PET/MRI in Endometrial Cancer: Imaging Biomarkers are Associated with Disease Progression and Overall Survival.

RATIONALE AND OBJECTIVES: To evaluate the association between positron emission tomography (PET)/magnetic resonance imaging (MRI) biomarkers and survival outcomes in patients with endometrial cancer. MATERIALS AND METHODS: Between April 2014 and April 2016, 88 patients with newly diagnosed endometrial cancer participated this prospective study and underwent [18F] fluorodeoxyglucose PET/MRI. Sixty-nine patients with measurable tumors on PET/MRI were included in the image analysis. Imaging biomarkers included the minimum and mean apparent diffusion coefficients (ADCmin and ADCmean), maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors. The log-rank test and Cox proportional hazards model were used to assess the relationship between imaging biomarkers and survival. RESULTS: After a median follow-up of 80 months, 15 (22%) patients had tumor progression and six (9%) patients died. The results of ADCmin, ADCmean, and SUVmax did not show a significant association with progression-free survival (PFS) and overall survival (OS). Significantly shorter PFS was noted in patients with primary tumors with higher MTV (P < 0.001) and TLG (P < 0.001). Significantly shorter OS was also noted in patients with primary tumors with higher MTV (P = 0.048) and TLG (P = 0.034). In the multivariate analysis, MTV was an independent predictor of PFS (hazard ratio = 10.84, P = 0.033). CONCLUSION: PET/MRI biomarkers, particularly MTV and TLG, are associated with PFS and OS in patients with endometrial cancer. MTV was an independent predictor of PFS.

Noninvasive cardiac radioablation for ventricular tachycardia: dosimetric comparison between linear accelerator- and robotic CyberKnife-based radiosurgery systems.

BACKGROUND: Few dosimetric comparisons have been published between linear accelerator (LA)-based systems and CyberKnife (CK)-based robotic radiosurgery systems for cardiac radio-ablation in ventricular tachycardia. This study aimed to compare the dosimetry of noninvasive cardiac radio-ablation deliverable on LA with that on CK. METHODS: Thirteen patients who underwent noninvasive cardiac radio-ablation by LA were included. The prescribed dose was 25 Gy in 1 fraction, and the average planning target volume was 49.8 ± 31.0 cm3 (range, 14.4-93.7 cm3). CK plans were generated for comparison. RESULTS: Both the CK and LA plans accomplished appropriate dose coverage and normal tissue sparing. Compared with the LA plans, the CK plans achieved significantly lower gradient indices (3.12 ± 0.71 vs. 3.48 ± 0.55, p = 0.031) and gradient measures (1.00 ± 0.29 cm vs. 1.17 ± 0.29 cm, p < 0.001). They had similar equivalent conformity indices (CK vs. LA: 0.84 ± 0.08 vs. 0.87 ± 0.07, p = 0.093) and maximum doses 2 cm from the planning target volume (PTV) in any direction (CK vs. LA: 50.8 ± 9.9% vs. 53.1 ± 5.3%, p = 0.423). The dosimetric advantages of CK were more prominent in patients with a PTV of ≤ 50 cm3 or a spherical PTV. In patients with a PTV of > 50 cm3 or a non-spherical PTV, the LA and CK plans were similar regarding dosimetric parameters. CK plans involved more beams (232.2 ± 110.8 beams vs. 10.0 ± 1.7 arcs) and longer treatment times (119.2 ± 43.3 min vs. 22.4 ± 1.6 min, p = 0.007). CONCLUSIONS: Both CK and LA are ideal modalities for noninvasive cardiac radio-ablation. Upfront treatment should be considered based on clinical intent.

Prognostic nutritional index and neutrophil-lymphocyte ratio predict toxicities and prognosis in patients with cervical cancer treated with curative radiochemotherapy.

