bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results of an open-label study to evaluate the efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with carboplatin-containing chemotherapy regimen in patients with ovarian cancer
Authors: Timmins P. F. , Kredentser D. , Hancock K. C. , Messing M. , Boehm K. A. , Mull S. , Ilegbodu D. , Asmar L.
Published: March 2020

19652

Background: The use of aprepitant has been shown to offer an advantage in preventing acute and delayed chemotherapy- induced nausea and vomiting (CINV). This study integrates palonosetron and dexamethasone into the regimen to determine the efficacy and safety of this combination. Methods: 50 patients (pts) have enrolled; data has been submitted for 43. Main inclusion criteria were: diagnosis of ovarian (OV), primary peritoneal (PP), fallopian tube (FT) carcinoma Stage I-IV, or papillary serous cancer of the uterus (UPSC); naive to emetogenic chemotherapy Hesketh ≥Level 4, is scheduled to receive paclitaxel 175 mg/m2 IV and carboplatin AUC=6 IV; is able to read and understand the Functional Living Index - Emesis (FLIE) questionnaire. Results: Median age was 61 years, 60% ECOG=0, 86% prior surgery; 68% OV, 14% PP cancers, 7% UPSC, and 5% FT. Metastases were noted in 30% of pts, 21% had visceral metastasis. To date, 70% of patients (32/46) have reported no vomiting, or use of rescue medications during the study and are deemed as complete responders. Based on the 35 pts for whom complete patient diaries have been submitted thus far, the complete response rate is 91% (32/25), compared to 50% (aprepitant alone [The MEC Trial]). No Grade 3–4 treatment related adverse events were reported; Grade 1–2 toxicities included neutropenia (10.5%); anemia, constipation, and nausea (7.9%, each), and fatigue, dyspepsia, and arthralgia (5.3%, each). Some of the toxicities may be related to the chemotherapy, and are not treatment-related to the aprepitant, palonsetron, or dexamethasone. Conclusions: The addition of aprepitant to palonsetron and dexamethasone appears to be very well tolerated. This combination is effective in the prevention of chemotherapy-induced nausea and vomiting when used with emetogenic therapy such as paclitaxel and carboplatin. This research was supported, in part, from a research grant from Merck & Co., Inc. Whitehouse Station, NJ.

No significant financial relationships to disclose.
Evaluation of psychological distress, anxiety and depression in oncologic patients admitted to a medical oncology unit
Authors: Buralli B. , Manai S. , Camerini A. , Aiosa C. , Amadei L. , Donati S. , Tartarelli G. , Valsuani C. , Garrone O. , Amoroso D.
Published: March 2020

19658

Background: psychological status influences patients’ compliance to treatments, quality of life and perhaps final outcome. Moreover, the screening for psychological disturbances may allow patients at risk to be identified so they can benefit from specific interventions. Methods: 133 consecutive unselected pts (76 F, mean age 63.7 ± 11.6 yrs) admitted to our Medical Oncology Unit were evaluated at hospital admittance. We employed the Italian validated version of the Hospital Anxiety Depression Scale (HADS) questionnaire, a self-administered questionnaire specifically developed to reveal states of distress (D), anxiety (A) end depression (DE) in non- psychiatric patients with an organic disease. Two cut-off values (7 and 11 points) to identify borderline (8–10 points) and probable clinically relevant cases (= 11 points) in A and DE scales were used. Scores between 15 and 21 were considered as borderline cases and >21 were considered to be of clinical relevance in total D scale. Results: mean total D, A and DE levels were 16.5 ± 11.6, 7.8 ± 4.7 and 8.3 ± 5.3 respectively. Females showed higher levels than males for all parameters (D: 17.6 ± 9.5 vs 14.2 ± 8.1, p=0.031; A: 8.6 ± 4.9 vs 6.9 ± 4.2, p=0.035; DE: 9.1 ± 5.6 vs 7.3 ± 4.7, p=0.06ns). Age-related subgroup analysis demonstrated a trend towards higher A scores in =40 yrs pts vs total population (11.0 ± 3.0 vs 7.8 ± 4.7, p=0.08ns) and significantly higher D and DE values in =80 yrs pts (22.6 ± 11.3 vs 16.2 ± 9.1, p=0.05 and 13.0 ± 6.6 vs 8.3 ± 5.3, p=0.025 respectively). Regression analysis showed in females a significant direct correlation between age - D (r = +0.46, p = 0.048) and age - DE (r = +0.62, p = 0.0019) and in males a significant inverse correlation between age - D (r = -0.52, p = 0.04), age - A (r = -0.45, p = 0.05) and a clear trend between age - DE (r = -0.42, p = 0.07ns). Conclusions: the study population presented with borderline admittance D, A and DE values. In particular, young males respect to A and old women respect to D and DE represent higher risk groups for future development of psychological abnormalities complicating disease treatment. Prospective studies are ongoing to evaluate the impact of pts recovery and/or treatment on psychological parameters.

