Cetuximab and anemia prevention in head and neck cancer patients undergoing radiotherapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) activation is associated with increased production of interleukin 6 (IL6), which is intensified by radiotherapy (RT) induced inflammatory response. Elevated IL6 levels intensifies RT-induced anemia by upregulating hepcidin causing functional iron deficiency. Cetuximab, an EGFR inhibitor, has been associated with lower rates of anemia for locally advanced head and neck squamous cell carcinoma (HNSCC). We hypothesized that concomitant cetuximab could prevent RT-induced anemia. METHODS: We queried our institutional head and neck cancers database for non-metastatic HNSCC cases that received RT with concomitant cetuximab or RT-only between 2006 and 2018. Cetuximab was administered for some high-risk cases medically unfit for platinum agents per multidisciplinary team evaluation. We only included patients who had at least one complete blood count in the 4 months preceding and after RT. We compared the prevalence of anemia (defined as hemoglobin (Hb) below 12 g/dL in females and 13 g/dL in males) and mean Hb levels at baseline and after RT. Improvement of anemia/Hb (resolution of baseline anemia and/or an increase of baseline Hb ≥1 g/dL after RT), and overall survival (OS) in relation to anemia/Hb dynamics were also compared. RESULTS: A total of 171 patients were identified equally distributed between cetuximab-plus-RT and RT-only groups. The cetuximab-plus-RT group had more locally-advanced stage, oropharyngeal and high grade tumors (p < 0.001 for all). Baseline anemia/Hb were similar, however anemia after RT conclusion was higher in the cetuximab-plus-RT vs RT-only (63.5% vs. 44.2%; p = 0.017), with a mean Hb of 11.98 g/dL vs. 12.9 g/dL; p = 0.003, for both respectively. This contributed to significantly worse anemia/Hb improvement for cetuximab-plus-RT (18.8% vs. 37.2%; p = 0.007). This effect was maintained after adjusting for other factors in multivariate analysis. The prevalence of iron, vitamin-B12 and folate deficiencies; and chronic kidney disease, was non-different. Baseline anemia was associated with worse OS (p = 0.0052) for the whole study cohort. Nevertheless, improvement of anemia/Hb was only marginally associated with better OS (p = 0.068). CONCLUSIONS: In contrast to previous studies, cetuximab was not associated with lower rates of anemia after RT for nonmetastatic HNSCC patients compared to RT-alone. Dedicated prospective studies are needed to elucidate the effect of cetuximab on RT-induced anemia.

How does CBCT reconstruction algorithm impact on deformably mapped targets and accumulated dose distributions?

PURPOSE: We performed quantitative analysis of differences in deformable image registration (DIR) and deformable dose accumulation (DDA) computed on CBCT datasets reconstructed using the standard (Feldkamp-Davis-Kress: FDK_CBCT) and a novel iterative (iterative_CBCT) CBCT reconstruction algorithms. METHODS: Both FDK_CBCT and iterative_CBCT images were reconstructed for 323 fractions of treatment for 10 prostate cancer patients. Planning CT images were deformably registered to each CBCT image data set. After daily dose distributions were computed, they were mapped to planning CT to obtain deformed doses. Dosimetric and image registration results based CBCT images reconstructed by two algorithms were compared at three levels: (A) voxel doses over entire dose calculation volume, (B) clinical constraint results on targets and sensitive structures, and (C) contours propagated to CBCT images using DIR results based on three algorithms (SmartAdapt, Velocity, and Elastix) were compared with manually delineated contours as ground truth. RESULTS: (A) Average daily dose differences and average normalized DDA differences between FDK_CBCT and iterative_CBCT were ≤1 cGy. Maximum daily point dose differences increased from 0.22 ± 0.06 Gy (before the deformable dose mapping operation) to 1.33 ± 0.38 Gy after the deformable dose mapping. Maximum differences of normalized DDA per fraction were up to 0.80 Gy (0.42 ± 0.19 Gy). (B) Differences in target minimum doses were up to 8.31 Gy (-0.62 ± 4.60 Gy) and differences in critical structure doses were 0.70 ± 1.49 Gy. (C) For mapped prostate contours based on iterative_CBCT (relative to standard FDK_CBCT), dice similarity coefficient increased by 0.10 ± 0.09 (p < 0.0001), mass center distances decreased by 2.5 ± 3.0 mm (p < 0.00005), and Hausdorff distances decreased by 3.3 ± 4.4 mm (p < 0.00015). CONCLUSIONS: The new iterative CBCT reconstruction algorithm leads to different mapped volumes of interest, deformed and cumulative doses than results based on conventional FDK_CBCT.

