Early Experience of the First Single-Room Gantry Mounted Active Scanning Proton Therapy System at an Integrated Cancer Center.

Introduction: Review the early experience with a single-room gantry mounted active scanning proton therapy system. Material and Methods: All patients treated with proton beam radiotherapy (PBT) were enrolled in an institutional review board-approved patient registry. Proton beam radiotherapy was delivered with a 250 MeV gantry mounted synchrocyclotron in a single-room integrated facility within the pre-existing cancer center. Demographic data, cancer diagnoses, treatment technique, and geographic patterns were obtained for all patients. Treatment plans were evaluated for mixed modality therapy. Insurance approval data was collected for all patients treated with PBT. Results: A total of 132 patients were treated with PBT between March 2018 and June 2019. The most common oncologic subsites treated included the central nervous system (22%), gastrointestinal tract (20%), and genitourinary tract (20%). The most common histologies treated included prostate adenocarcinoma (19%), non-small cell lung cancer (10%), primary CNS gliomas (8%), and esophageal cancer (8%). Rationale for PBT treatment included limitation of dose to adjacent critical organs at risk (67%), reirradiation (19%), and patient comorbidities (11%). Patients received at least one x-ray fraction delivered as prescribed (36%) or less commonly due to unplanned machine downtime (34%). Concurrent systemic therapy was administered to 57 patients (43%). Twenty-six patients (20%) were initially denied insurance coverage and required peer-to-peers (65%), written appeals (12%), secondary insurance approval (12%), and comparison x-ray to proton plans (8%) for subsequent approval. Proton beam radiotherapy approval required a median of 17 days from insurance submission. Discussion: Incorporation of PBT into our existing cancer center allowed for multidisciplinary oncologic treatment of a diverse population of patients. Insurance coverage for PBT presents as a significant hurdle and improvements are needed to provide more timely access to necessary oncologic care.

IMRT with Stereotactic Body Radiotherapy Boost for High Risk Malignant Salivary Gland Malignancies: A Case Series.

Patients with high risk salivary gland malignancies are at increased risk of local failure. We present our institutional experience with dose escalation using hypofractionated stereotactic body radiotherapy (SBRT) in a subset of this rare disease. Over the course of 9 years, 10 patients presenting with skull base invasion, gross disease with one or more adverse features, or those treated with adjuvant radiation with three or more pathologic features were treated with intensity-modulated radiation therapy followed by hypofractionated SBRT boost. Patients presented with variable tumor histologies, and in all but one, the tumors were classified as poorly differentiated high grade. Four patients had gross disease, three had gross residual disease, three had skull base invasion, and two patients had rapidly recurrent disease (≤6 months) that had been previously treated with surgical resection. The median stereotactic radiosurgery boost dose was 17.5 Gy (range 10-30 Gy) given in a median of five fractions (range 3-6 fractions) for a total median cumulative dose of 81.2 Gy (range 73.2-95.6 Gy). The majority of the patients received platinum based concurrent chemotherapy with their radiation. At a median follow-up of 32 months (range 12-120) for all patients and 43 months for surviving patients (range 12-120), actuarial 3-year locoregional control, distant control, progression-free survival, and overall survival were 88, 81, 68, and 79%, respectively. Only one patient failed locally and two failed distantly. Serious late toxicity included graft ulceration in one patient and osteoradionecrosis in another patient, both of which underwent surgical reconstruction. Six patients developed fibrosis. In a subset of patients with salivary gland malignancies with skull base invasion, gross disease, or those treated adjuvantly with three or more adverse pathologic features, hypofractionated SBRT boost to intensity-modulated radiotherapy yields good local control rates and acceptable toxicity.

Spectral analysis of two coupled diatomic rotor molecules.

In a previous article the theory of frame transformation relation between Body Oriented Angular (BOA) states and Lab Weakly Coupled states (LWC) was developed to investigate simple rotor-rotor interactions. By analyzing the quantum spectrum for two coupled diatomic molecules and comparing it with spectrum and probability distribution of simple models, evidence was found that, as we move from a LWC state to a strongly coupled state, a single rotor emerges in the strong limit. In the low coupling, the spectrum was quadratic which indicates the degree of floppiness in the rotor-rotor system. However in the high coupling behavior it was found that the spectrum was linear which corresponds to a rotor deep in a well.

Molecular eigensolution symmetry analysis and fine structure.

Spectra of high-symmetry molecules contain fine and superfine level cluster structure related to J-tunneling between hills and valleys on rovibronic energy surfaces (RES). Such graphic visualizations help disentangle multi-level dynamics, selection rules, and state mixing effects including widespread violation of nuclear spin symmetry species. A review of RES analysis compares it to that of potential energy surfaces (PES) used in Born-Oppenheimer approximations. Both take advantage of adiabatic coupling in order to visualize Hamiltonian eigensolutions. RES of symmetric and D(2) asymmetric top rank-2-tensor Hamiltonians are compared with O(h) spherical top rank-4-tensor fine-structure clusters of 6-fold and 8-fold tunneling multiplets. Then extreme 12-fold and 24-fold multiplets are analyzed by RES plots of higher rank tensor Hamiltonians. Such extreme clustering is rare in fundamental bands but prevalent in hot bands, and analysis of its superfine structure requires more efficient labeling and a more powerful group theory. This is introduced using elementary examples involving two groups of order-6 (C(6) and D(3)~C(3v)), then applied to families of O(h) clusters in SF(6) spectra and to extreme clusters.