BACKGROUND: This study aimed to investigate the influence of immunonutritional factors on treatment-related toxicities and survival outcomes in patients with cervical cancer undergoing definitive radiochemotherapy. METHODS: Patients with cervical cancer who received curative radiochemotherapy between 2016 and 2021 were retrospectively investigated. Pretreatment prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) were measured. Survival outcomes, acute and late toxicities were evaluated. RESULTS: Among the 138 patients, those with larger tumor diameters had significantly lower pre-treatment PNI (p = 0.005). Pre-treatment immunonutritional factors were predictive of clinical survival, whereas post-treatment factors did not correlate with prognosis. Patients with low pre-treatment PNI (<49.5) or high NLR (>2.4) had shorter progression-free survival (PFS, HR: 1.86, p = 0.045 for PNI; HR: 3.15, p = 0.002 for NLR) and overall survival (OS, HR: 1.80, p = 0.048 for PNI; HR: 3.83, p = 0.015 for NLR). High pre-treatment NLR was associated with an increased risk of acute diarrhea (p = 0.049) and late severe toxicities (p = 0.046). Combined analysis revealed that pre-treatment good nutritional status and low systemic inflammation were linked to longer PFS (p = 0.007) and OS (p = 0.002), and poor nutritional status and substantial systemic inflammation were associated with higher rates of late severe toxicities (p = 0.036), with higher prognostic value in advanced stage patients. CONCLUSIONS: Pretreatment immunonutritional measures serve as quantitative biomarkers for predicting survivals and treatment toxicities in patients with cervical cancer treated with definitive radiochemotherapy.

Cisplatin and Albumin-Based Gold-Cisplatin Nanoparticles Enhance Ablative Radiation Therapy-Induced Antitumor Immunity in Local and Distant Tumor Microenvironment.

PURPOSE: Ablative radiation therapy (RT) is an important strategy to eliminate primary tumor and can potentially induce the abscopal effect. Human serum albumin nanoparticle (NP) was used for controlled release of cisplatin to decrease cisplatin's systemic toxicity, and gold (Au) was added to increase RT-induced immunogenic cell death and potentiate the abscopal antitumor immunity. METHODS AND MATERIALS: The designed albumin-based cisplatin-conjugated AuNPs were administered concurrently with ablative RT. C57BL/6 mice implanted with syngeneic murine Lewis lung carcinoma or murine MB49 tumor models were treated with ablative RT (12 Gy per fraction for 2 fractions, total 24 Gy), cisplatin, or Au-cisplatin NPs. RESULTS: Combining ablative RT with cisplatin or Au-cisplatin NPs both destroyed the primary tumor effectively and elicited immunogenic cell death accompanied by release of danger-associated molecular patterns. This enhanced recruitment of effector tumor-infiltrating immune cells, including natural killer T cells and CD8+ T cells, and elicited an increased percentage of professional antigen-presenting CD11c+ dendritic cells. Transient weight loss, accompanying hepatotoxicity, nephrotoxicity, and hematopoietic suppression, was observed as a systemic adverse event in the cisplatin but not the Au-cisplatin NPs group. Cisplatin and Au-cisplatin NPs both showed equivalent ability to reduce metastatic potential when combined with ablative RT, confirmed by suppressed unirradiated flank tumor growth and decreased metastatic lung tumor burden, which translated to improved survival. Mobilization and abundance of effector tumor-infiltrating immune cells including CD8+ T cells and dendritic cells were observed in the distant lung tumor microenvironment after ablative RT with cisplatin or Au-cisplatin NPs, demonstrating increased antitumor immunotherapeutic activity as an abscopal effect. CONCLUSIONS: Compared with cisplatin, the albumin-based Au-cisplatin NPs exhibited equivalent but no superior antitumor immunotherapeutic activity while reducing systemic adverse events and can be safely administered concurrently with ablative RT. Alternative NP formulations may be designed to further improve anticancer outcomes.

Obesity promotes radioresistance through SERPINE1-mediated aggressiveness and DNA repair of triple-negative breast cancer.

Obesity is a risk factor in various types of cancer, including breast cancer. The disturbance of adipose tissue in obesity highly correlates with cancer progression and resistance to standard treatments such as chemo- and radio-therapies. In this study, in a syngeneic mouse model of triple-negative breast cancer (TNBC), diet-induced obesity (DIO) not only promoted tumor growth, but also reduced tumor response to radiotherapy. Serpine1 (Pai-1) was elevated in the circulation of obese mice and was enriched within tumor microenvironment. In vitro co-culture of human white adipocytes-conditioned medium (hAd-CM) with TNBC cells potentiated the aggressive phenotypes and radioresistance of TNBC cells. Moreover, inhibition of both cancer cell autonomous and non-autonomous SERPINE1 by either genetic or pharmacological strategy markedly dampened the aggressive phenotypes and radioresistance of TNBC cells. Mechanistically, we uncovered a previously unrecognized role of SERPINE1 in DNA damage response. Ionizing radiation-induced DNA double-strand breaks (DSBs) increased the expression of SERPINE1 in cancer cells in an ATM/ATR-dependent manner, and promoted nuclear localization of SERPINE1 to facilitate DSB repair. By analyzing public clinical datasets, higher SERPINE1 expression in TNBC correlated with patients' BMI as well as poor outcomes. Elevated SERPINE1 expression and nuclear localization were also observed in radioresistant breast cancer cells. Collectively, we reveal a link between obesity and radioresistance in TNBC and identify SERPINE1 to be a crucial factor mediating obesity-associated tumor radioresistance.