No significant financial relationships to disclose.
Bone mineral density of pretreatment Japanese women with breast cancer; Efficacy of oral bisphosphonates with aromatase inhibitor
Authors: Yamada K. , Kohno N. , Kaise H. , Ohta D. , Ogata A. , Ueno F.
Published: March 2020

19679

Background: From the good results of the ATAC trial and the ITA trial, standard hormonal therapy for postmenopausal breast cancer has changed from tamoxifen to aromatase inhibitor. However concerning the rate of skeletal-related events(SREs) including bone fracture, osteopenia and osteoporosis, a decrease in bone mineral density (BMD), It is reported that aromatase inhibitor cause higher than tamoxifen. According to the 2003 ASCO guidelines on the role of bisphosphonates in women with breast cancer, most women with newly diagnosed breast cancer are at risk of osteoporosis due to either their age or their breast cancer treatment. The purpose of the study is to investigate BMD of pretreatment Japanese women with breast cancer, and to investigate the efficacy of bisphosphonate for prevention from osteoporosis by aromatase inhibitor. Methods: From 2002, we have investigated BMD of 130 patients with breast cancer who underwent breast cancer operations in this hospital. BMD measurement was performed at A-P spine (L2–4) before treatment for breast cancer. The mean value of BMD for postmenopausal and premenopausal patients is compared with the value of average for Japanese women.Also we experienced 92 cases of postmenopausal breast cancer patients who were undergone breast cancer operations and take aromatase inhibitor after operations in this hospital. We selected 2 drugs. One is Anastrozole(ArimidexR) as an aromatase inhibitor, and the other is Alendronate(BonaronR) as a oral bisphosphonate drug. Results: The mean value of BMD for postmenopausal and premenopausal patients is 0.823 (vs. 0.90 for average) and 1.013 (vs. 1.03), respectively. This study shows that BMD of postmenopausal patients is trend lower than average. Tumor markers did not show significant difference. In the other study, the number of NTX which patients take Alendronate with Anastrozole decreased about 40% than which patients take Anastrozole alone. Also the rate of SRE is lower. Conclusions: The results suggest that the efficacy of bisphosphonates for prevention from SREs by aromatase inhibitor. Also BMD measurement seems significant for breast cancer patients before treatment including hormonal therapy.

No significant financial relationships to disclose.
Opinions of the Turkish population on cancer and being informed for the diagnosis of cancer: An opinion survey
Authors: Yalcin B. , Yalcin S. , Buyukcelik A. , Sencan O. , Dogan M. , Turk M. , Ozdemir F. , Isikdogan A. , Er O. , Akbulut H. , Icli F.
Published: March 2020

19680

Background: Opinions of the Turkish population on cancer, and their probable attitudes if one of their relative or themselves would have cancer diagnosis are investigated. Methods: The age, gender, profession, education levels of the subjects, their overall opinions on cancer are recorded by an opinion survey. Questions regarding if one of their first degree relatives had cancer, would they like the diagnosis being told to the patient and if they were to be the patient with cancer, would they prefer to be informed about the diagnosis are also asked. Results: 6566 subjects from various geographical regions of Turkey are participated in this survey. Participants’ median age were 33 years (range: 18–100), 53.3% were male. 57.7% of the participants would prefer to hide the cancer diagnosis from their first degree relatives. 54.8% of the participants had relatives with cancer and 69.9% of them said that the diagnosis had been told to the patient. The timing of the disclosure of the diagnosis were immediately in 71.5%, months after the diagnosis in 16.9% and in terminal stage in 9% of the patients. 62.8% of these patients are told to be died from cancer. When their overall opinion on cancer is asked, 76.5% were optimistic, 16.3% were pessimistic and did not believe the medicine, and 2.9% had both positive and negative opinions. Logistic regression analyses showed that 1) younger subjects; female subjects; subjects with lower education levels; subjects having a relative with cancer diagnosis which had not been revealed to the patient or revealed late in the course of the disease, or the patient had been died; subjects with pessimistic opinions about the treatment of the cancer were likely to hide the cancer diagnosis form their first degree relatives. 2) Elder subjects; subjects with lower education levels; subjects having a relative with cancer diagnosis which had been revealed to the patient; subjects having a relative with cancer diagnosis who died from cancer, subjects optimistic about cancer treatment; subjects preferring the diagnosis be hidden from patients were preferring not to be informed about the diagnosis if they were to have cancer. Conclusions: These results are comperable with reports form Eastern Europe and Asian countries.

No significant financial relationships to disclose.
Individualized versus fixed dosing of L-asparaginase during intensification therapy in children treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 00–001
Authors: Waghorne C. , Stevenson K. E. , Neuberg D. S. , Sallan S. E. , Relling M. V. , Supko J. G. , Kutok J. , Silverman L. B.
Published: March 2020

20000

Background: Asparaginase (ASP) is an important agent in the treatment of ALL, but is associated with multiple toxicities. In an attempt to reduce toxicity and improve ASP tolerability, we investigated individualizing the dose to maintain nadir serum ASP levels at the minimum concentration (0.01 - 0.014 IU/ml) required to achieve asparagine depletion. Methods: 399 children (1–18 years) with newly diagnosed ALL were randomized to receive intramuscular E.coli ASP either as fixed dose (FD) (N=201; 25,000 IU/m2/week) or individualized dose (ID) (N=198; 12,500 IU/m2/week starting dose, adjusted up or down every 3 weeks based upon nadir serum ASP level) for 30 weeks during post-induction intensification. We report here on 365 randomized patients (pts) who had 7-day nadir ASP levels measured (185 FD and 180 ID). Serum ASP levels were measured prior to ASP doses 2, 4 and every third subsequent dose. ASP-antibodies (ab) were measured every six weeks. Results: The median dose for ID pts was17,500 IU/m2 (range 6,000–28,000 IU/m2). The median ASP concentration was 0.11 IU/ml (range < 0.025- 2.16 IU/ml) for FD (N=1190 samples) and 0.08 IU/ml (range < 0.025–0.74 IU/ml) for ID (N= 1238 samples) (p<0.01). The interpatient variability in ASP concentration was smaller for ID vs. FD at all 10 time points measured. The proportion of pts who had detectable E.coli-ASP antibodies did not differ between the two arms (35% FD vs. 40% ID) (p= 0.33). The median ASP concentration was lower for ab-positive pts (0.08 IU/ml vs. 0.1 IU/ml, (p<0.01). Toxicity was similar in the two arms: local allergy: 6% FD vs. 8% ID (p= 0.55); systemic allergy: 12% FD vs. 14% ID (p= 0.54); pancreatitis: 5% FD vs. 7% ID (p= 0.66); thrombosis: 8% FD vs. 7% ID (p= 0.84). No association was observed between nadir ASP levels and either pancreatitis or thrombosis. Conclusions: Individualized dosing of E.coli ASP during intensification therapy reduced peak nadir ASP levels and interpatient variability but did not significantly decrease the incidence of ASP-related toxicity. Longer follow-up is necessary to determine event-free survival of the randomized pts.