The Efficacy of Surgical Excision Plus Adjuvant Multimodal Therapies in the Treatment of Keloids: A Systematic Review and Meta-Analysis.

BACKGROUND: Research evaluating the efficacy of multimodal therapy for the treatment of keloids has reported combination regimens are most effective. OBJECTIVE: To compare recurrence rates for keloids treated with surgery plus one adjuvant intervention (dual therapy) versus surgery plus 2 or more adjuvant interventions (triple therapy). MATERIALS AND METHODS: Systematic literature review and meta-analysis of combination treatment for keloids. RESULTS: After full-text review, we included 60 articles representing 5,547 keloids: 5,243 received dual therapy, 259 received triple therapy, and 45 received quadruple therapy (the latter 2 groups were combined for analysis). The difference in recurrence rates between dual (19%) and triple therapy (11.2%) was not significant (p = .343). However, the difference in recurrence rates between dual therapy using surgery and radiation (18.7%) and triple therapy using surgery, radiation, and a third intervention (7.7%) was significant (p = .002). The differences for surgery and intralesional triamcinolone (TAC) showed trends toward significance, because keloids treated with dual therapy (21.7%) had a higher recurrence rate than those treated with triple therapy comprised of surgery, TAC, and another intervention (13.7%; p = .099). CONCLUSION: Triple therapy using surgery plus radiation and/or TAC as one of the adjuvant treatment modalities may achieve the lowest recurrence rates for keloids.

Survey of current practices from the International Stereotactic Body Radiotherapy Consortium (ISBRTC) for head and neck cancers.

AIM: To provide a multi-institutional description of current practices of stereotactic body radiotherapy (SBRT) for head and neck cancer. MATERIALS & METHODS: 15 international institutions with significant experience in head and neck SBRT were asked to complete a questionnaire covering clinical and technical factors. RESULTS: SBRT is used 10-100% of the time for recurrent primary head and neck cancer, and 0-10% of the time in newly diagnosed disease. Five centers use a constraint for primary disease of 3-5 cm and 25-30 cc. Nine institutions apply a clinical target volume expansion of 1-10 mm and 14 use a planning target volume margin of 1-5 mm. Fractionation regimens vary between 15 and 22 Gy in 1 fraction to 30-50 Gy in 5 or 6 fractions. The risk of carotid blowout quoted in the re-irradiation setting ranges from 3 to 20%. CONCLUSION: There is considerable heterogeneity in patient selection and techniques in head and neck SBRT practice among experienced centers.

Application of morphometric analysis to patients with lung cancer metastasis to the spine: a clinical study.

OBJECTIVE Predicting the survival rate for patients with cancer is currently performed using the TNM Classification of Malignant Tumors (TNM). Identifying accurate prognostic markers of survival would allow better treatment stratification between more aggressive treatment strategies or palliation. This is especially relevant for patients with spinal metastases, who all have identical TNM staging and whose surgical decision-making is potentially complex. Analytical morphometrics quantifies patient frailty by measuring lean muscle mass and can predict risk for postoperative morbidity after lumbar spine surgery. This study evaluates whether morphometrics can be predictive of survival in patients with spinal metastases. METHODS Utilizing a retrospective registry of patients with spinal metastases who had undergone stereotactic body radiation therapy, the authors identified patients with primary lung cancer. Morphometric measurements were taken of the psoas muscle using CT of the lumbar spine. Additional morphometrics were taken of the L-4 vertebral body. Patients were stratified into tertiles based on psoas muscle area. The primary outcome measure was overall survival, which was measured from the date of the patient's CT scan to date of death. RESULTS A total of 168 patients were identified, with 54% male and 54% having multiple-level metastases. The median survival for all patients was 185.5 days (95% confidence interval [CI] 146-228 days). Survival was not associated with age, sex, or the number of levels of metastasis. Patients in the smallest tertile for the left psoas area had significantly shorter survival compared with a combination of the other two tertiles: 139 days versus 222 days, respectively, hazard ratio (HR) 1.47, 95% CI 1.06-2.04, p = 0.007. Total psoas tertiles were not predictive of mortality, but patients whose total psoas size was below the median size had significantly shorter survival compared with those greater than the median size: 146 days versus 253.5 days, respectively, HR 1.43, 95% CI 1.05-1.94, p = 0.025. To try to differentiate small body habitus from frailty, the ratio of psoas muscle area to vertebral body area was calculated. Total psoas size became predictive of mortality when normalized to vertebral body ratio, with patients in the lowest tertile having significantly shorter survival (p = 0.017). Left psoas to vertebral body ratio was also predictive of mortality in patients within the lowest tertile (p = 0.021). Right psoas size was not predictive of mortality in any calculations. CONCLUSIONS In patients with lung cancer metastases to the spine, morphometric analysis of psoas muscle and vertebral body size can be used to identify patients who are at risk for shorter survival. This information should be used to select patients who are appropriate candidates for surgery and for the tailoring of oncological treatment regimens.

