Cancers of the head and neck region are associated with high symptom burden and elevated levels of psychological distress. Radiotherapy (RT) is a common treatment for patients with head and neck ...cancer (HNC) that is associated with psychological distress related to the immobilizing nature of the treatment, frequency of treatment delivery, and side effects. Guided imagery is a relaxation technique that is beneficial in reducing psychological distress in patients with other cancer diagnoses but has not been studied in this patient population. The purpose of this study is to evaluate the feasibility and acceptability of a brief guided imagery intervention (guided imagery for treatment, GIFT) to reduce RT-related anxiety and depression in patients with HNC relative to treatment as usual (TAU).
Patients with HNC planning to receive RT will be recruited to participate in a randomized controlled trial evaluating a brief, two-session guided imagery intervention (GIFT) relative to TAU alone. Primary aims include acceptability and feasibility evaluated through quantitative and qualitative methods. Measures of anxiety and depression, symptom burden, health-related quality of life, and anxiolytic medication use will be collected at baseline, during treatment, and at 1-month follow-up.
There are no published interventions of guided imagery for anxiety and depression in patients with HNC despite its efficacy in other populations of patients with cancer. This proposed project evaluates the feasibility and acceptability of an intervention that has the potential to reduce psychological distress in a vulnerable population. Additionally, we will preliminarily examine the impact of behavioral intervention on psychological distress and the use of anxiolytic medication, a novel area of study.
Clinicaltrials.gov NCT03662698 ; registered on 9/6/2018.
To report on the single-catheter high-dose-rate brachytherapy treatment of a 21-month-old girl child with an embryonal, botryoid-type, rhabdomyosarcoma limited to the external auditory canal (EAC).
A ...2.4-mm diameter catheter was inserted into the right EAC and placed against the tympanic membrane. A computed tomography simulation scan was acquired. A brachytherapy treatment plan, in which 21 Gy in seven fractions was prescribed to a 1-mm depth along the distal 2 cm of the catheter, was generated. Treatments were delivered under anesthesia without complication. A dosimetric comparison between this plan and an intensity-modulated radiation therapy (IMRT) plan was then conducted. A clinical target volume (CTV), which encompassed a 1-mm margin along the distal 2 cm of the catheter, was delineated for both plans. Given positioning uncertainty under image guidance, a planning target volume (PTV = CTV + 3-mm margin) was defined for the IMRT plan. The IMRT plan was optimized for maximal CTV coverage but subsequently normalized to the same CTV volume receiving 100% of the prescription dose (V
) of the brachytherapy plan.
The IMRT plan was normalized to the brachytherapy CTV V
of 82.0%. The PTV V
of this plan was 34.1%. The PTV exhibited dosimetric undercoverage within the middle ear and toward the external ear. Mean cochlea doses for the IMRT and brachytherapy plans were 26.7% and 10.5% of prescription, respectively.
For rhabdomyosarcomas limited to the EAC, a standard brachytherapy catheter can deliver a highly conformal radiation plan that can spare the nearby cochlea from excess radiation.
Background: Inflammatory changes and residual disease are difficult to distinguish after high dose, definitive radiotherapy of head and neck malignancies. FDG uptake located within a high dose field ...may more likely represent inflammatory changes, and FDG uptake outside of the radiation field could represent unsuspected and under treated disease. In situknowledge of the precise radiotherapy fields, therefore, may be useful in distinguishing these etiologies. This study evaluates the clinical feasibility of rapid integration of radiation treatment field images during follow-up FDG PET/CT imaging. Materials and Methods: Twenty head and neck cancer patients who underwent radiation therapy were identified. A MIM based workflow was created which fused the radiation treatment CT, including the planning volumes and isodose curves, into the follow-up imaging. Two board certified physicians, blinded to treatment outcome, reviewed the follow-up exams, half with the treatment information and half without. Each exam was scored for recurrent/residual disease, confidence of the read and a qualitative assessment to the overall usefulness of the treatment plan. Results: Interpretation accuracy improved from 80 to 90% with integration of the treatment plan. Similarly, the sensitivity improved from 71% to 86%, while the specificity increased from 85% to 92%. Confidence also increased by 0.7 on a 5-point scale for both readers. Conclusion: Data demonstrate the clinical feasibility of rapidly incorporating radiation treatment dosimetry into follow-up FDG PET / CT exams in patients with head and neck cancer. Preliminary results demonstrated a simple, efficient method which improved accuracy of interpretation and overall reader confidence.
