). Results: A total of 95 women (median [med] age 52, ECOG 0/1 48/52%) have been enrolled (A:50, B:24, C:21) with data available for 72 pts. Med number of prior chemotherapy regimens: 4 (1–10). Med number of T cycles administered: 2 (1–12) for all groups. The most commonly reported grade 3/4 AEs are neutropenia (29/21%), ALT (28/2%) and AST (13/0). Alopecia/stomatitis, only G1, was reported in <2% each. Long-lasting disease stabilizations were described in all groups. While OR were rare among TN MBC pts (2PR/43 evaluable), preliminary analysis by investigator shows efficacy in group C (4PR/11 evaluable). Tissue samples from 36 pts were collected for RNA expression analysis (XPG + ERCC1 + BRCA1). Preliminary results show high XPG is associated with longer PFS: 4.1 months (95% CI 2.6-not reached) versus 1.3 months (95% CI 1.2–3.7), p = 0.01. Analyses are ongoing. Conclusions: Trabectedin shows a manageable safety profile in the 3 groups of MBC with promising efficacy in certain DNA-repair machinery sub-categories defined molecularly. TN group was closed due to low response. More mature PGx results will be discussed to help selecting the patients who are at highest chance for response.

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Dasatinib in advanced HER2/neu amplified and ER/PR-positive breast cancer: Phase II study CA180088
Authors: Mayer E. , Baurain J. , Sparano J. , Strauss L. , Campone M. , Fumoleau P. , Rugo H. , Awada A. , Sy O. , Llombart A.
Published: August 2020

1011

Background: SRC family kinases (SFKs) are involved in numerous signaling pathways including from ER and HER-2 receptors, as well as osteoclast function. Dasatinib is a potent oral inhibitor of SFKs. A phase II trial was performed in patients (pts) with ER+ and/or PR+ and/or HER-2-amplified progressive advanced breast cancer. Subsequent to study initiation, dasatinib demonstrated similar efficacy with a lower incidence of key side-effects at 100 mg once daily in CML and prostate cancer. Methods: Pts with measurable disease and progression after chemotherapy and other targeted agents were treated with dasatinib on a continuous twice-daily (BID) schedule; RECIST-defined response rate was primary endpoint. Results: Sixty-eight pts, 24 with HER-2-amplified and 44 with HER-2-normal, ER+ and/or PR+ disease, were treated. Original starting dose of 100 mg BID (23 pts) was reduced to 70 mg BID (45 pts) due to fluid retention, fatigue, or GI toxicity. Median age was 55 years; nearly all pts (93%) had prior therapy in advanced setting. 59 were radiographically-evaluable (8 discontinued for toxicity and 1 inevaluable). We observed 3 partial responses lasting 9, 9 and 8+ mos plus 6 stable disease ≥16 weeks (range 24–33 wks). All 9 controlled tumors were ER/PR+, 2 were also HER-2-amplified; thus, disease control rate was 19% in the 47 radiographically-evaluable pts with ER/PR+ disease. Median dose intensity was 136 mg/day at 70 mg BID and 175 mg/day at 100 mg BID; median duration of therapy was 1.8 mos in both dose groups. Most pts (75%) discontinued for disease progression. The most common drug-related AEs were diarrhea (49%), headache (34%), nausea (34%), asthenia (32%), pleural effusion (31%), musculoskeletal pain (25%), and vomiting (24%). Drug-related grade 3–4 AEs were reported in 37% of pts and comparable between doses, but related serious AEs were less frequent at 70 mg BID than 100 mg BID (16% vs 26%). Grade 3–4 laboratory abnormalities were uncommon. PK and biomarker analyses will be presented. Conclusions: Encouraging single-agent activity was observed with dasatinib in pts with advanced ER+ breast cancers. Future studies will address the combination of dasatinib with hormonal therapies using a better-tolerated once daily schedule.

[Table: see text]