Characteristics of a novel treatment system for linear accelerator-based stereotactic radiosurgery.

The purpose of this study is to characterize the dosimetric properties and accuracy of a novel treatment platform (Edge radiosurgery system) for localizing and treating patients with frameless, image-guided stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Initial measurements of various components of the system, such as a comprehensive assessment of the dosimetric properties of the flattening filter-free (FFF) beams for both high definition (HD120) MLC and conical cone-based treatment, positioning accuracy and beam attenuation of a six degree of freedom (6DoF) couch, treatment head leakage test, and integrated end-to-end accuracy tests, have been performed. The end-to-end test of the system was performed by CT imaging a phantom and registering hidden targets on the treatment couch to determine the localization accuracy of the optical surface monitoring system (OSMS), cone-beam CT (CBCT), and MV imaging systems, as well as the radiation isocenter targeting accuracy. The deviations between the percent depth-dose curves acquired on the new linac-based system (Edge), and the previously published machine with FFF beams (TrueBeam) beyond D(max) were within 1.0% for both energies. The maximum deviation of output factors between the Edge and TrueBeam was 1.6%. The optimized dosimetric leaf gap values, which were fitted using Eclipse dose calculations and measurements based on representative spine radiosurgery plans, were 0.700 mm and 1.000 mm, respectively. For the conical cones, 6X FFF has sharper penumbra ranging from 1.2-1.8 mm (80%-20%) and 1.9-3.8 mm (90%-10%) relative to 10X FFF, which has 1.2-2.2mm and 2.3-5.1mm, respectively. The relative attenuation measurements of the couch for PA, PA (rails-in), oblique, oblique (rails-out), oblique (rails-in) were: -2.0%, -2.5%, -15.6%, -2.5%, -5.0% for 6X FFF and -1.4%, -1.5%, -12.2%, -2.5%, -5.0% for 10X FFF, respectively, with a slight decrease in attenuation versus field size. The systematic deviation between the OSMS and CBCT was -0.4 ± 0.2 mm, 0.1± 0.3mm, and 0.0 ± 0.1 mm in the vertical, longitudinal, and lateral directions. The mean values and standard deviations of the average deviation and maximum deviation of the daily Winston-Lutz tests over three months are 0.20 ± 0.03 mm and 0.66 ± 0.18 mm, respectively. Initial testing of this novel system demonstrates the technology to be highly accurate and suitable for frameless, linac-based SRS and SBRT treatment.

BUB1 inhibition sensitizes lung cancer cell lines to radiotherapy and chemoradiotherapy.

Background: Lung cancer is a major public health concern, with high incidence and mortality. Despite advances in targeted therapy and immunotherapy, microtubule stabilizers (paclitaxel, docetaxel), DNA intercalating platinum drugs (cisplatin) and radiation therapy continue to play a critical role in the management of locally advanced and metastatic lung cancer. Novel molecular targets would provide opportunities for improving the efficacies of radiotherapy and chemotherapy. Hypothesis: We hypothesize that BUB1 (Ser/Thr kinase) is over-expressed in lung cancers and that its inhibition will sensitize lung cancers to chemoradiation. Methods: BUB1 inhibitor (BAY1816032) was combined with platinum (cisplatin), microtubule poison (paclitaxel), a PARP inhibitor (olaparib) and radiation in cell proliferation and radiation sensitization assays. Biochemical and molecular assays were used to evaluate their impact on DNA damage signaling and cell death mechanisms. Results: BUB1 expression assessed by immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in NSCLC and SCLC compared to that of normal tissues. BUB1 overexpression in lung cancer tissues correlated directly with expression of TP53 mutations in non-small cell lung cancer (NSCLC). Elevated BUB1 levels correlated with poorer overall survival in NSCLC and small cell lung cancer (SCLC) patients. A BUB1 inhibitor (BAY1816032) synergistically sensitized lung cancer cell lines to paclitaxel and olaparib. Additionally, BAY1816032 enhanced cell killing by radiation in both NSCLC and SCLC. Molecular changes following BUB1 inhibition suggest a shift towards pro-apoptotic and anti-proliferative states, indicated by altered expression of BAX, BCL2, PCNA, and Caspases 9 and 3. Conclusion: A direct correlation between BUB1 protein expression and overall survival was shown. BUB1 inhibition sensitized both NSCLC and SCLC to various chemotherapies (cisplatin, paclitaxel) and targeted therapy (PARPi). Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies.