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Background: Soft tissue sarcomas (STSs) are a heterogeneous group of cancers with high unmet need. Trabectedin (T) is an FDA-approved chemotherapy that blocks cell cycling and DNA repair ...pathways. Combination T and conventional radiation (XRT) in STS nonrandomized phase 1/2 trials demonstrated objective response rates (ORR) of 36-72% in localized and low burden metastatic disease, while pre-treated metastatic STS treated with T alone has an ORR of 10-14%. We hypothesize that the combination of T and hypofractionated radiation (hXRT) will exhibit a tolerable safety profile and improve ORR relative to historical outcomes with T or hXRT alone. Here we report our experience in the treatment of oligometastatic STS with combined T and hXRT. Methods: We reviewed our institutional experience to identify patients treated with T and XRT. We included patients with high risk localized or metastatic STS (majority of patients had metastatic disease at time of treatment). All patients received at least 1 cycle of T and concurrent XRT to at least 1 lesion. ORR and local control rate (LCR) were determined for irradiated lesions by RECIST 1.1. Results: Between 2020 – 2021, 9 STS patients with 21 tumors were treated at the University of Colorado with XRT and concurrent T. The median age was 39.2 (range 26.0 – 64.6) years. 8 patients had metastatic disease at the time of treatment. Treated tumor sites included 1 lung,1 extremity, 2 liver, 2 retroperitoneal, 5 bone, and 10 peritoneal. The following histologic subtypes were included: myxoid liposarcoma (3), uterine leiomyosarcoma (2), non-uterine leiomyosarcoma (1), dedifferentiated liposarcoma (1), undifferentiated pleomorphic sarcoma (1), and synovial sarcoma (1). All metastatic patients were pre-treated with a median of 3 lines of systemic therapy. The median number of T cycles delivered was 5 (range 1 – 20). The median XRT prescription dose was 3000cGy (range 2000cGy – 5000cGy), with 8 patients having received hXRT (5 -10 fractions) and 1 having received conventionally fractionated XRT. 8 patients underwent 1 course of XRT, while 1 received 3 courses in combination with T. All patients had a Karnofsky performance status equal to or greater than 60. After a median follow-up 5.4 months, the LCR of treated lesions was 90.5%. The ORR (CR or PR) was 57.1% and median decrease in tumor diameter at time of maximum response was 52.0%. The median time until maximum response was 3.7 months. 2 patients experienced grade 3 toxicity (LFT elevation) attributable to T, and 2 patients experienced grade 3 toxicity due to XRT. There were no grade 4 or 5 toxicities. Conclusions: T in combination with hXRT appears to be safe and feasible in this patient population. Based on these data, a phase 1/2 prospective clinical trial is being planned in oligometastatic and high risk localized STS. Table: see text
Abstract
Purpose: The abnormal function of tumor blood vessels causes hypoxia fueling disease progression and conferring treatment resistance. The local level of oxygen experienced by a cell will ...determine its response, making it critical to understand tissue oxygen levels with a spatial resolution on the order of the size of a cell. While microenvironment normalization strategies alleviate global hypoxia, how local oxygen levels change are not known because there are no in vivo techniques to longitudinally assess tumor vessels and interstitial oxygen in tumors with sufficient resolution. Understanding the heterogeneity of oxygen levels after microenvironmental normalization will help improve the efficacy of various normalization strategies.
Experimental Design: We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular weight palladium porphyrin probe to measure perfused vessels, oxygen tension and their spatial correlations in vivo in mouse skin, bone marrow, and tumors. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to microenvironmental normalization.
Results: We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen carrying ability than normal skin, most tumors had inefficient vessels. Further, inter-vessel heterogeneity in tumors coincided with heterogeneous response to microenvironmental normalizing agents. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persist, even with global reductions in hypoxia.