Inhibition of interleukin-1beta converting enzyme (ICE or caspase 1) by aspartyl acyloxyalkyl ketones and aspartyl amidooxyalkyl ketones.

A series of acyloxyalkyl and amidooxyalkyl ketones appended to a carbobenzyloxy aspartic acid core have been prepared. The most potent of these new inhibitors was 4i with a K(i) of 0.5 microM. These two series provide an improved understanding of the binding requirements for the hydrophobic prime side of ICE.

Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1).

Succinic acid amides have been found to be effective P2-P3 scaffold replacements for peptidic ICE inhibitors. Heteroarylalkyl fragments occupying the P4 position provided access to compounds with nM affinities. Utilization of an acylal prodrug moiety was required to overcome biopharmaceutical issues which led to the identification of 17f, a potential clinical candidate.

Smoothened antagonists for hair inhibition.

A series of aminomethylpyrazoles were prepared and evaluated using cell-based Smoothened beta-lactamase reporter assay and Smoothened binding assay. Potent Smoothened antagonists 10k and 10l were found to inhibit hair growth in vivo in the C3H/HeN mouse hair growth model. The more selective compound 10l was tested negative in the 3T3 NRU assay, indicating a low risk for causing photo-irritation and was efficacious using the C3H/HeN mouse hair growth model although it was slightly less efficacious than that of the reference compound eflornithine (7).

Treatment of chordomas with CyberKnife: georgetown university experience and treatment recommendations.

OBJECTIVE: To determine the efficacy and safety of chordoma treatment with CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (CK/SRS). METHODS: Eighteen patients with chordoma were treated with CK/SRS as a primary adjuvant (17 patients) or the only treatment (1 patient). The series included 24 lesions (28 treatments). The median age of the patients was 60 years (range, 24-85 years). Forty-four percent of the tumors were located in the mobile spine, 39% inside the cranium, and 17% in the sacral region. The male-to-female ratio was 1:1. The mean tumor volume was 128.0 mL (range, 12.0-457.3 mL), and the median dose of 35 Gy (range, 24.0-40.0 Gy) was delivered in 5 sessions. The median follow-up period was 46 months (range, 7-65 months). RESULTS: There were 3 significant complications in patients with previous irradiation, including infection in the surgical/radiation site (2 patients) and decreased vision (1 patient). Improvement in pain and quality of life did not reach statistical significance (alpha = 0.05). Seven patients experienced recurrence at a median of 10 months (range, 5-38 months), and 4 patients with disseminated disease died 7 to 48 months after therapy. Two patients had a partial response, whereas 9 others had stable disease. The local control rate at 65 months was 59.1%, with an overall survival of 74.3% and disease-specific survival of 88.9%. We estimated an alpha/beta ratio of 2.45 for chordomas, which supports hypofractionation. CONCLUSION: The CK/SRS safety and efficacy profile compares favorably with those of other treatment delivery systems. CK/SRS appears to reduce tumor volume, given an adequate dose. The authors recommend treatment with 40 Gy in 5 sessions to the clinical treatment volume, which includes the gross tumor volume and at least a 1-cm margin.

Rational design and synthesis of 4-((1R,2R)-2-hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile (PF-998425), a novel, nonsteroidal androgen receptor antagonist devoid of phototoxicity for dermatological indications.

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.

(1R,2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile, a potent androgen receptor antagonist for stimulating hair growth and reducing sebum production.

Synthesis, pharmacology, and pharmacokinetic profiles of (1R, 2S)-4-(2-cyano-cyclohexyl-oxy)-2-trifluoromethyl-benzonitrile are reported. This compound demonstrated remarkable potency for stimulating hair growth in a male C3H mouse model as well as reducing sebum production in the male Syrian hamster ear model.

Frame transformation relations for fluxional symmetric rotor dimers.

The theory of frame transformation relation connecting body oriented angular momentum states and lab weakly coupled momentum states have been extended from rotor-electron to rotor-dimer systems. Coupling schemes are analyzed for weak and strong cases of correlation between lab and two different rotor body frames. It is shown that the frame transformation relation is a purely quantum effect at low angular momentum but an approach to a classical limit for high J. Symmetry analysis of frame transformation is compared to eigensolutions of model coupling Hamiltonian.

The design and synthesis of sulfonamides as caspase-1 inhibitors.

A series of sulfonamides (1) has been prepared as inhibitors of interleukin-1beta converting enzyme (ICE), also known as caspase 1. These compounds were designed to improve potency by rigidifying the enzyme bound molecule through an intramolecular hydrogen bond. An X-ray crystal structure of a representative member of this series bound to the active site of ICE, confirms the presence of the hydrogen bonding interaction.