Long-Term Follow-Up of Phase I Trial of Oncolytic Adenovirus-Mediated Cytotoxic and Interleukin-12 Gene Therapy for Treatment of Metastatic Pancreatic Cancer.

The long-term follow-up findings of the phase I trial evaluating the efficacy of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy in metastatic pancreatic cancer (mPC) seem very promising. The study employed a replication-competent Adenovector in combination with chemotherapy in a dose-escalation format. The trial demonstrated a clinically meaningful median overall survival (OS) benefit, with patients in the highest dose cohort exhibiting an impressive median OS of 18.4 months. This contrasts starkly with patients receiving lower doses who experienced a median OS of 4.8 and 3.5 months, respectively. Remarkably, subject number 10, who received the highest dose, demonstrated an extraordinary survival of 59.1 months, presenting a compelling case for further exploration. Additionally, this patient displayed complete responses in lung and liver metastases, a rare occurrence in mPC treatment. Statistical analyses supported the observed survival benefit. The unprecedented OS results emphasize the potential of this treatment strategy and pave the way for future investigations into this promising gene therapy approach.

BUB1 Inhibition Sensitizes TNBC Cell Lines to Chemotherapy and Radiotherapy.

BUB1 is overexpressed in most human solid cancers, including breast cancer. Higher BUB1 levels are associated with a poor prognosis, especially in patients with triple-negative breast cancer (TNBC). Women with TNBC often develop resistance to chemotherapy and radiotherapy, which are still the mainstay of treatment for TNBC. Our previous studies demonstrated that a BUB1 kinase inhibitor (BAY1816032) reduced tumor cell proliferation and significantly enhanced radiotherapy efficacy in TNBC. In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. BUB1 inhibitors sensitized BRCA1/2 wild-type SUM159 and MDA-MB-231 cells to olaparib, cisplatin, and paclitaxel synergistically (combination index; CI < 1). BAY1816032 significantly increased the radiation sensitization of SUM159 and MDA-MB-231 by olaparib, cisplatin, or paclitaxel at non-toxic concentrations (doses well below the IC50 concentrations). Importantly, the small molecular inhibitor of BUB1 synergistically (CI < 1) sensitized the BRCA mutant TNBC cell line HCC1937 to olaparib. Furthermore, the BUB1 inhibitor significantly increased the radiation enhancement ratio (rER) in HCC1937 cells (rER 1.34) compared to either agent alone (BUB1i rER 1.19; PARPi rER 1.04). The data presented here are significant as they provide proof that inhibition of BUB1 kinase activity sensitizes TNBC cell lines to a PARP inhibitor and radiation, irrespective of BRCA1/2 mutation status. Due to the ability of the BUB1 inhibitor to sensitize TNBC to different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors), this work strongly supports the role of BUB1 as a novel molecular target to improve chemoradiation efficacy in TNBC and provides a rationale for the clinical evaluation of BAY1816032 as a chemosensitizer and chemoradiosensitizer in TNBC.

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. METHODS: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. RESULTS: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t1/2, ~8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. CONCLUSIONS: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. Methods: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC 50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. Results: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t 1/2 , ∼8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. Conclusions: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

Imaging and Biomarker Surveillance for Head and Neck Squamous Cell Carcinoma: A Systematic Review and American Radium Society Appropriate Use Criteria Statement.

Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers.

The impact of race on outcomes of patients with early stage uterine endometrioid carcinoma.