Conclusions: We present the first study to examine the high-resolution spatial and temporal response of tumor vessels to two agents known to improve vascular perfusion globally. Our measurements demonstrate that the heterogeneities in the local imbalance of pro- and anti-angiogenic signaling lead to spatially heterogeneous changes in vessel structure and function. Microscale dynamic vascular changes should be considered in optimizing the dose and schedule of microenvironment normalizing therapies to improve function.
Citation Format: John Martin, Ryan Lanning, Dai Fukumura, Timothy Padera, Rakesh Jain. Multiphoton phosphorescence quenching microscopy reveals kinetics of tumor oxygenation during anti-angiogenesis and angiotensin signaling inhibition abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB557.
Inflammatory changes and residual disease are difficult to distinguish after high dose, definitive radiotherapy of head and neck malignancies. FDG uptake located within a high dose field may more ...likely represent inflammatory changes, and FDG uptake outside of the radiation field could represent unsuspected and under treated disease. In situ knowledge of the precise radiotherapy fields, therefore, may be useful in distinguishing these etiologies. This study aimed to evaluate the clinical feasibility of rapid integration of radiation treatment field images during follow-up FDG PET/CT imaging. Twenty head and neck cancer patients who underwent radiation therapy were identified. A MIM based workflow was created which fused the radiation treatment CT, including the planning volumes and isodose curves, into the follow-up imaging. Two board certified physicians, blinded to treatment outcome, reviewed the follow-up exams, half with the treatment information and half without. Each exam was scored for recurrent or residual disease, confidence of the read and a qualitative assessment to the overall usefulness of the treatment plan. Interpretation accuracy improved from 80 to 90% with integration of the treatment plan. Similarly, the sensitivity improved from 71% to 86%, while the specificity increased from 85% to 92%. Confidence also increased by 0.7 on a 5 point scale for both readers. Data demonstrate the clinical feasibility of rapidly incorporating radiation treatment dosimetry into follow-up FDG PET/CT exams in patients with head and neck cancer. Preliminary results demonstrated a simple, efficient method which improved accuracy of interpretation and overall reader confidence.
Abstract
Rationale: The CA19-9 antigen is frequently overexpressed in pancreatic and other GI tumors. MVT-5873 (HuMab-5B1), a fully human monoclonal antibody currently in phase I study, targets the ...sialyl Lewis A (sLea) epitope on CA19-9, and is a promising platform for development of a targeted radioimmunotherapy (RIT). MVT-5873 was conjugated with the chelator CHX-A″-DTPA and radiolabeled with the beta-emitting isotopes Lutetium -177 (177Lu) or Yttrium-90 (90Y) to form the RIT agents MVT-1075 (177Lu- CHX-A″-DTPA-HuMAb-5B1) and MVT-1916 (90Y- CHX-A″-DTPA-HuMAb-5B1), respectively. The antitumor efficacy of each of the constructs was studied in nude mice bearing BxPC3 human pancreatic tumor xenografts, known to express CA19-9.
Methods: The initial dose-finding studies utilized doses of MVT-1075 of 75-450 μCi and MVT-1916 of 25-250 μCi, administered to groups of mice (n = 8) bearing subcutaneous (subQ) BxPC3 tumors (~ 150 mm3). Further studies focused on MVT-1075 and assessed antitumor effect in an orthotopic xenograft model, the effect of dose fractionation, and biodistribution in nontumor bearing (normal) and BxPC3 tumor-bearing mice.
Results: A single dose of MVT-1075 at 75, 150, 300, or 450 μCi significantly inhibited subQ BxPC3 tumor growth at all dose levels, with sustained suppression with higher doses. MVT-1916 produced similar results. MVT-1075 was selected based on the favorable half-life of 177Lu (6.7 d) and its utility for clinical biodistribution assessments. In an orthotopic BxPC3 tumor model, treatment with a single dose of MVT-1075 at 300 μCi significantly inhibited tumor growth, with Day 20 tumor volume approximately 50% that of the initial starting volume. A third BxPC3 xenograft study evaluated fractionated dosing schedules, (150 μCi x 1, 75 μCi x 2, 50 μCi x3), with both single-dose and fractionated schedules effectively inhibiting subQ BxPC3 tumor growth. Biodistribution studies in normal mice showed an expected gradually decreasing activity in blood, heart, and lungs, with low uptake in normal pancreas. In subQ BxPC3 tumor-bearing mice, tumor uptake was rapid, reaching 69% ID/g by 24 h and 86% ID/g by 120 h. Otherwise, the biodistribution pattern paralleled that of normal mice, with relative %ID/g values within about ± 25% of normal mice across all time points comparing blood, heart, lungs, kidneys, and pancreas, with slightly higher uptake in liver and slightly lower uptake in spleen.
