Approach to Stereotactic Body Radiotherapy for the Treatment of Advanced Hepatocellular Carcinoma in Patients with Child-Pugh B-7 Cirrhosis.

OPINION STATEMENT: Patients with hepatocellular carcinoma (HCC) with underlying Child-Pugh B-7 cirrhosis benefit from management from an experienced, multidisciplinary team. In patients with localized disease who meet criteria for liver transplant, establishing care at a liver transplant center is crucial. For those awaiting transplant, local bridge therapies have emerged as a strategy to maintain priority status and eligibility. Multiple liver-directed therapies exist to provide locoregional tumor control. The careful selection of locoregional therapy is a multidisciplinary endeavor that takes into account patient factors including tumor resectability, underlying liver function, performance status, previous treatment, tumor location/size, and vascular anatomy to determine the optimal management strategy. Technological advances in external beam radiation therapy have allowed stereotactic body radiation therapy (SBRT) to emerge in recent years as a versatile and highly effective bridge therapy consisting of typically between 3 and 5 high dose, highly focused, and non-invasive radiation treatments. When treating cirrhotic patients with HCC, preserving liver function is of utmost importance to prevent clinical decline and decompensation. SBRT has been shown to be both safe and effective in carefully selected patients with Child-Pugh B cirrhosis; however, care must be taken to prevent radiation-induced liver disease. This review summarizes the evolving role of SBRT in the treatment of HCC in patients with Child-Pugh B-7 cirrhosis.

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.

Activation of phenotypic subpopulations in response to ciprofloxacin treatment in Acinetobacter baumannii.

The multidrug-resistant, opportunistic pathogen, Acinetobacter baumannii, has spread swiftly through hospitals worldwide. Previously, we demonstrated that A. baumannii regulates the expression of various genes in response to DNA damage. Some of these regulated genes, especially those encoding the multiple error-prone DNA polymerases, can be implicated in induced mutagenesis, leading to antibiotic resistance. Here, we further explore the DNA damage-inducible system at the single cell level using chromosomal transcriptional reporters for selected DNA damage response genes. We found the genes examined respond in a bimodal fashion to ciprofloxacin treatment, forming two phenotypic subpopulations: induced and uninduced. This bimodal response to ciprofloxacin treatment in A. baumannii is unique and quite different than the Escherichia coli paradigm. The subpopulations are not genetically different, with each subpopulation returning to a starting state and differentiating with repeated treatment. We then identified a palindromic motif upstream of certain DNA damage response genes, and have shown alterations to this sequence to diminish the bimodal induction in response to DNA damaging treatment. Lastly, we are able to show a biological advantage for a bimodal response, finding that one subpopulation survives ciprofloxacin treatment better than the other.

Predictors of Pneumonitis in Patients With Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation Followed by Consolidative Durvalumab.

Purpose: In patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab. Methods and Materials: Patients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival. Results: Sixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% (P = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy (P = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively. Conclusions: The modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed.

Comparison of Tumor Bed Delineation Using a Novel Radiopaque Filament Marker Versus Surgical Clips for Targeting Breast Cancer Radiotherapy.

BACKGROUND: Accuracy of tumor bed (TB) delineation is essential for targeting boost doses or partial breast irradiation. Multiple studies have shown high interobserver variability with standardly used surgical clip markers (CMs). We hypothesize that a radiopaque filament marker (FM) woven along the TB will improve TB delineation consistency. METHODS: An FDA-approved FM was intraoperatively used to outline the TB of patients undergoing lumpectomy. Between January 2020 and January 2022, consecutive patients with FM placed after either (1) lumpectomy or (2) lumpectomy with oncoplastic reconstruction were identified and compared with those with CM. Six "experts" (radiation oncologists specializing in breast cancer) across 2 institutions independently defined all TBs. Three metrics (volume variance, dice coefficient, and center of mass [COM] deviation). Two-tailed paired samples t tests were performed to compare FM and CM cohorts. RESULTS: Twenty-eight total patients were evaluated (14 FM and 14 CM). In aggregate, differences in volume between expert contours were 29.7% (SD ± 58.8%) with FM and 55.4% (SD ± 105.9%) with CM ( P < 0.001). The average dice coefficient in patients with FM was 0.54 (SD ± 0.15), and with CM was 0.44 (SD ± 0.22) ( P < 0.001). The average COM deviation was 0.63 cm (SD ± 0.53 cm) for FM and 1.05 cm (SD ± 0.93 cm) for CM; ( P < 0.001). In the subset of patients who underwent lumpectomy with oncoplastic reconstruction, the difference in average volume was 21.8% (SD ± 20.4%) with FM and 52.2% (SD ± 64.5%) with CM ( P <0.001). The average dice coefficient was 0.53 (SD ± 0.12) for FM versus 0.39 (SD ± 0.24) for CM ( P < 0.001). The average COM difference was 0.53 cm (SD ± 0.29 cm) with FM versus 1.25 cm (SD ± 1.08 cm) with CM ( P < 0.001). CONCLUSION: FM consistently outperformed CM in the setting of both standard lumpectomy and complex oncoplastic reconstruction. These data suggest the superiority of FM in TB delineation.