No significant financial relationships to disclose.
Findings from the screening echocardiograms performed on survivors of childhood cancer treated with anthracyclines and/or chest radiation
Authors: Andolina J. , Dilley K. J.
Published: March 2020

20001

Background: Treatment with anthracyclines or chest radiation confers an increased risk of cardiomyopathy persisting for years after treatment ends. The Children’s Oncology Group (COG) has created guidelines for how often to screen cardiac function in long-term survivors of pediatric cancers based on age at treatment and total cumulative dose of anthracyclines. The objective was to examine the findings from a screening program using these guidelines. Methods: Medical record reviews were performed for all patients ever seen in the past 10 years in the long-term follow-up (LTFU) program at a single institution. Reviews examined treatment variables such as diagnosis, age at diagnosis and anthracycline cumulative dose as well as the shortening fraction (SF) from any echocardiogram (echo) performed as a screening study at =4 years from diagnosis (LTFU screening echo). Analyses include Chi-square and logistic regression. Results: 365 patients seen in the LTFU program at =5 years from diagnosis were considered at risk for cardiomyopathy due to anthracycline therapy or radiation exposure to the chest (including total body irradiation). Patients were 56.4% male and 65.5% white. Acute leukemia, neuroblastoma, Wilm’s tumor and lymphoma made up 82.2% of the diagnoses. 312/365 (85.5%) had ever had an LTFU screening echo. Younger age group at treatment as divided in the COG guidelines (<1y, 1–4y, =5y) was associated with likelihood of ever having an LTFU screening echo (p=0.018). 25/312 (8.0%) ever had a SF <28% in one of those LTFU studies. Only 5 of those 25 had an abnormal echo prior to presenting to LTFU. Age group at treatment was not significantly associated with likelihood of a SF <28% (p=0.939), but anthracycline dose of =250 mg/m2 was associated (OR 5.9, 95% CI 2.3–15.3). Radiation exposure, stem cell transplant and history of relapse were not associated with SF <28%, but prior abnormal echo was associated (p=0.032 exact). Cardiology referral was more likely in patients who ever had a SF <28% (p<0.001). Conclusions: Only 8% of patients being screened in a LTFU program for anthracycline-induced cardiomyopathy ever had a SF <28%. Further exploration of whether the age- and dose- stratified screening guidelines can be simplified is warranted.

No significant financial relationships to disclose.
Demographics, clinical profile, management, and outcome of retinoblastoma in a tertiary care center in southern India
Authors: Reddy V. P. , Honavar S. G. , Shome D. , Shah K. , Naik M. N. , Rao R.
Published: March 2020

20011

Background: Retinoblastoma is the most common malignant intraocular tumor in children. The estimated incidence of retinoblastoma in India is about 2,000 a year. However, there is scant data on the clinical manifestations and outcome of retinoblastoma in India. Methods: In this retrospective case series, the medical records of 460 consecutive cases of retinoblastoma from January 1990 to December 2004 were analyzed for demographics, clinical profile, treatment and outcome (survival, organ and function salvage). Results: An integrated Ocular Oncology Service was established at the treatment center in the year 2000 and a specialized Children’s Eye Cancer Center was founded in 2004. The annual referral increased from <20 a year before 2000 to 38 in 2000, and 120 in 2005. Two hundred and six (45%) patients were economically underprivileged. A majority (303, 66%) presented <3 years of age. There were 277 (60%) males. Although 188 (41%) were bilateral, family history was forthcoming in only 19 (4%). Of 648 involved eyes, 531 (82%) eyes were symptomatic. Leucocoria (71%) was the most common symptom, followed by visual loss (12%), eyelid edema or proptosis (7%), squint (6%), pain (2%), redness (2%), enlarged eyeball (2%), or shrunken eyeball (1%). The tumor was intraocular in 609 (94%) eyes while 39 (6%) were extraocular. Enucleation was the most common primary treatment for intraocular retinoblastoma (236 of 451, 52%), followed by chemoreduction coupled with focal therapy (26%), focal therapy alone (11%), external beam radiation (55) or chemotherapy alone (4%). Histopathologic risk factors predictive of metastasis were found in 152 of 277 (55%) eyes that underwent enucleation. Chemoreduction with focal therapy resulted in eye and vision salvage in 109 of 118 (92%). At the final follow-up (minimum 24 months), 434 (94%) were alive and well. Conclusions: Retinoblastoma has excellent prognosis for survival, eye salvage and vision salvage with the current management modalities. An integrated approach involving a team of a pediatric oncologist and an ocular oncologist at a comprehensive tertiary care center may augment referrals and help implement systematic treatment strategies.