Therapeutic efficacy of cyclin-dependent kinase inhibition in combination with ionizing radiation for lung cancer.

PURPOSE: To evaluate the therapeutic efficacy of cyclin-dependent kinase (CDK) inhibition in combination with ionizing radiation for lung cancer. MATERIALS AND METHODS: Human lung adenocarcinoma (A549) and squamous cell carcinoma (H520) cells were used to evaluate the therapeutic efficacy of CDK inhibition in combination with ionizing radiation in vitro using colony formation assay, γH2AX immunofluorescence staining, western blotting, and cell cycle phase analysis. We also performed in vivo evaluations of ectopic tumor growth. RESULTS: In vitro pretreatment with the CDK inhibitor, seliciclib, before irradiation significantly decreased the survival of A549 and H520 cells in a dose-dependent manner. Although CDK inhibition alone did not increase the intensity of γH2AX foci, its combination with ionizing radiation increased DNA double-strand breaks, as shown by γH2AX immunofluorescence staining and western blotting. The combination of CDK inhibition and ionizing radiation-induced G2/M arrest and increased apoptosis, as evidenced by the increased proportion of cells in G2/M arrest, subG1 apoptotic population, and expression of apoptotic markers (cleaved PARP-1 and cleaved caspase-3). Mechanistic studies showed reduced expression of cyclin A with combined treatment, indicating cell cycle shifting effects. An in vivo xenograft model showed that the combination of CDK inhibition and ionizing radiation delayed xenograft tumor growth, and increased the proportion of cleaved PARP-1- and cleaved caspase-3-positive cells, compared to either treatment alone. CONCLUSIONS: We provide preclinical tumoricidal evidence that the combination of CDK inhibition and ionizing radiation is an efficacious treatment for lung cancer.

Cisplatin-loaded gold nanoshells mediate chemo-photothermal therapy against primary and distal lung cancers growth.

Lung cancer is the most common cause of cancer mortality worldwide. The advances in surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs have progressed in the past decades, but the prognosis of lung cancer is still poor. In this study, we developed cisplatin (CDDP)-loaded human serum albumin (HSA)-based gold nanoshells (HCP@GNSs) for synergistic chemo-photothermal therapy (chemo-PTT). The HCP@GNSs not only acted as drug nanocarriers for chemotherapy but also serve as a superior mediator for PTT, which could exhibit a temperature increase upon a near infrared (NIR) laser exposure that was sufficient for photothermal ablation. HCP@GNSs were highly biocompatible and hemocompatible nanocarriers, while the synergistic chemo-PTT resulting from HCP@GNSs plus NIR exposure displayed stronger cytotoxicity effect than HCP@GNSs or PTT alone, especially at a low CDDP concentration. In vivo analysis demonstrated that HCP@GNSs-mediated chemo-PTT increased necrosis in tumors to achieve a high tumor clearance rate with no adverse side effects. Moreover, HCP@GNSs-medicated chemo-PTT induced the recruitment of dendritic cells, B-cells, and natural killer T-cells in distal tumors to inhibit the growth of the tumors. Therefore, the CDDP-loaded HCP@GNSs may be a potential nanomedicine candidate for curative lung cancer treatment in the future.

Xenon-Enhanced Ventilation Computed Tomography for Functional Lung Avoidance Radiation Therapy in Patients With Lung Cancer.

