Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y belongs to a class of materials known as electron-doped superconductors (Ln̳2̳-x̳Mx̳CuO̳4̳-̳y;Ln = Pr, Nd, Sm, Eu; M = Ce, Th) and has a moderately high superconducting critical temperature, T̳c, of ̃ 20 K at optimal doping (x = 0.15). The trivalent rare earth site is doped with tetravalent Ce or Th; hence the name "electron-doped". Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y also exhibits a unique magnetic structure at low temperatures (T < 6 K) due to the antiferromagnetic ordering of the Sm³⁺ ions. In this study, thin films of the electron-doped superconductor Sm̳2̳-x̳C̳ex̳CuO̳4̳-̳y (SCCO) have been grown by pulsed laser deposition (PLD) for a cerium concentration range of x = 0.13 to x = 0.19. The films have been characterized through x-ray diffraction, electrical transport, and thermal transport measurements. A temperature versus cerium content (T-x) phase diagram has been constructed from the electrical transport measurements and yields a superconducting region similar to that of two of the other electron-doped superconductors Nd̳2̳-x̳C̳ex̳CuO̳4̳-̳y and Pr̳2̳- x̳C̳ex̳CuO̳4̳-̳y. Thermopower measurements were also performed on the samples and show a dramatic change from the underdoped region (x < 0.15) to the overdoped region (x < 0.15). Additionally, the standard Fisher-Fisher-Huse (FFH) vortex glass scaling model has been applied to the magnetoresistance data, as well as a modified scaling model (RRA), and the analysis yields values of the vortex glass melting temperature, T̳g, and critical exponent, v(z- 1). A magnetic field versus temperature (H-T) phase diagram has been constructed for the films with cerium content x >̲ 0.14, displaying the vortex glass melting lines. Magnetoresistance data taken as a function of angle, [theta], is also discussed in the context of the vortex glass scaling model

Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP-cRGD-MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP-cRGD-MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides.

Purpose

The purpose of this study is to explore knowledge-based organ-at-risk dose estimation for intracavitary brachytherapy planning for cervical cancer. Using established external-beam knowledge-based dose-volume histogram (DVH) estimation methods, we sought to predict bladder, rectum, and sigmoid D_2cc for tandem and ovoid treatments.

Methods and materials

A total of 136 patients with loco-regionally advanced cervical cancer treated with 456 (356:100 training:validation ratio) CT-based tandem and ovoid brachytherapy fractions were analyzed. Single fraction prescription doses were 5.5-8 Gy with dose criteria for the high-risk clinical target volume, bladder, rectum, and sigmoid. DVH estimations were obtained by subdividing training set organs-at-risk into high-risk clinical target volume boundary distance subvolumes and computing cohort-averaged differential DVHs. Full DVH estimation was then performed on the training and validation sets. Model performance was quantified by ΔD_2cc = D_2cc(actual)-D_2cc(predicted) (mean and standard deviation). ΔD_2cc between training and validation sets were compared with a Student's t test (p < 0.01 significant). Categorical variables (physician, fraction-number, total fractions, and case complexity) that might explain model variance were examined using an analysis of variance test (Bonferroni-corrected p < 0.01 threshold).

Results

Training set deviations were bladder ΔD_2cc = -0.04 ± 0.61 Gy, rectum ΔD_2cc = 0.02 ± 0.57 Gy, and sigmoid ΔD_2cc = -0.05 ± 0.52 Gy. Model predictions on validation set did not statistically differ: bladder ΔD_2cc = -0.02 ± 0.46 Gy (p = 0.80), rectum ΔD_2cc = -0.007 ± 0.47 Gy (p = 0.53), and sigmoid ΔD_2cc = -0.07 ± 0.47 Gy (p = 0.70). The only significant categorical variable was the attending physician for bladder and rectum ΔD_2cc. CONCLUSION: A simple boundary distance-driven knowledge-based DVH estimation exhibited promising results in predicting critical brachytherapy dose metrics. Future work will examine the utility of these predictions for quality control and automated brachytherapy planning.

Purpose

Currently, there is a lack of patient-specific tools to guide brachytherapy planning and applicator choice for cervical cancer. The purpose of this study is to evaluate the accuracy of organ-at-risk (OAR) dose predictions using knowledge-based intracavitary models, and the use of these models and clinical data to determine the dosimetric differences of tandem-and-ring (T&R) and tandem-and-ovoids (T&O) applicators.

Materials and methods

Knowledge-based models, which predict organ D_2cc, were trained on 77/75 cases and validated on 32/38 for T&R/T&O applicators. Model performance was quantified using ΔD_2cc=D_2cc,actual-D_{2cc,predicted}, with standard deviation (σ(ΔD_2cc)) representing precision. Model-predicted applicator dose differences were determined by applying T&O models to T&R cases, and vice versa, and compared to clinically-achieved D_2cc differences. Applicator differences were assessed using a Student's t-test (p < 0.05 significant).

Results

Validation T&O/T&R model precision was 0.65/0.55 Gy, 0.55/0.38 Gy, and 0.43/0.60 Gy for bladder, rectum and sigmoid, respectively, and similar to training. When applying T&O/T&R models to T&R/T&O cases, bladder, rectum and sigmoid D_2cc values in EQD2 were on average 5.69/2.62 Gy, 7.31/6.15 Gy and 3.65/0.69 Gy lower for T&R, with similar HRCTV volume and coverage. Clinical data also showed lower T&R OAR doses, with mean EQD2 D_2cc deviations of 0.61 Gy, 7.96 Gy (p < 0.01) and 5.86 Gy (p < 0.01) for bladder, rectum and sigmoid.