No significant financial relationships to disclose.
Comparative study of safety and efficacy of imatinib mesylate therapy in pediatric and adult chronic myeloid leukemia
Authors: Raizada N. , Sagar T. , Ramanan S.
Published: March 2020

20016

Background: Chronic Myeloid Leukemia (CML) is one of the rare pediatric cancers. Imatinib is now the standard of care in adult CML (ACML) with newer compounds being investigated to overcome the burden of Imatinib resistance. Pediatric CML (PCML) has been an area little explored and effective strategies are not yet defined. Although, allogenic hematopoietic stem cell transplantation (HSCT) still remains the gold-standard treatment, the choice of drug in the subset in which HSCT is not a suitable option remains to be determined. Methods: This was a single-institution prospective study conducted from April 2004-March 2006, analyzing and comparing 293 Philadelphia chromosome (PH) positive CML patients in pediatric and adolescent subsets (i.e. age =18 years) not eligible for allogenic HSCT with ACML. After obtaining a written informed consent, a starting dose of 400 mg/m2/d Imatinib mesylate was administered in adults, whereas in pediatric and adolescents it was 400 mg/m2/d if the body surface area (BSA) was <1 m2, or 400 mg/d if BSA was >1m2. Results: 27 patients were in the age group =18 years; male to female ratio was 1.07:1. Gender ratio in 266 ACML patients showed a male preponderance (2.5:1). The mean age in ACML was 37.4 years. In pediatric subsets, a trend toward CML in adolescents was observed with mean age 14.85 years. Majority of the patients were in chronic phase (81.5% PCML and 85.7% ACML) with overall 93% patients receiving prior hydroxyurea as a cytoreductive agent. An unusual finding was higher incidence of Hypodiploidy (significance undetermined) and 5 patients had double PH. 80.1% ACML patients achieved complete hematological response, but it was significantly lower (59.3%) in PCML. 39.5% ACML achieved major cytogenetic response which was less than most published western data. Hematologic and non-hematologic toxicities (GI, dermatological etc) were found to be higher in ACML. Low toxicities in PCML were attributed to good tolerance to Imatinib therapy; however a higher dropout rate in pediatric subsets was possibly due to poor social and parental support. Conclusion: We conclude that imatinib mesylate is both safe and efficacious drug for ACML, however further research is warranted in pediatric and adolescent population to establish its efficacy.

No significant financial relationships to disclose.
Retrospective study of relapsed ALL in a single institution in Brazil
Authors: Marconcini J. F. , Gomes C. F. , Delbuono E. , Costa V. , Pacheco C. D. , Seber A. , Lee M. M.
Published: March 2020

20018

Background: With contemporary protocols, 25–30% of children with ALL who achieve first complete remission (CR1) are expected to relapse. Although the majority of patients can achieve a second complete remission (CR2) with re-induction chemotherapy, only a few will maintain prolonged clinical remission. To study the pattern of ALL relapse in our institution, we performed a retrospective analysis of such events between 1994 and 2006. Methods: In the study period, 65 out of 292 (22%) patients treated at our institution for ALL suffered isolated or combined relapse. Median age was 7.2 years (range 0.4–18.2 years); 65% were male. Patients were analyzed according to immunophenotype, WBC, site of relapse and time to relapse. Kaplan-Meier life-table analyses were used to estimate survival; differences were assessed by the log-rank test. Results: Of 63 relapsed ALL that were immunophenotyped, 65% were B-cell precursors and 35% were T-cell. WBC was >50,000/mm3 in 47% of patients; 54% of them had isolated bone marrow (BM) relapse, 23% combined relapse and 23% isolated extramedullary (EM) relapse (11CNS and 4 testicular relapse); 58% had very early relapse (VER) (<18 months from CR1), 17% early relapse (ER) (18–30 months from CR1) and 25% late relapse (LR) (>30 months from CR1). The therapeutic approach was chemotherapy in 60 patients and BMT in five. CR2 was achieved in 63% of patients. Of these, 35% had a second relapse. Death rate was 66% with median follow-up of 5,3 months; 40% had cumulative survival rate = 4 years. Initial imunophenotype and WBC did not affect outcome. Patients with isolated EM relapse presented a significant superior outcome when compared with those with combined relapse (p=0.024). There was no difference in survival between isolated BM and combined relapse. As for the time to relapse, there was significant inferior outcome for patients with VER when compared with ER (p=0.0089) and LR (p=0.0041). However, there was no difference in survival between ER and LR group. Conclusions: In our casuistic, time to relapse was the main predictor of outcome. Despite continuous improvement in therapy of childhood ALL, survival rate of relapsed patients remains disappointing.

No significant financial relationships to disclose.
The efficacy of I-131 metaiodobenzylguanidine (MIBG) treatment in previously heavily treated stage IV neuroblastoma patients (age more than 1 year): Preliminary experiences
Authors: Chotipanich C. , Cheuamsamakkee K. , Changmuang W. , Chouplywech P. , Wittayachokkitikhum S. , Musikarat S. , Sritara C. , Utamakul C. , Pakakasama S. , Hongeng S.
Published: March 2020