PURPOSE: This phase 2 trial aimed to determine whether xenon-enhanced ventilation computed tomography (XeCT)-guided functional-lung-avoidance radiation therapy could reduce the radiation pneumonitis (RP) rate in patients with lung cancer undergoing definitive chemoradiation therapy. METHODS AND MATERIALS: Functional lung ventilation was measured via pulmonary function testing (PFT) and XeCT. A standard plan (SP) without reference to XeCT and a functional-lung-avoidance plan (fAP) optimized for lowering the radiation dose to the functional lung at the guidance of XeCT were designed. Dosimetric parameters and predicted RP risks modeled by biological evaluation were compared between the 2 plans in a treatment planning system (TPS). All patients received the approved fAP. The primary endpoint was the rate of grade ≥2 RP, and the secondary endpoints were the survival outcomes. The study hypothesis was that fAP could reduce the rate of grade ≥2 RP to 12% compared with a 30% historical rate. RESULTS: Thirty-six patients were evaluated. Xenon-enhanced total functional lung volumes positively correlated with PFT ventilation parameters (forced vital capacity, P = .012; forced expiratory volume in 1 second, P = .035), whereas they were not correlated with the diffusion capacity parameter. We observed a 17% rate of grade ≥2 RP (6 of 36 patients), which was significantly different (P = .040) compared with the historical control. Compared with the SP, the fAP significantly spared the total ventilated lung, leading to a reduction in predicted grade ≥2 RP (P = .001) by TPS biological evaluation. The median follow-up was 15.2 months. The 1-year local control (LC), disseminated failure-free survival (DFFS), and overall survival (OS) rates were 88%, 66%, and 91%, respectively. The median LC and OS were not reached, and the median DFFS was 24.0 months (95% confidence interval, 15.7-32.3 months). CONCLUSIONS: This report of XeCT-guided functional-lung-avoidance radiation therapy provided evidence showing its feasibility in clinical practice. Its benefit should be assessed in a broader multicenter trial setting.

Preclinical evaluation of PEGylated liposomal doxorubicin as an effective radiosensitizer in chemoradiotherapy for lung cancer.

PURPOSE: Development of a safe and effective systemic chemotherapeutic agent for concurrent administration with definitive thoracic radiotherapy remains a major goal of lung cancer management. The synergistic effect of PEGylated liposomal doxorubicin and irradiation was evaluated in lung cancer cell lines both in vitro and in vivo. METHODS: In vitro radiosensitization of A549 and LLC cell lines was evaluated by colony formation assay, γH2AX fluorescent staining and western blot assay, and annexin V staining. A radiosensitization study with healthy human lung-derived cell line BEAS-2B was performed for comparative purposes. In vivo radiosensitization was evaluated by tumor ectopic growth, cell survival, pharmacokinetics, and biodistribution analyses. Cleaved caspase­3, the marker for apoptosis, was assessed immunohistochemically in A549 xenograft tumors. RESULTS: Treatment with PEGylated liposomal doxorubicin decreased A549 and LLC cell proliferation in a dose-dependent manner. In vitro studies revealed comparable radiosensitizer advantages of PEGylated liposomal doxorubicin and free doxorubicin, showing equivalent DNA double-strand breaks according to γH2AX fluorescent staining and western blot assays, similar numbers of apoptotic cells in the annexin­V staining assay, and moderately decreased clonogenic survival. In vivo studies demonstrated markedly slow ectopic tumor growth with prolonged survival following treatment with PEGylated liposomal doxorubicin plus irradiation in both A549 and LLC mouse models, suggesting that PEGylated liposomal doxorubicin is more effective as a radiosensitizer than free doxorubicin in vivo. Pharmacokinetics evaluation showed a longer half-life of approximately 40 h for PEGylated liposomal doxorubicin, confirming that the liposomal carrier achieved controlled release. Biodistribution evaluation of PEGylated liposomal doxorubicin confirmed high accumulation of doxorubicin in tumors, indicating the promising drug delivery attributes of PEGylated liposomal doxorubicin. Although free doxorubicin caused histopathologic myocarditis with the cardiac muscle fibers showing varying degrees of damage, PEGylated liposomal doxorubicin caused no such effects. The immunohistochemical expression of cleaved caspase-3-positive cells was greatest expressed in the irradiation and PEGylated liposomal doxorubicin combined treatment group, indicating prolonged tumoricidal effects. CONCLUSIONS: Our study provides preclinical in vitro and in vivo evidence of the effectiveness of PEGylated liposomal doxorubicin as a radiosensitizer, supporting its potential clinical development as a component of chemoradiotherapy.