Conclusions: MVT-1075 demonstrates promising antitumor activity in a human pancreatic cancer xenograft model, with efficacy shown in both single dose and fractionated schedules. Biodistribution shows rapid and substantial tumor uptake, with much lower uptake in normal organs. These findings support the phase I clinical trial of MVT-1075 in patients with CA19-9 positive pancreatic cancers planned to begin in early 2017.
Citation Format: Jacob L. Houghton, Ryan Lanning, Dayla Abdel-atti, Toni Jun, Christine M. Kearns, Michael Schlosser, Wolfgang Scholz, Jason S. Lewis, Paul W. Maffuid. Preclinical development of MVT-1075 as radioimmunotherapy for pancreatic cancer and other CA19-9 positive malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5204. doi:10.1158/1538-7445.AM2017-5204
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Background: HER2 overexpression is associated with an increased risk of LRR after mastectomy in the era prior to the use of adjuvant trastuzumab. The purpose of this study was to ...examine the effect of adjuvant trastuzumab on rates of LRR and whether this effect varied with the use of PMRT. Methods: From our institutional database, 474 women with Stage I-III HER2+ invasive breast cancer treated with mastectomy +/- adjuvant therapy from 1999-2007 were identified. Those patients lost to follow-up, treated with lapatinib, or diagnosed between 5/2004 to 5/2005 (when trastuzumab prescribing practices varied) were excluded; leaving 395 in the final study population. Two cohorts were compared: 139 women who received trastuzumab (5/2005-12/2007) and 256 women who did not (prior to 5/2005). Competing risks analyses were used to estimate cumulative incidence of LRR. Competing risks regression was used to evaluate the association between treatment factors and LRR. To minimize lead-time bias, patient data was censored at 5 years after mastectomy in both groups. Results: There were 18 LRRs in the entire cohort (16 no trastuzumab, 2 trastuzumab). Women in the no trastuzumab group were less likely to be node positive, receive chemotherapy or PMRT (all p<0.001). The hazard ratio for LRR was 0.218in the trastuzumab group (p= 0.04, 95% C.I. 0.05-0.94) with a 5-year risk of LRR of 1.5% in the trastuzumab versus 6.6% in the no trastuzumab group. After adjusting for PMRT and chemotherapy receipt, trastuzumab trended towards significance in decreasing LRR (p= 0.063). On subset analysis of 139 women who received PMRT, trastuzumab significantly reduced LRR (7.3% no trastuzumab, 0% trastuzumab, p=0.025). Among those who did not receive PMRT (256), trastuzumab did not significantly decrease LRR (6.3% no trastuzumab, 2.9 % trastuzumab, p=0.28). Conclusions: Adjuvant trastuzumab significantly reduced LRR in women with HER2+ breast cancer who received PMRT. A trend toward decreased LRR was observed in the entire population, but did not reach statistical significance, suggesting that the benefit is greater in HER2+ patients receiving multimodality therapy.
A ratiometric fluorescent pH sensor based on CdSe/CdZnS nanocrystal quantum dots (NCs) has been designed for biological pH ranges. The construct is formed from the conjugation of a pH dye (SNARF) to ...NCs coated with a poly(amido amine) (PAMAM) dendrimer. The sensor exhibits a well-resolved ratio response at pH values between 6 and 8 under linear or two-photon excitation, and in the presence of a 4% bovine serum albumin (BSA) solution.
A CdSe/CdZnS nanocrystal modified with a SNARF dye exhibits a ratiometric sensing response in a physiologically relevant pH range (6-9) under linear and two-photon excitation.
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