20025

Background: The outcome of advanced stage neuroblastoma patients with multiple relapsed or refractory diseases is very dismal. We therefore would like to study the efficacy and the safety of I-131 MIBG treatment in this group of patients. Method: A retrospective study of six stage IV neuroblastoma patients (pts) (2 males and 4 females), age at the diagnosis range 3 to 8 years from January 2005 to December 2006 were studied. All pts were previously treated with multiple regimens of chemotherapy, high-dose chemotherapy with autologous peripheral stem cells (PBSCs) rescue, salvage surgery, and local radiation ( table ). All these patients had relapsed or refractory disease at the time of I-131 MIBG treatment. The therapeutic dose of I-131 MIBG activity per course was given on the basis of weight, the hematological parameter, and tumor response assessment. The cycle of treatment was more 4 weeks apart. The treatment response was evaluated by imaging. and neuron-specific enolase (NSE) levels. Results: A total of 21 courses of I-131 MIBG were administered: one patient received one course, two received three courses, two received four courses and one received six courses. The median therapeutic dose of I-131 MIBG was 5.5 GBq (range; 1.1–5.5). Median duration of response was 10 months (range, 1–19). A partial response achieved in 1, and stable response in 5 patients. Pain relief was observed in 1/1 patients with bone pain. The most common side effect found was thrombocytopenia which became more severe with increasing number of course, grade 2 thrombocytopenia occurring in 4/6 patients over 3 courses of therapy. Three children died whereas three are still alive. There is no morbidity from the therapy. Conclusion: It can be concluded that MIBG treatment is effective and less toxic in patients with relapsed or refractory neuroblastoma and further studies of the role of I-131 MIBG treatment in advanced neuroblastoma in Thailand are needed.

[Table: see text]

No significant financial relationships to disclose.
Profile of infantile malignancies at tertiary cancer center—A study from south India
Authors: HS M. , Kumari B. Aruna , Appaji L. , Attili S. V. , Padma D. , Vidya J.
Published: March 2020

20026

Background: Infantile malignancies are peculiar in the way they present with lot of diversity and had poor prognosis compared to other pediatric malignancies. The spectrum of malignancies had a great regional variability owing to the environmental and genetic differences (both aquired, maternal and paternal). Methods: It is a retrospective data analysis conducted at a tertiary care cancer center, Bangalore, India. The institute has an annual attendance of 16,000 new cases with reasonably good follow-up. The contribution of pediatric malignancies is 18%. The details were collected from the case records and percentages were calculated for the variables. Results: Between 2003–2006 we diagnosed 1,798 pediatric tumors. Of them 198 (11%) are infantile malignancies. The commonest diagnosis at our center is leukemia (30% of all infantile malignancies). The main types of leukemia are ALL-80%, AML-13%, and CML-7%. Other hematological malignancies are lymphomas- 2%, myelo proliferative disorders and Langerhan Cell histiocytosis-3% each. The next common diagnosis is benign neoplasms, wrongly diagnosed as malignant at the secondary referral center which contributed 16% of all cases. The reminder 46% is solid malignancies. In the decreasing frequency the incidences are Wilm’s tumor-12%, neuroblastoma-10%, germ cell tumors-8%, retinoblastoma- 6% CNS malignancies and 3% hepatoblastoma -2%. The reminders are other rare malignancies. Conclusion: The contribution of infantile malignancies at our center is relatively higher compared to the west. Similarly Relative contribution of AML to the all hematological malignancies and neurblastoma & CNS tumors to solid malignancies is less compared to the existing literature. Wilm’s tumor and ALL diagnosed more frequently than expected in our population. All these findings together suggest that south Indian population had a different spectrum of infantile malignancies compared to rest of the world and their genetic and environmental risk factors need further exploration.

No significant financial relationships to disclose.
Final report of a phase II trial of nimotuzumab in the treatment of refractory and relapsed high-grade gliomas in children and adolescents
Authors: Bode U. , Buchen S. , Warmuth-Metz M. , Pietsch T. , Bach F. , Fleischhack G.
Published: March 2020

2006

Background: Despite multimodal therapy most children with high grade gliomas (HGG), including glioblastoma multiforme (GM), anaplastic astrocytoma (AA) and intrinsic pontine glioma (PG) have an infaust prognosis if they relapse or are refractory to the primary treatment. Recently novel therapeutic approaches are investigated in order to improve the survival of these patients while preserving a good quality of life. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (nimotuzumab) in the treatment of these patients. Patients and Methods: Pediatric patients with GM, AA or PG with radiologically proven progressive disease following primary or relapse treatment and a life expectancy of less than 4 weeks were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 nimotuzumab for six weeks, and in case of non-PD a consolidation therapy of 4 infusions in a 3 week interval. The response was documented by MRI in week 8 and 21 and only clinically in rapidly progresssive disease. Results: Between June 2004 and April 2006 47 patients aged 4 to 17 years (median 11 years) were enrolled in this study. 46 patients were evaluable for response. According to RECIST 14 out of 46 patients showed objective responses (PR n=4, SD n=10) in the MRI as the best response with a median change in the largest diameter of the index lesion of -11% (-50% to +16%). The PR/SD were seen in 2/13 patients with GM, 2/11 with AA and 10/22 with PG. Thirteen patients continued with the consolidation therapy and showed 4 PR, 3 SD and 6 PD in week 21. The median overall survival was 4.4 months (0.3–25.4 months) and was significantly better for repsonders (median 10 months) than for nonresponders (median 4.0 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of nimotuzumab is well tolerated and safe. Nimotuzumab has cytotoxic efficacy in heavily pre- treated relapsed HGG. Based on this data a phase III trial with nimotuzumab in newly diagnosed diffuse intrinsic pontine gliomas concomittent with radiotherapy was introduced in first quarter 2006.