First Asian population study of stereotactic body radiation therapy for ventricular arrhythmias.

We report the first Asian series on stereotactic body radiation (SBRT) for refractory ventricular arrhythmia (VA) in Taiwanese patients. Three-dimensional electroanatomic maps, delayed-enhancement magnetic resonance imaging (DE-MRI), and dual-energy computed tomography (CT) were used to identify scar substrates. The main target volume was treated with a single radiation dose of 25 Gy and the margin volume received 20 Gy using simultaneous integrated boost delivered by the Varian TrueBeam system. Efficacy was assessed according to VA events recorded by an implantable cardioverter-defibrillator (ICD) or a 24-h Holter recorder. Pre- and post-radiation therapy imaging studies were performed. From February 2019 to December 2019, seven patients (six men, one woman; mean age, 55 years) were enrolled and treated. One patient died of hepatic failure. In the remaining six patients, at a median follow-up of 14.5 months, the VA burden and ICD shocks significantly decreased (only one patient with one ICD shock after treatment). Increased intensity on DE-MRI might be associated with a lower risk for VA recurrence, whereas dual-energy CT had lower detection sensitivity. No acute or minimal late adverse events occurred. In patients with refractory VA, SBRT is associated with a marked reduction in VA burden and ICD shocks, and DE-MRI might be useful for monitoring treatment effects.

Real-World Evaluation of Modern Adjuvant Radiotherapy in Women with Stage IB Endometrial Cancer.

The optimal adjuvant treatment for stage IB endometrial cancer remains undefined. We investigated the benefit of modern adjuvant radiotherapy for women with stage IB endometrial cancer. We retrospectively reviewed patients with surgically staged, pure stage IB endometrioid adenocarcinoma (2010 to 2018). Adjuvant modern radiotherapy consists of external-beam radiotherapy (EBRT) by intensity, volumetric-modulated arc radiotherapy, or image-guided vaginal brachytherapy (VBT). The study included 180 stage IB patients. Patients with grade 3 diseases had frequent aggressive histology patterns (lymphovascular space invasion (LVSI); low uterine segment involvement) and experienced significantly shorter recurrence-free survival (RFS) and overall survival (OS) than patients with grade 1/2 diseases. Adjuvant modern radiotherapy decreased the incidence of acute/chronic grade ≥2 gastrointestinal toxicity. In IB grade 1/2 patients, EBRT significantly lengthened survival (RFS/OS); patients with age >60 years, myometrial invasion beyond the outer third, or LVSI benefited the most from EBRT. EBRT also significantly improved survival (RFS/OS) in IB grade 3 patients, where patients with bulky tumors or LVSI benefited the most from EBRT. Therefore, EBRT may be beneficial for all stage IB patients.

Assessing tumor angiogenesis using dynamic contrast-enhanced integrated magnetic resonance-positron emission tomography in patients with non-small-cell lung cancer.

BACKGROUND: Angiogenesis assessment is important for personalized therapeutic intervention in patients with non-small-cell lung cancer (NSCLC). This study investigated whether radiologic parameters obtained by dynamic contrast-enhanced (DCE)-integrated magnetic resonance-positron emission tomography (MR-PET) could be used to quantitatively assess tumor angiogenesis in NSCLC. METHODS: This prospective cohort study included 75 patients with NSCLC who underwent DCE-integrated MR-PET at diagnosis. The following parameters were analyzed: metabolic tumor volume (MTV), maximum standardized uptake value (SUVmax), reverse reflux rate constant (kep), volume transfer constant (Ktrans), blood plasma volume fraction (vp), extracellular extravascular volume fraction (ve), apparent diffusion coefficient (ADC), and initial area under the time-to-signal intensity curve at 60 s post enhancement (iAUC60). Serum biomarkers of tumor angiogenesis, including vascular endothelial growth factor-A (VEGF-A), angiogenin, and angiopoietin-1, were measured by enzyme-linked immunosorbent assays simultaneously. RESULTS: Serum VEGF-A (p = 0.002), angiogenin (p = 0.023), and Ang-1 (p <  0.001) concentrations were significantly elevated in NSCLC patients compared with healthy individuals. MR-PET parameters, including MTV, Ktrans, and kep, showed strong linear correlations (p <  0.001) with serum angiogenesis-related biomarkers. Serum VEGF-A concentrations (p = 0.004), MTV values (p <  0.001), and kep values (p = 0.029) were significantly higher in patients with advanced-stage disease (stage III or IV) than in those with early-stage disease (stage I or II). Patients with initial higher values of angiogenesis-related MR-PET parameters, including MTV > 30 cm3 (p = 0.046), Ktrans > 200 10- 3/min (p = 0.069), and kep > 900 10- 3/min (p = 0.048), may have benefited from angiogenesis inhibitor therapy, which thus led to significantly longer overall survival. CONCLUSIONS: The present findings suggest that DCE-integrated MR-PET provides a reliable, non-invasive, quantitative assessment of tumor angiogenesis; can guide the use of angiogenesis inhibitors toward longer survival; and will play an important role in the personalized treatment of NSCLC.

