Synthesis of 5,9‐Diaza[5]helicenes Weiß, Aaron; Podlech, Joachim
European journal of organic chemistry,
October 24, 2019, Volume:
2019, Issue:
39
Journal Article
Peer reviewed
Open access
A new method for the synthesis of 5,9‐diaza5helicenes is presented using 2,3‐bis(acylamino)‐substituted ortho‐terphenyls as precursors. Activation of the amide groups and electrophilic substitution ...at the ortho positions of the adjacent phenyl groups leads to the 5,9‐diaza5helicenes. A stepwise reaction including protection of the first amino group, amide formation at the second amino group with subsequent cyclization, followed by deprotection, amide formation and cyclization at the first amino group ensures that both electrophilic substitutions take place at sufficiently activated arenes and allows for the different substituents at the diaza5helicenes brought in with the amide groups. The terphenyl precursors are synthesized by two Suzuki couplings of suitably substituted building blocks. Three different 5,9‐diaza5helicenes with aliphatic, alkenyl and methoxycarbonylalkyl substituents were prepared; the latter would allow to attach further functionalities by ester or amide linkage.
ortho‐Terphenyldiamines can be used as precursors for diaza5helicenes. A stepwise protocol allows for different substituents at positions C‐6 and C‐10.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Fog Is Leaking In Weiss, Aaron J.; Karamlou, Tara
The Annals of thoracic surgery,
March 2022, 2022-03-00, 20220301, Volume:
113, Issue:
3
Journal Article
Soft tissue sarcomas (STS) represent a heterogeneous group of extraskeletal mesenchymal tumors that affect individuals throughout the entire age continuum. Despite this pervasive influence, key ...differences exist in the presentation of these sarcomas across varying age groups that have prevented a more uniform approach to management. Notably, rhabdomyosarcoma (RMS) is more common in children, while most nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) subtypes are more prevalent in adults. Older patients with NRSTS appear to have more molecularly complex biology and often present with more advanced disease compared with children. Poorer outcome disparities are observed in older patients with RMS despite receiving similar treatment as younger patients. In this review, we highlight differences in epidemiology, biology, and management paradigms for pediatric and adult patients with STS and explore opportunities for a unified approach to enhance the care and outcomes within the AYA population.
Background
The aim of this study was to estimate the event‐free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in ...nonrandomized phase 2 studies conducted by the Children’s Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents.
Methods
A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan–Meier method. The log‐rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response.
Results
In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial‐specified thresholds. The estimated median EFS and 6‐month EFS of the entire study cohort was 1.5 months (95% confidence interval CI, 1.3–1.8 months) and 19.4% (95% CI, 12.7%–26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response.
Conclusions
The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single‐agent phase 2 trials incorporating potentially active novel agents in this population.
The survival outcomes of children and young adults with relapsed/refractory nonrhabdomyosarcoma soft tissue sarcoma remain unknown. These results show that survival remains suboptimal for these patients and provide benchmark survival estimates for future phase 2 trials testing novel agents in this population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach ...to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.
This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).
Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.
For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.
Finding Balance on the Seesaw Frankel, William C.; Weiss, Aaron J.
The Annals of thoracic surgery,
June 2023, 2023-06-00, 20230601, Volume:
115, Issue:
6
Journal Article
Commentary: Relational coordination… a mechanism to improve data interoperability Weiss, Aaron J.; Karamlou, Tara
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
July 2020, 2020-07-00, 20200701, Volume:
160, Issue:
1
Journal Article
Peer reviewed
Open access
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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