No significant financial relationships to disclose.
A regulatory network of canonical nuclear factor-κB activation predicts high-grade glioma outcome
Authors: Bredel M. , Phillips H. , Harsh G. R. , Aldape K. , Sikic B. I.
Published: March 2020

2007

Background:
The mechanism for decision between cell death and survival is under fine regulation. Nuclear factor-κB is a transcription regulator that is known to promote survival in many cellular events. Excessive and prolonged activation of NF-κB has been established as a principal mechanism of tumor chemoresistance, which is primarily mediated by its antiapoptotic activity. The pathway leading to the activation of NF-κB involves a complicated network that includes multiple modulatory signaling molecules. We have discovered alterations in several NF-κB pathway modulators in glioblastoma cells, which may act synergistically in activating NF-κB during resistance formation to O6-alkylating agents, including the TNFAIP3, NFKBIA, and TNIP1 genes.
Methods:
We have retrospectively evaluated the outcome relationship for these and additional endogenous inhibitors of canonical NF-κB activation in three independent high-grade glioma cohorts comprising 175 tumors.
Results:
We here confirmed the putative importance of NF-κB pathway activation status in predicting high-grade glioma outcome. Our data indicate an increasing complexity and linkage of several modulatory molecules (TNFAIP3, NFKBIA, TNIP1, and TNIP2) to patient outcome that interact physical and functionally in a cooperative fashion to regulate NF-κB activation. We found that for many of these molecules combined predictor models outperform the predictive power of the individual molecules. This observation is consistent with recent evidence suggesting the cooperation of these endogenous inhibitors in a negative feedback regulation of NF-κB activation and a mutual facilitation of their repressive ability. In terms of outcome prediction, we found several of these inhibitors to outperform established clinical and morphological prognostic variables such as patient age and tumor grade (III
vs
. IV), as well as the O6-methylguanine DNA methyltransferase (MGMT) gene, the currently most established outcome marker in glioblastomas.
Conclusions:
These findings raise the hope for this regulatory network as an amenable target to modulate NF-κB-mediated resistance in glioblastoma cells, with the ultimate goal of increasing the efficacy of chemotherapy in patients harboring these challenging tumors.

No significant financial relationships to disclose.
Iatrogenic immunosuppression in patients with newly diagnosed high-grade gliomas
Authors: Grossman S. A. , Desideri S. , Ye X. , Szajna K. , Chamberlain M. , Lesser G.
Published: March 2020

2012

Background: Vaccines and other immunologic interventions hold promise for patients (pts) with high grade gliomas (HGG). However, a prior report noted that CD4 counts dropped significantly during the 6 weeks of radiation (RT) in patients receiving only RT and dexamethasone (Dex). This is the first study to follow CD4 counts in HGG treated with RT, Dex, and temozolomide (TMZ) and to obtain serial CD4 counts for 12 months. Methods: 70 pts with newly diagnosed HGG were accrued before they started RT and TMZ. CD4 counts were obtained before therapy and monthly thereafter for one year. Information on hospitalizations, infections, steroid doses, and survival is also being collected. Descriptive statistics were used. Results: Data is available on 60 pts: 54% are female and 97% are Caucasian. The median age of the pts was 57 (range 30–77) and 78% had a diagnosis of glioblastoma. The median CD4 count before RT was 640 (range 145–1445) which fell to 363 (32–1055), 272 (8–558), and 250 (44–845) in 1, 2, and 3 months respectively. The median CD4 counts during months 4, 6, 8, 10 and 12 were 373, 319, 329, 395, and 269. CD4 counts <200 were recorded in 34 pts (57%) and CD4 <100 in 13 pts (22%) during the study period. Conclusions: This study demonstrates that CD4 counts: 1) are relatively normal prior to radiation, 2) nadir to a median of 250 during the first three months of therapy, and 3) generally remain depressed following the completion of radiation. Severe iatrogenic immunosuppression as evident by CD4 counts is common in this population. Correlations with outcome and steroid doses are underway. These findings have implications for the recommended duration of PCP prophylaxis, the optimal design for therapeutic interventions that require a relatively intact immune system, and studies seeking to increase the intensity or duration of TMZ.

No significant financial relationships to disclose.
What is the role of whole brain radiation therapy (WBRT) and high-dose cytarabine (Ara-C) as consolidation treatment after initial chemotherapy for primary CNS lymphoma (PCNSL)?
Authors: Ekenel M. , Iwamoto F. M. , Porat L. S. Ben , Panageas K. S. , Yahalom J. , DeAngelis L. M. , Abrey L. E.
Published: March 2020

2013

Background: Optimal management of PCNSL is not defined. To date the best outcomes have been achieved by combined modality therapy using methotrexate (MTX)-based chemotherapy and WBRT. However, WBRT carries a significant risk of neurotoxicity and may not be required in all patients. Methods: We retrospectively analyzed the data of 122 patients who had complete response (CR) after initial chemotherapy, from a total of 338 PCNSL patients treated in our institution since 1986. Descriptive variables including sex, age, KPS at diagnosis, histology, and extent of CNS involvement were reported. We specifically studied the benefit of consolidation therapy with WBRT and/or high dose Ara-C on OS and PFS. Results: The median age was 60 (19–89) years and a median KPS was 70. Men constituted 57% of the patients. Median follow up was 30 months. Histologically, 83% had diffuse large B cell lymphoma. Ocular and CSF involvements were 13%, and 27%, respectively. Most patients received MTX-based regimens (96%). Five-year OS was 43% and five-year PFS was 50% for all patients. There was no significant difference in OS, between patients who received consolidation therapy with Ara-C (n=35), WBRT (n=12), Ara-C + WBRT (n=28), or no consolidation (n=42) [data from 5 patients are missing]. There was a trend towards improved disease control for patients treated with WBRT; however, these patients were also younger than the other groups. Risk of neurotoxicity was significantly higher in patients who received WBRT (p=0.005). Conclusions: Consolidation therapy does not clearly improve survival in PCNSL patients with a CR to initial treatment. However other important prognostic factors including age and KPS may have been used in the decision making related to consolidation therapy.