A retrospective study of clinicopathologic and molecular features of inoperable early-stage non-small cell lung cancer treated with stereotactic ablative radiotherapy.

BACKGROUND/PURPOSE: Stereotactic ablative radiotherapy (SABR) is the treatment of choice for medically inoperable, early-stage non-small cell lung cancer (ES-NSCLC). The influence of oncogenic driver alterations and comorbidities are not well known. Here we present treatment outcomes based on clinicopathologic features and molecular profiles. METHODS: We retrospectively analyzed patients treated with SABR for inoperable ES-NSCLC. Molecular features of oncogenic driver alterations included EGFR, ALK, and ROS1. Comorbidities were assessed using the age-adjusted Charlson Comorbidity Index (ACCI). Survival was calculated using the Kaplan-Meier method. The Cox regression model was performed for univariate and multivariate analyses of prognostic factors. Competing risk analysis was used to evaluate the cumulative incidence of disease progression. RESULTS: From 2008 to 2020, 100 patients (median age: 82 years) were enrolled. The majority of patients were male (64%), ever-smokers (60%), and had adenocarcinoma (65%). With a median follow-up of 21.5 months, the median overall survival (OS) and real-world progression-free survival were 37.7 and 25.1 months, respectively. The competing-risk-adjusted 3-year cumulative incidences of local, regional, and disseminated failure were 8.2%, 14.5%, and 31.2%, respectively. An ACCI ≥7 was independently associated with inferior OS (hazard ratio [HR] 2.45, p = 0.03). Tumor size ≥4 cm (HR 4.16, p < 0.001) was the most important independent prognostic factor predicting real-world progression. EGFR mutation status had no impact on the outcomes. CONCLUSION: SABR provides excellent local control in ES-NSCLC, although disseminated failures remains a major concern. ACCI is the best indicator for OS, while tumor sizes ≥4 cm predicts poor disease control.

Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial.

BACKGROUND: Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT (C-WBRT) is better for preserving neurocognitive function. METHODS: This single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned them to receive HA-WBRT or C-WBRT. Primary endpoint is decline of the Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From March 2015 to December 2018, seventy patients were randomized to yield a total cohort of 65 evaluable patients (33 in the HA-WBRT arm and 32 in the C-WBRT arm) with a median follow-up of 12.4 months. No differences in baseline neurocognitive function existed between the 2 arms. The mean change of HVLT-R delayed recall at 4 months was -8.8% in the HA-WBRT arm and +3.8% in the C-WBRT arm (P = 0.31). At 6 months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, P = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, P = 0.019) and memory score (mean difference = 4.38, P = 0.020) compared with patients undergoing C-WBRT. There were no differences in Trail Making Test Part A or Part B or the Controlled Oral Word Association test between the 2 arms at any time point. There were no differences in brain PFS or OS between arms as well. CONCLUSION: Patients receiving HA-WBRT without memantine showed better preservation in memory at 6-month follow-up, but not in verbal fluency or executive function.

Evaluation of antitumor immunity by a combination treatment of high-dose irradiation, anti-PDL1, and anti-angiogenic therapy in murine lung tumors.