OBJECTIVES: The purpose of the present study was to determine whether racial disparity exists between African American (AA) and non-African American (NAA) patients with uterine endometrioid carcinoma who received similar multidisciplinary management. METHODS: We identified 766 patients with endometrioid adenocarcinoma 2009 FIGO stages I-II who underwent hysterectomy. Patients were divided into two groups; AA and NAA. Recurrence-free survival (RFS), disease specific survival (DSS) and overall survival (OS) for two groups were calculated. RESULTS: Median follow-up was 5.1 years. 27% were AA and 73% were NAA. All patients underwent hysterectomy and oophorectomy. 80% had peritoneal cytology examination and 69% underwent lymphadenectomy. AA patients were more likely to have higher grade tumors, and higher incidence of lymphovascular space involvement (LVSI). Although the two groups were balanced with regards to surgical staging and adjuvant treatment received, the 5-year RFS and DSS were significantly lower in AA compared to NAA patients (91% vs 84%, p=0.030; 95% vs 88%, p=0.011, respectively). Overall survival was not significantly different between the two groups. On multivariate analysis, after adjusting for other prognostic factors, race (AA vs NAA) was not a significant predictor of outcome. Grade 3 tumors and the presence of LVSI were the only two independent predictors of RFS and DSS with p ≤ 0.001 and p ≤ 0.001, respectively. CONCLUSION: In this large hospital-based study, AA race was associated with a higher incidence of adverse pathological features and worse recurrence-free and disease-specific survival. However, on multivariate analysis race was not an independent prognostic factor. Further studies are needed to elucidate possible underlying molecular mechanisms for these poorer outcomes.

Molecular targets that sensitize cancer to radiation killing: From the bench to the bedside.

Radiotherapy is a standard cytotoxic therapy against solid cancers. It uses ionizing radiation to kill tumor cells through damage to DNA, either directly or indirectly. Radioresistance is often associated with dysregulated DNA damage repair processes. Most radiosensitizers enhance radiation-mediated DNA damage and reduce the rate of DNA repair ultimately leading to accumulation of DNA damages, cell-cycle arrest, and cell death. Recently, agents targeting key signals in DNA damage response such as DNA repair pathways and cell-cycle have been developed. This new class of molecularly targeted radiosensitizing agents is being evaluated in preclinical and clinical studies to monitor their activity in potentiating radiation cytotoxicity of tumors and reducing normal tissue toxicity. The molecular pathways of DNA damage response are reviewed with a focus on the repair mechanisms, therapeutic targets under current clinical evaluation including ATM, ATR, CDK1, CDK4/6, CHK1, DNA-PKcs, PARP-1, Wee1, & MPS1/TTK and potential new targets (BUB1, and DNA LIG4) for radiation sensitization.

Oncolytic virus-based suicide gene therapy for cancer treatment: a perspective of the clinical trials conducted at Henry Ford Health.

Gene therapy manipulates or modifies a gene that provides a new cellular function to treat or correct a pathological condition, such as cancer. The approach of using gene manipulation to modify patient's cells to improve cancer therapy and potentially find a cure is gaining popularity. Currently, there are 12 gene therapy products approved by US-FDA, EMA and CFDA for cancer management, these include Rexin-G, Gendicine, Oncorine, Provange among other. The Radiation Biology Research group at Henry Ford Health has been actively developing gene therapy approaches for improving clinical outcome in cancer patients. The team was the first to test a replication-competent oncolytic virus armed with a therapeutic gene in humans, to combine this approach with radiation in humans, and to image replication-competent adenoviral gene expression/activity in humans. The adenoviral gene therapy products developed at Henry Ford Health have been evaluated in more than 6 preclinical studies and evaluated in 9 investigator initiated clinical trials treating more than100 patients. Two phase I clinical trials are currently following patients long term and a phase I trial for recurrent glioma was initiated in November 2022. This systematic review provides an overview of gene therapy approaches and products employed for treating cancer patients including the products developed at Henry Ford Health.

Single-Fraction Radiation Therapy for Localized Cutaneous T-Cell Lymphoma.