Consolidative Thoracic Radiation Therapy After First-Line Chemotherapy and Immunotherapy in Extensive-Stage Small Cell Lung Cancer: A Multi-Institutional Case Series.

Purpose: Survival for patients with extensive-stage small cell lung cancer (ES-SCLC) remains poor. Consolidative thoracic radiation therapy (cTRT) and upfront immunotherapy with chemotherapy have each incrementally improved patient outcomes, but have not yet been combined in clinical trials. We sought to characterize outcomes and toxicities after first-line chemotherapy and immunotherapy followed by cTRT. Methods and Materials: Patients with ES-SCLC who were treated with first-line chemotherapy and immunotherapy followed by cTRT were identified at 2 institutions. Patient outcomes including overall survival (OS), progression-free survival, local progression-free survival, distant progression free-survival, and toxicity were assessed. Results: Twenty patients were included in our data set treated from 2018 to 2021 with a median follow-up of 12 months. Median OS in this cohort was 16 months with 6-month OS of 94.7% and 12-month OS of 77.5% (comparable to historical controls). There were also low rates of toxicity, including 0% grade 3+ toxicity, 0% grade 2 pneumonitis, and 5% grade 2 esophagitis. Conclusions: Treatment of ES-SCLC with first-line chemoimmunotherapy followed by cTRT appears to be safe and to have outcomes comparable to published modern clinical trials. Further studies are warranted to determine the therapeutic effect of cTRT after chemoimmunotherapy.

Disparities in Radiation Therapy: Practice Patterns Analysis of Deep Inspiratory Breath Hold Use in Non-English Speakers.

PURPOSE: Our purpose was to examine current practice patterns in non-English-speaking patients with breast cancer undergoing deep inspiratory breath hold (DIBH). METHODS AND MATERIALS: An anonymous, voluntary REDCap survey was distributed to 60 residency program coordinators of US radiation oncology departments to survey their faculty and recent graduates. Eligibility was limited to board-certified radiation oncologists who had treated breast cancer within the prior 6 months. RESULTS: There were 69 respondents, 53 of whom were eligible. Forty-two percent (n = 22) of eligible respondents were from the main site at an academic center, with 28% (n = 15) representing a satellite site and 30% (n = 16) from private practice. Fifty-three percent reported at least 10% of their patients were non-English speaking. Ninety percent offered DIBH at their institution; of those, 74% used DIBH for at least one-fourth of their patients with breast cancer. Ninety-eight percent of those who use DIBH performed coaching at simulation, with 32% answering they would be "less likely" to use DIBH for non-English speakers. When used, 94% take into consideration potential language barriers for proper execution of DIBH. However, 51% had an interpreter present 76% to 100% of the time at computed tomography simulation, which decreased to 31% at first fraction and 11% at subsequent treatments. For non-English-speaking patients undergoing DIBH coaching without a certified interpreter, 55% of respondents indicated that they provided verbal coaching in English, 32% indicated "not applicable" because they always use a certified interpreter, 11% used visual aids, and 32% indicated "other." Of those who answered "other," the most commonly cited response was using therapists or staff who spoke the patient's native language. CONCLUSIONS: Disparities in the application of DIBH exist despite its established utility in reducing cardiac dose. This study provides evidence that language barriers may affect physician treatment practices from initial consideration of DIBH to subsequent delivery. These data suggest that breast cancer treatment considerations and subsequent execution are negatively affected in non-English-speaking patients.

Linear accelerator-based single-fraction stereotactic radiosurgery versus hypofractionated stereotactic radiotherapy for intact and resected brain metastases up to 3 cm: A multi-institutional retrospective analysis.

INTRODUCTION: Single-fraction stereotactic radiosurgery (SF-SRS) is typically used to provide local control of brain metastases. Recently, hypofractionated stereotactic radiotherapy (HF-SRT) has been utilized for large brain metastases. Data comparing these two modalities are limited for brain metastases ≤3 cm. METHODS: Patients with brain metastases receiving linear accelerator-based SF-SRS or HF-SRT were identified at three institutions. Local progression-free survival (LPFS), intracranial progression-free survival (ICPFS), overall survival (OS), and radionecrosis-free survival (RNFS) were determined from time of treatment. RESULTS: 108 patients (76 intact, 32 resected) with 184 brain metastases (142 intact, 42 resected) were included. There were no significant differences between SF-SRS and HF-SRT for intact metastases in 1-year LPFS (62.8% vs. 58.5%, p=0.631), ICPFS (56.9% vs. 55.3%, p=0.300), and OS (71.6% vs. 70.6%, p=0.096), or for resected metastases in 1-year LPFS (67.3% vs. 57.8%, p=0.288), ICPFS (64.8% vs. 57%, p=0.291), and OS (64.8% vs. 66.1%, p=0.603). There were also no significant differences in 1-year RNFS between SF-SRS and HF-SRT (92% vs. 92%, p=0.325). CONCLUSIONS: There were no significant differences in LPFS, ICPFS, OS, and RNFS between SF-SRS and HF-SRT for brain metastases ≤3 cm suggesting SF-SRS may be preferred due to similar outcomes and reduced number of fractions.