C57BL/6 mice implanted in the flank with murine Lewis lung carcinoma cells were randomized into control, anti-angiogenic, anti-PD-L1, radiotherapy (RT), RT + anti-angiogenic, RT + anti-PD-L1, and RT + anti-PD-L1 + anti-angiogenic therapy groups. Immune response and immunophenotyping were determined by flow cytometry. Vasculature analysis after RT and anti-angiogenic therapy was assessed by quantified power Doppler sonography. Antitumor response, survival, and rechallenged tumor growth were evaluated. RT increased PD-L1 expression on CD8+ T, CD4+ T, dendritic, myeloid-derived suppressor cells (MDSCs), and tumor cells and increased PD-1 expression on CD8+ and CD4+ T cells. Anti-angiogenic therapy insignificantly decreased the RT-induced PD-1 expression on CD8+ and CD4+ T cells, implying a weak reversal of the immune-suppressive environment. Transient vessel collapse was observed within days after RT, and blood flow recovered at 1 week after RT. RT + anti-PD-L1 suppressed the tumor growth, improved survival, and prolonged immune memory capable of protecting against tumor recurrence, evidenced by local accumulation of CD8+ T cells and reduction in MDSCs in microenvironment. Similar and more prominent effects were observed when anti-VEGF was added to RT + anti-PDL1 therapies, implying an additive, rather than synergistic, antitumor immunity. Phenotypic analyses revealed that anti-cancer treatments increased the proportion of effector memory T cells in TILs and splenocytes, and RT, alone or in combination with other treatments, further increased the proportion of central memory T cells in splenocytes. These results provide evidence on operating the immunosuppressive tumor environment and offer insights into the design of the new combination treatment.

Impact of adjuvant radiotherapy on the survival of women with optimally resected stage III endometrial cancer in the era of modern radiotherapy: a retrospective study.

BACKGROUND: The optimal adjuvant treatment for stage III endometrial cancer in the era of modern radiotherapy remains undefined. We investigated the benefit of adjuvant radiotherapy for women who underwent optimal resection for stage III endometrial cancer in the era of modern radiotherapy. METHODS: We retrospectively reviewed patients with endometrial cancer who were treated between 2010 and 2018. Adjuvant treatment included radiotherapy by modern radiotherapy techniques (intensity-modulated or volumetric modulated arc radiotherapy), chemotherapy, or both. Recurrence-free survival (RFS) and overall survival (OS) were calculated using the Kaplan-Meier method and analyzed via multivariate Cox proportional hazards models. RESULTS: One hundred sixty-one patients were initially included (52, 9, and 100 with stages IIIA, IIIB, and IIIC cancer, respectively); 154 patients (96%) received adjuvant therapy. Such adjuvant treatment was associated with improved RFS (p = 0.014) and OS (p = 0.044) over surgery alone. Adjuvant radiotherapy by modern radiotherapy techniques led to low incidence of acute (25%) and chronic (7%) grade ≥ 2 gastrointestinal toxicity. On univariate analysis, non-endometrioid histology and grade 3 status were associated with higher risks of tumor recurrence and death, whereas adjuvant radiotherapy alone or in combination chemotherapy reduced their risks. On multivariate analysis, non-endometrioid histology was associated with increased recurrence (hazard ratio [HR], 2.95; p = 0.009), whereas adjuvant radiotherapy alone or with chemotherapy was associated with lower recurrence (HR, 0.62; p = 0.042). Patients > 60 years of age (p = 0.038) as well as those with endometrioid histology (p = 0.045), lymphovascular space invasion (p = 0.031), and ≥ 2 positive lymph nodes (p = 0.044) benefited most from adjuvant radiotherapy. CONCLUSIONS: Modern adjuvant radiotherapy (intensity-modulated or volumetric modulated arc radiotherapy) alone or with chemotherapy should be considered for women with optimally resected stage III endometrial cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04251676. Registered 24 January 2020. Retrospectively registered.

Extended-field bone marrow sparing radiotherapy for primary chemoradiotherapy in cervical cancer patients with para-aortic lymphadenopathy: Volumetric-modulated arc therapy versus helical tomotherapy.