PURPOSE: Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL). Single-fraction radiation therapy has been used as a skin-targeted therapy to treat localized CTCL lesions. The objective of this study was to investigate the treatment outcomes associated with single-fraction radiation therapy for CTCL. METHODS AND MATERIALS: We retrospectively studied the outcomes among patients with CTCL treated with single-fraction radiation therapy at our institution between October 2013 and August 2022. Clinical response (complete response [CR], partial response [PR], or no response [NR]) and retreatment response were evaluated. RESULTS: A total of 242 lesions from 46 patients were analyzed, for an average of 5.3 lesions treated per patient. The majority of lesions presented with a plaque morphology (n = 145, 60.0%). All lesions were treated to a dose of 8 Gy in 1 fraction. Median follow-up was 24.6 months (range, 1-88 months). Of the 242 lesions, 36 (14.8%) had an initial PR or NR; all were retreated with the same regimen to the same site at a median interval of 8 weeks. Eighteen of the retreated lesions (50.0%) went on to have a CR. Thus, the overall CR rate for CTCL lesions was 92.6%. No recurrences were noted in the treated areas after achieving CR. CONCLUSIONS: Single-fraction radiation therapy to a dose of 8 Gy in 1 fraction to localized areas provided a high rate of complete and durable responses in the affected sites.

Cognitive Function and Postoperative Outcomes in Patients with Head and Neck Cancer.

OBJECTIVE: Determine the relationship between cognitive function and postoperative outcomes. METHODS: This IRB-approved retrospective cohort study included all patients treated between August 2015 and March 2020 undergoing major surgery for aerodigestive cancer or cutaneous/thyroid cancer that required free-flap reconstruction at Henry Ford Hospital. Routine administration of the Montreal Cognitive Assessment (MoCA) was completed as part of preoperative psychosocial evaluation. Outcomes included postoperative diagnosis of delirium, discharge disposition, return to the emergency department within 30 days of surgery, and readmission within 30 days of surgery. Univariate and multivariate logistic regression were used to determine the associations between preoperative MoCA score and each outcome measure. RESULTS: One hundred thirty-five patients with HNC were included in the study (mean [SD] age, 60.7 [±10.8] years; 70.4% [n = 95] male; 83.0% [n = 112] White, 16.3% [n = 22] Black). The average preoperative MoCA score was 23.4 (SD ± 4.5). Based on the MoCA score, 35% (n = 47) scored ≥26 (i.e., normal cognitive status), 55.6% (n = 75) scored between 18 and 25 (i.e., mild impairment), 8.1% (n = 11) scored between 10 and 17 (i.e., moderate impairment), and 1.5% (n = 2) scored <10 (i.e., severe impairment). After adjusting for other variables, a lower MoCA score was associated with discharge disposition to a location other than home and prolonged length of hospital stay. CONCLUSIONS: Preoperative cognitive function in patients undergoing major head and neck surgery for head and neck cancer was associated with discharge destination and length of stay. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2999-3005, 2023.

A phase I clinical trial of oncolytic adenovirus mediated suicide and interleukin-12 gene therapy in patients with recurrent localized prostate adenocarcinoma.

In a phase I dose escalation and safety study (NCT02555397), a replication-competent oncolytic adenovirus expressing yCD, TK and hIL-12 (Ad5-yCD/mutTKSR39rep-hIL-12) was administered in 15 subjects with localized recurrent prostate cancer (T1c-T2) at increasing doses (1 × 1010, to 1 × 1012 viral particles) followed by 7-day treatment of 5-fluorocytosine (5-FC) and valganciclovir (vGCV). The primary endpoint was toxicity through day 30 while the secondary and exploratory endpoints were quantitation of IL-12, IFNγ, CXCL10 and peripheral blood mononuclear cells (PBMC). The study maximum tolerated dose (MTD) was not reached indicating 1012 viral particles was safe. Total 115 adverse events were observed, most of which (92%) were grade 1/2 that did not require any treatment. Adenoviral DNA was detected only in two patients. Increase in IL-12, IFNγ, and CXCL10 was observed in 57%, 93%, and 79% patients, respectively. Serum cytokines demonstrated viral dose dependency, especially apparent in the highest-dose cohorts. PBMC analysis revealed immune system activation after gene therapy in cohort 5. The PSA doubling time (PSADT) pre and post treatment has a median of 1.55 years vs 1.18 years. This trial confirmed that replication-competent Ad5-IL-12 adenovirus (Ad5-yCD/mutTKSR39rep-hIL-12) was well tolerated when administered locally to prostate tumors.

Nasogastric Feeding Tube/Dobhoff Placement: A Multidisciplinary Approach to the Management of Malnutrition During Radiation Therapy in Patients With Head and Neck Cancer.