Conclusions

Accurate knowledge-based dose prediction models were developed for two common intracavitary applicators. These models could be beneficial for standardizing and improving the quality of brachytherapy plans. Both models and clinical data suggest that significant OAR sparing can be achieved with T&R over T&O applicators, particularly for the rectum.

Purpose

The use of interstitial needles, combined with intracavitary applicators, enables customized dose distributions and is beneficial for complex cases, but increases procedure time. Overall, applicator selection is not standardized and depends on physician expertise and preference. The purpose of this study is to determine whether dose prediction models can guide needle supplementation decision-making for cervical cancer.

Materials and methods

Intracavitary knowledge-based models for organ-at-risk (OAR) dose estimation were trained and validated for tandem-and-ring/ovoids (T&R/T&O) implants. Models were applied to hybrid cases with 1-3 implanted needles to predict OAR dose without needles. As a reference, 70/67 hybrid T&R/T&O cases were replanned without needles, following a standardized procedure guided by dose predictions. If a replanned dose exceeded the dose objective, the case was categorized as requiring needles. Receiver operating characteristic (ROC) curves of needle classification accuracy were generated. Optimal classification thresholds were determined from the Youden Index.

Results

Needle supplementation reduced dose to OARs. However, 67%/39% of replans for T&R/T&O met all dose constraints without needles. The ROC for T&R/T&O models had an area-under-curve of 0.89/0.86, proving high classification accuracy. The optimal threshold of 99%/101% of the dose limit for T&R/T&O resulted in classification sensitivity and specificity of 78%/86% and 85%/78%.

Conclusions

Needle supplementation reduced OAR dose for most cases but was not always required to meet standard dose objectives, particularly for T&R cases. Our knowledge-based dose prediction model accurately identified cases that could have met constraints without needle supplementation, suggesting that such models may be beneficial for applicator selection.

Purpose/objectives

A report of clinical outcomes of a computed tomography (CT)-based image guided brachytherapy (IGBT) technique for treatment of cervical cancer.

Methods and materials

Seventy-six women with International Federation of Gynecology and Obstetrics stage IB to IVA cervical carcinoma diagnosed between 2007 and 2014 were treated with definitive external beam radiation therapy (EBRT) with or without concurrent chemotherapy followed by high-dose-rate (HDR) IGBT. All patients underwent planning CT simulation at each implantation. A high-risk clinical target volume (HRCTV) encompassing any visible tumor and the entire cervix was contoured on the simulation CT. When available, magnetic resonance imaging (MRI) was performed at implantation to assist with tumor delineation. The prescription dose was prescribed to the HRCTV.

Results

The median follow-up time was 17 months. Thirteen patients (17%) had an MRI done before brachytherapy, and 16 patients (21%) were treated without MRI guidance. The mean EBRT/IGBT sum 2-Gy equivalent dose (EQD2) delivered to the 90% volume of the HRCTV was 86.3 Gy. The mean maximum EQD2s delivered to 2 cm(3) of the rectum, sigmoid, and bladder were 67.5 Gy, 66.2 Gy, and 75.3 Gy, respectively. The 2-year cumulative incidences of local, locoregional, and distant failure were 5.8% (95% confidence interval [CI]: 1.4%-14.8%), 15.1% (95% CI: 5.4%-29.4%), and 24.3% (95% CI: 12.1%-38.9%), respectively. The 2-year overall and disease-free survival rates were 75% (95% CI, 61%-91%) and 73% (95% CI, 60%-90%), respectively. Twenty-nine patients (38%) experienced grade ≥ 2 acute toxicity, with 5 cases of acute grade 3 toxicity and no grade ≥ 4 toxicities. One patient experienced grade 3 gastrointestinal toxicity. No other late grade ≥ 3 events were observed.

Conclusions

This is the largest report to date of CT/MRI-based IGBT for the treatment of cervical cancer. The results are promising, with excellent local control and acceptable toxicity. Further investigation is needed to assess the long-term safety and efficacy of this treatment.

The most successful therapeutic strategies for locally advanced cancers continue to combine decades-old classical radiosensitizing chemotherapies with radiotherapy. Molecular targeted radiosensitizers offer the potential to improve the therapeutic ratio by increasing tumor-specific kill while minimizing drug delivery and toxicity to surrounding normal tissue. Auristatins are a potent class of anti-tubulins that sensitize cells to ionizing radiation damage and are chemically amenable to antibody conjugation. To achieve tumor-selective radiosensitization, we synthesized and tested anti-HER2 antibody-drug conjugates of two auristatin derivatives with ionizing radiation. Monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) were attached to the anti-HER2 antibodies trastuzumab and pertuzumab through a cleavable linker. While MMAE is cell permeable, MMAF has limited cell permeability as free drug resulting in diminished cytotoxicity and radiosensitization. However, when attached to trastuzumab or pertuzumab, MMAF was as efficacious as MMAE in blocking HER2-expressing tumor cells in G₂-M. Moreover, MMAF anti-HER2 conjugates selectively killed and radiosensitized HER2-rich tumor cells. Importantly, when conjugated to targeting antibody, MMAF had the advantage of decreased bystander and off-target effects compared with MMAE. In murine xenograft models, MMAF anti-HER2 antibody conjugates had less drug accumulated in the normal tissue surrounding tumors compared with MMAE. Therapeutically, systemically injected MMAF anti-HER2 conjugates combined with focal ionizing radiation increased tumor control and improved survival of mice with HER2-rich tumor xenografts. In summary, our results demonstrate the potential of cell-impermeable radiosensitizing warheads to improve the therapeutic ratio of radiotherapy by leveraging antibody-drug conjugate technology.

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control.