BACKGROUND: Extended-field (EF) bone marrow-sparing (BMS) radiotherapy is attracting interest for cervical cancer patients with para-aortic lymphadenopathy. OBJECTIVE: To compare dosimetric quality of volumetric-modulated arc therapy (VMAT) vs. helical tomotherapy (HT) during EF BMS radiotherapy. METHODS: HT dose-volume histogram parameters including (1) coverage, homogeneity, and conformity of target volumes, (2) sparing of organs-at-risk, (3) monitor units, and (4) estimated treatment time were compared with those of VMAT in 20 cervical cancer patients who underwent EF BMS radiotherapy. The pelvic and para-aortic regions received 45-Gy dose (25 fractions), with simultaneous integrated boost of 55 Gy (25 fractions) for pelvic and para-aortic lymphadenopathy, followed by a parametrial boost of 9 Gy (5 fractions). RESULTS: The HT-based and VMAT techniques achieved adequate and similar target volume coverage with good dose homogeneity and conformity, while sparing all organs-at-risk, including the rectum, bladder, bowel, bone marrow, femoral head, kidney, and spinal cord. The HT treatment plan had significantly higher monitor units (p < 0.001) and longer estimated treatment times (p < 0.001). CONCLUSIONS: VMAT and HT plans are suitable for EF BMS radiotherapy, which can achieve adequate target volume coverage while sufficiently sparing normal tissue. In addition, VMAT, compared to HT planning, yielded shorter estimated treatment times.

Impact of smoking cessation on clinical outcomes in patients with head and neck squamous cell carcinoma receiving curative chemoradiotherapy: A prospective study.

BACKGROUND: We hypothesized that patients with head and neck squamous cell carcinoma (HNSCC) with smoking cessation during curative chemoradiotherapy (CRT) had fewer complications and lower tumor progression risks. METHODS: Sixty-three patients with nonmetastatic HNSCC who were smokers at diagnosis (carbon monoxide [CO] breath concentrations ≥3 ppm) and underwent curative CRT were prospectively enrolled. Successful smoking cessation throughout CRT was confirmed by CO breath concentrations <3 ppm at CRT completion. RESULTS: Forty-one patients (65%) successfully discontinued smoking throughout CRT. With a median 33-month follow-up, patients with successful smoking cessation during CRT had significantly fewer, greater, and lower probabilities of grade ≥3 acute toxicities (P = .01), progression-free survival (P = .03), and permanent gastrostomy or tracheostomy (P = .04), respectively, than those continuing smoking throughout CRT. In multivariate analysis, successful smoking cessation during CRT significantly reduced tumor progression risks (hazard ratio: 0.4, P = .05). CONCLUSION: Smoking cessation during curative CRT reduced treatment-related toxicities and tumor progression risks in patients with HNSCC.

Predicting tumor responses and patient survival in chemoradiotherapy-treated patients with non-small-cell lung cancer using dynamic contrast-enhanced integrated magnetic resonance-positron-emission tomography.

PURPOSE: We investigated whether radiologic parameters by dynamic contrast-enhanced (DCE) integrated magnetic resonance-positron-emission tomography (MR-PET) predicts tumor response to treatment and survival in non-metastatic non-small-cell lung cancer (NSCLC) patients receiving chemoradiotherapy (CRT). METHODS: Patients underwent DCE integrated MR-PET imaging 1 week before CRT. The following parameters were analyzed: primary tumor size, gross tumor volume, maximal standardized uptake value (SUVmax), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC), volume transfer constant (Ktrans), reverse reflux rate constant (kep), extracellular extravascular volume fraction (ve), blood plasma volume fraction (vp), and initial area under the time-concentration curve defined over the first 60 s post-enhancement (iAUC60). CRT responses were defined using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). RESULTS: Thirty patients were included. Non-responders demonstrated higher baseline TLG (p = 0.012), and lower baseline Ktrans (p = 0.020) and iAUC60 (p = 0.016) compared to responders, indicating the usefulness of DCE integrated MR-PET to predict treatment responses. Receiver operating characteristic curve indicated that TLG has the best differentiation capability to predict responders. By setting the threshold of TLG to 277, the sensitivity, specificity, and accuracy were 66.7%, 83.3%, and 75.0%, respectively, with an area under the curve of 0.776. The median follow-up time was 19.6 (range 7.8-32.0) months. In univariate analyses, baseline TLG >277 (p = 0.005) and baseline Ktrans <254 (10-3 min-1; p = 0.015) correlated with poor survival after CRT. In multivariate analysis, baseline TLG >277 remained the significant factor in predicting progression (p = 0.012) and death (p = 0.031). CONCLUSIONS: The radiologic parameters derived from DCE integrated MR-PET scans are useful for predicting treatment response in NSCLC patients treated with CRT; furthermore, these parameters are correlated with clinical and survival outcomes including tumor progression and death.