Background Radiation therapy (RT)-associated oral mucositis, xerostomia, thick mucoid saliva, nausea/vomiting, and loss of taste may result in significantly compromised oral intake in patients undergoing treatment for head and neck cancers (HNC). Feeding tube placement allows patients to receive enteral nutrition and continue the planned course of treatment. Objectives RT-associated oral mucositis, xerostomia, and loss of taste may result in significantly compromised oral intake in patients undergoing treatment for head and neck cancers. We sought to determine if reactive nasogastric (NG) tube placement was an effective strategy for nutritional support in these patients and if invasive percutaneous endoscopic gastrostomy (PEG) tube insertion could be avoided. Methods This is an institutional review board (IRB)-approved study of patients treated for head and neck cancer using definitive or adjuvant RT with or without concurrent chemotherapy between June 2017 and December 2020. We evaluated the indications for NG tube (Dobhoff) placement, time of placement during the course of RT, patient tolerance of NG tube, and median duration of NG tube placement. In addition, we followed weight loss during treatment, treatment interruptions, and treatment-related toxicities. Complications associated with having the NG tube, if the NG tube needed to be replaced during treatment, and if the patient had any hospitalization during the course of treatment were tracked. Results Of the 441 patients treated for head and neck cancer during the time period of this study, 47 required reactive NG tube placement for nutritional support. Patients included 40 with primary oropharynx, three with oral cavity, two with larynx, one with nasopharyngeal, and one was unknown. Chemotherapy was given concurrently with radiation in 87.2% (n=41) patients. The median time of NG tube placement was during Week 5 of the six to seven-week course of RT. The median percentage of weight loss from baseline to the date of NG tube placement was 12.9% (range, -0.9% to 25.9%). The median rate of weight loss decreased by 8.7% from the date of NG tube placement to the end of treatment. The median duration of NG tube placement was 29 days (range, 5 to 151 days). There were no serious medical complications associated with having the NG tube in place during treatment. Twenty-seven point six percent (27.6%; n=13) of patients had the NG tube dislodged or displaced and needed replacement. Thirty-eight point three percent (38.3%; n=18) of patients with an NG tube had to be hospitalized during the course of RT, with the predominant symptoms being failure to thrive (22.2%; n=4) and nausea/vomiting 22.2% (n=4). Six point four percent (6.4%; n=3) of patients requested the removal of the NG tube due to local irritation. Seventy-six point six percent (76.6%; n=36) of patients did not require further nutritional support with the placement of a percutaneous endoscopic gastrostomy (PEG) tube. Conclusion This study indicates that clinic placement of an NG tube for patients receiving RT for head and neck cancer is a safe and effective way to maintain nutrition during treatment. The rate of weight loss decreased after the patient had an NG tube placed. The placement procedure is well-tolerated and there were no complications associated with having the NG tube during treatment. PEG tube insertion was avoided in approximately 80% of the patients.

The 2021 landscape of FDA-approved artificial intelligence/machine learning-enabled medical devices: An analysis of the characteristics and intended use.

BACKGROUND: Machine learning (ML), a type of artificial intelligence (AI) technology that uses a data-driven approach for pattern recognition, has been shown to be beneficial for many tasks across healthcare. To characterize the commercial availability of AI/ML applications in the clinic, we performed a detailed analysis of AI/ML-enabled medical devices approved/cleared by the US Food and Drug Administration (FDA) by June 2021. METHODS/MATERIALS: The publicly available approval letters by the FDA on 343 AI/ML-enabled medical devices compiled by the agency were reviewed. The characteristics of the devices and the patterns of their intended use were analyzed, and basic descriptive statistical analysis was performed on the aggregated data. RESULTS: Most devices were reviewed by radiology (70.3%) and cardiovascular (12.0%) medical specialty panels. The growth of these devices sharply rose since the mid-2010s. Most (95.0%) devices were cleared under the 510(k) premarket notification pathway, and 69.4% were software as a medical device (SaMD). Of the 241 radiology-related devices, the most common applications were for diagnostic assistance (48.5%) and image reconstruction (14.1%). Of the 117 radiology-related devices for diagnostic assistance, 20.5% were developed for breast lesion assessment and 14.5% for cardiac function assessment on echocardiogram. Of the 41 cardiology-related devices, the most common applications were electrocardiography-based arrhythmia detection (46.3%) and hemodynamics & vital signs monitoring (26.8%). CONCLUSION: In this study, we characterized the patterns and trends of AI/ML-enabled medical devices approved or cleared by the FDA. To our knowledge, this is the most up-to-date and comprehensive analysis of the landscape as of 2021.