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No significant financial relationships to disclose.
Temozolomide as a vaccine adjuvant in GBM
Authors: Sampson J. H. , Aldape K. D. , Gilbert M. R. , Hassenbusch S. J. , Sawaya R. , Schmittling B. , Archer G. E. , Mitchell D. , Bigner D. D. , Reardon D. A. , Heimberger A. B.
Published: March 2020

2020

Background: Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide (TMZ) is an effective chemotherapeutic for patients with glioblastoma multiforme (GBM), but it induces significant lymphopenia. Methods: In a Phase II trial, patients with newly-diagnosed, completely resected GBM are vaccinated with an EGFRvIII-specific peptide q2 weeks X 3 after radiation (XRT)(∼60Gy) and TMZ (75mg/m2/d) and then monthly with 5 day TMZ cycles (200mg/m2/d). Results: TMZ induces transient, Grade 3 lymphopenia (< 500 cells/uL) in 70% of patients after the first TMZ cycle with nadirs occurring 14–21 days after treatment (n=10). Regulatory T cell (TReg) (CD4+CD25++CD45RO+FOXP3+) levels increased from 5.2+1.5% (3.3 - 7.5) to 11.8+2.6% (6.9 - 13.8)(P=0.0004; paired t-test) with TMZ and XRT and averaged 12.2+4.0% (6.4 - 18.1) after the second TMZ cycle (P=0.007) (n=6). Despite these findings, in patients assayed, both humoral and cellular EGFRvIII-specific immune responses appear to be enhanced with TMZ. Median survival and TTP after vaccination is 26.2 weeks with no patients progressing (n=8). Conclusions: Despite conventional dogma, we demonstrated that both chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. TMZ-induced lymphopenia may prove to be synergistic with a peptide vaccine.

No significant financial relationships to disclose.
Phase I trial of imatinib mesylate, hydroxyurea and vatalanib for patients with recurrent glioblastoma multiforme (GBM)
Authors: Sathornsumetee S. , Rich J. N. , Vredenburgh J. J. , Desjardins A. , Quinn J. A. , Gururangan S. , Egorin M. J. , Salvado A. J. , Friedman H. S. , Reardon D. A.
Published: March 2020

2027

Background: Recent studies have demonstrated promising anti-glioma activity of imatinib mesylate (IM) and hydroxyurea (H). Angiogenesis is one of the hallmarks of GBM with VEGF as a key regulator. This study attempts to extend the efficacy of IM and H by adding a VEGF receptor inhibitor, vatalanib (V; PTK787/ZK22584). Methods: We employ a ‘3+3‘ dose escalation design to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IM and V when administered with fixed dose of H in adult recurrent GBM patients with < 3 prior recurrences, KPS = 70% and adequate organ function. Patients are stratified based on concurrent enzyme-inducing anticonvulsant (EIAC) administration, and both strata (A- not on EIAC and B- on EIAC) are independently dose-escalated. Initial dose levels for stratum A: IM - 400 mg/day; H - 500 mg bid; V- 250 mg bid and for stratum B: IM- 500 bid; H-500 mg bid; V- 500 mg bid. Patients are given only V on day 1–7 of cycle 1 and then IM+H+V daily thereafter. Only cycle 1 is 35 days with subsequent cycles of 28 days. Response is evaluated every other cycle. Pharmacokinetic (PK) studies are performed on days 7 and 35 of cycle 1. Results: Thirty-five recurrent GBM patients have enrolled. The median age is 51.5 (range 31 to 75), 66% are male, and 51% are on EIAC. One DLT (grade 3 thrombocytopenia) occurred in a stratum A patient on dose level three . For stratum B, two DLTs (grade 3 hypertension and ALT elevation) occurred in a patient on dose level two and one DLT (grade 3 fatigue) occurred in a patient on dose level three. MTDs for each stratum have not been reached and accrual is ongoing. PK results are pending. Ten partial responses (29%) have been observed and nine patients remain on study including three who have received more than 6 cycles of therapy. Conclusions: Combination of imatinib, hydroxyurea and vatalanib is safe and well-tolerated with an encouraging rate of radiographic response. Further accrual is in progress to define the MTD.

No significant financial relationships to disclose.
An analysis of two different schedules of radiochemotherapy with concomitant temozolomide in high grade gliomas
Authors: D’Agostino G. R. , Balducci M. , Anile C. , Manfrida S. , Di Lella G. , Fiorentino A. , Mantini G. , Apicella G. , Pompucci A. , Cellini N.
Published: March 2020

2035

Background: We compared two different schedules of temozolomide (TMZ) concomitant therapy in terms of toxicity and outcome. Methods: 70 patients (median age 61 years, range 27–80) affected by high grade gliomas were treated with concomitant chemoradiation. Conformal radiotherapy (5,940 cGy, 180 cGy/day; CTV2: tumor bed + residual tumor if present + oedema, 3,960 cGy; CTV1: tumor bed + residual tumor if present + margins, 1,980 cGy) was associated with one of the following TMZ schedules: TMZ1: (75 mg/m2 × 5 days, first and last week of radiotherapy); TMZ2 (75 mg/m2, 7 days/week, from the first to the last day of radiotherapy); Toxicities were graded according to RTOG criteria. Survival analysis based on the Kaplan-Meier model. Results: From October, 2000 to March, 2006, 54 patients high grade gliomas were evaluated. 41 patients (29 GBL, 70.7%; 12 AA, 29.3%) were treated between October 2003 and March 2006 with TMZ2, and compared to an historical series of 29 patients (25 GBL, 86.2%; 4 AA, 13.%) treated in our Institution before 2003 with TMZ1. All patients received adjuvant chemotherapy with TMZ for 6 cycles or until disease progression. Hematological toxicity was mild in both group, whereas neurological toxicity (seizures) was higher in TMZ2 group, with a grade > 2 toxicity registered in 11/41 pts (26.8%) compared to 1/29 of the TMZ1 group (3.5%), even if this difference failed to achieve statistical significance (p=0.06). The overall survival did not significantly differ among the 2 schedules (p=0.60). In fact, at a median follow-up of 21 months (range 3- 68), median survival time was 21 months and 19 months, for TMZ1 and TMZ2 groups, respectively, with a 1-year and 2-year overall survival of 73.1% in the TMZ1 group and 75.3% in the TMZ2 group, respectively. Conclusions: In our experience, the concomitant administration of TMZ at the daily dose of 75 mg/m2 given continuously or only in the first and the last week of radiotherapy obtained comparable results in terms of outcome, with a heavier neurological toxicity when given 7 days per week, from the first to the last day of radiotherapy. These data suggest that, in selected cases, the TMZ1 schedule can be considered as a safe, alternative strategy, which does not impact significantly on patient outcome, compared to the standard TMZ2.

No significant financial relationships to disclose.
Phase II trial of Gliadel plus O6-benzylguanic (O6-BG) for patients with recurrent glioblastoma multiforme
Authors: Quinn J. A. , Vredenburgh J. J. , Rich J. N. , Reardon D. A. , Desjardins A. , Gururangan S. , Friedman A. H. , Carter J. H. , Threatt S. , Friedman H. S.
Published: March 2020

2036

Background: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) which removes chloroethylation or methylation damage from the O6- position of guanine. O6-BG is an AGT substrate that inhibits AGT by suicide inactivation. A previous phase III randomized, placebo- controlled trial has shown that Gliadel wafer (G) significantly prolongs 6-month survival (55.5% for G vs. 35.6% for placebo) and median survival (28 weeks for G vs. 20 weeks for placebo) in patients with recurrent glioblastoma multiforme (GBM) (Brem et al 1995). Despite the success of G in prolonging survival we may be able to improve on this success by depleting AGT. Methods: Thus, we have designed a phase 2 trial where we define the activity and the toxicity of G in combination with a 5-day infusion of O6-BG in patients with recurrent GBM. In a prior study the O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. In order to guarantee depletion of tumor AGT activity for at least 5 days after G placement, this O6-BG bolus was repeated on days 3 and 5 while continuing the infusion. Results: To date, 47 patients have been enrolled out of a planned accrual of 50 patients. The 6-month survival is 80% and the median survival is 47 weeks. The adverse events include the following: 3 episodes of grade 3 CSF leak (6%), 7 episodes of grade 3 wound infection at craniotomy site (15%), 6 episodes of hyponatremia (13%), 3 episodes of hydrocephalus (6%), 1 episode of hygroma (2%), 1 episode of infectious meningitis (2%), 1 episode of arachnoiditis (2%), 1 episode of grade 3 fever (2%). Conclusions: Thus far, this data demonstrates an increase in the efficacy of G when combined with O6-BG. Three additional patients will be enrolled for a total accrual of 50 patients.

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Identification of occult brain metastases amenable to stereotactic radiosurgery by motexafin gadolinium (MGd) based treatment planning MRI: Results of a phase II trial of MGd and whole brain radiotherapy (WBRT) with stereotactic radiosurgery (SRS)
Authors: Mehta M. P. , Dagnault A. , Chabot P. , Suh J. , Chang E. , Fortin M. , Timmerman R. , Grecula J. , Eubank L. , Renschler M. F.
Published: March 2020

2037

Background: Motexafin gadolinium (MGd) is a novel anti-cancer agent that selectively localizes in tumors and is detectable by MRI. Previous studies of patients (pts) with brain metastases (BM) demonstrated the detection of occult lesions after MGd administration not visible with gadolinium MRI contrast. The purpose of this study was to evaluate if MRI scanning after MGd improves SRS treatment-planning and treatment outcome by identifying and better defining lesions that can be treated with the SRS boost. Methods: Pts with 1–4 BM (< 4 cm diameter, or, if multiple, < 3cm) received WBRT (37.5 Gy) and MGd, 5 mg/kg/day during weeks 2–3 of WBRT, plus MGd, 5 mg/kg prior to treatment planning MRI and prior to SRS (21 Gy for lesions = 2 cm, 18 Gy for lesions 2.1–3.0 cm, and 15 Gy for lesions 3.1–4.0 cm). MRI was obtained within 4 weeks prior to enrollment with standard contrast, and after WBRT for SRS treatment planning with MGd and standard contrast. Patients were followed for neurologic progression and survival. Results: 45 patients with either lung cancer (76%), breast cancer (11%), melanoma (7%), or other cancers (7%), a median age of 58 years (range 42–74), and a median of 2 BM (range 1–4) were evaluable. In 9 of 42 patients (21%) with MRI data available, the MGd-based treatment planning MRI demonstrated at least one occult lesion not visualized on the screening MRI. The MGd-based treatment planning MRI detected 1 occult lesion in 6 pts, 2 occult lesions in 1 patient, and 3 occult lesions in 2 patients. Median survival for evaluable pts is 10 months; median time to neurologic progression or radiologic progresssion is not reached at 15 months. Grade 3+ neurotoxicity was limited to 1 pt with tumor necrosis and 1 pt with motor weakness. Most common Grade 3+ adverse events were pneumonia (9%) and DVT (9%). Conclusions: MGd-based treatment planning MRI for SRS identified occult BM that are amenable to SRS and are undetected with standard gadolinium contrast agents in 21% of the pts enrolled in this phase II trial. Treatment with MGd, WBRT and SRS to all lesions visualized resulted in improved survival and local control compared with historical results.

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