Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies.

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING signaling in mice inhibits DNA damage-induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

Patterns of relapse for children with localized intracranial ependymoma.

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted.

Long-term outcomes of adult medulloblastoma patients treated with radiotherapy.

Medulloblastoma (MB) is rare in adults and treatment guidelines are consequently not well-established. Few modern series have reported long-term follow-up and treatment sequelae. We examined long-term outcomes of adult MB patients at one institution. Records of 29 consecutive patients (18 male, 11 female) aged ≥ 18 years who received radiotherapy (RT) for primary MB from 1990 to 2016 were reviewed. Median age at diagnosis was 28 years (range 18-72 years). Seventeen patients were standard risk and 12 were high risk. Nineteen patients had gross total resection, seven had subtotal resection, and three had biopsy only. Median craniospinal irradiation and boost doses were 36 Gy (range 23.4-39.6 Gy) and 55.8 Gy (range 54-59.4 Gy), respectively. Of 24 patients receiving chemotherapy, 20 received concurrent + adjuvant and 4 received adjuvant only. At median follow-up of 9.0 years (range 1.1-20.5 years), five patients recurred: four in the posterior fossa and one in both the posterior fossa and above the tentorium. Five patients died: two of disease progression and three after possible treatment complications (seizure, lobar pneumonia, and multifactorial sepsis). At last follow-up, 23 patients were alive with no evidence of disease. Long-term effects include executive dysfunction (n = 17), weakness/ataxia (n = 16), and depression/anxiety (n = 13). Kaplan-Meier estimates of 10-year overall survival and failure-free survival are 83% (95% confidence interval [CI] 59-93%) and 79% (CI 55-91%), respectively. Despite encouraging disease control in this cohort, long-term sequelae may limit quality of life. Multimodality pediatric regimens using lower RT doses may be considered to reduce treatment-related morbidity.

Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib.

OBJECTIVES: Patients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. MATERIALS AND METHODS: We reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing-risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. RESULTS: Of 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and ≥4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. CONCLUSION: The main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC.

Combining immunotherapy and radiation therapy for small cell lung cancer and thymic tumors.

Recent work with immunotherapy has shown promising results with treatment of several solid malignancies, and there are several reports of good systemic responses with the combination of immunotherapy and radiation therapy (RT), most notably in advanced melanoma. Given the rapid increase in the use of checkpoint blockade as well as anti-tumor vaccines, we review here the preclinical rationale and ongoing clinical work in combining immunotherapy with RT for small cell lung cancer (SCLC) and thymic tumors. While there are several reports of promising results with the combination of immunotherapy and conventional systemic treatment, we focus here on the ongoing clinical studies that combine immunotherapy with RT, and highlight the emerging data for this multimodality approach as well as key preclinical and clinical issues that remain to be addressed. With regards to SCLC, trials exploring to the combination of immunotherapy and RT are already ongoing, but clinical studies for this combination in thymoma are lacking.

Evidence supporting contemporary post-operative radiation therapy (PORT) using linear accelerators in N2 lung cancer.

PURPOSE: Post-operative radiotherapy (PORT) treatment for lung cancer declined since a meta-analysis failed to show benefit in patients with N2 disease. Because several included studies employed outmoded radiation planning and delivery techniques, we sought to determine whether PORT with modern technology benefits patients with N2 disease. METHODS: We conducted searches of the published literature. For inclusion, studies must have included patients with stage III-N2 lung cancer treated with PORT using only linear accelerators, used a control group that did not receive PORT, and reported outcome data for overall survival (OS). Prospective and retrospective analyses were included. Exclusion criteria were the use of cobalt devices or orthovoltage radiation. RESULTS: Data were evaluated with random-effects models. Three prospective and eight retrospective studies were included. The PORT and no-PORT groups included 1368 and 1360 patients, respectively. The PORT group had significantly improved OS over the no-PORT group (hazard ratio [HR] = 0.77, 95% confidence interval [CI] 0.62-0.96, P = 0.020). Locoregional recurrence-free survival (LRFS) in 10 studies for which data was available was also improved in the PORT group (HR = 0.51, CI 0.41-0.65, P < 0.001). CONCLUSIONS: PORT was associated with significantly lower risk of death and locoregional recurrence in patients with N2 lung cancer. Our study was limited by lack of access to individual patient data, which would have enabled more detailed analyses. Regardless, data thus far suggest PORT may be associated with a survival benefit. Given a lack of large-scale prospective data, clinical trials evaluating PORT with modern technology are warranted.

Comparing the rates of urinary tract infections among patients receiving adjuvant pelvic intensity modulated radiation therapy, 3-dimensional conformal radiation therapy, and brachytherapy for newly diagnosed endometrial cancer.

PURPOSE: The purpose of this study was to compare the rates of urinary tract infection (UTI) among patients with endometrial cancer receiving vaginal brachytherapy alone and brachytherapy plus 3-dimensional conformal radiation therapy (3DCRT) or intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: We retrospectively evaluated the rates of UTI among 581 patients diagnosed with endometrial cancer, treated between 2004 and 2012. A total of 37% (216/581) received brachytherapy alone, 28% (161/581) received brachytherapy plus 3DCRT, and 35% (204/581) received brachytherapy plus IMRT. UTI during the treatment was defined as evidence of pyuria detected by either urine dipstick or urinalysis. All specimens were collected as a clean catch, midstream void to avoid contamination and resultant false positives. The χ(2) and logistic regression analyses were subsequently employed for statistical analyses. RESULTS: UTI was diagnosed in 14.6% (85/581) of all patients. Only 2.8% (6/216) of patients receiving brachytherapy were diagnosed with a UTI during treatment, whereas UTI was diagnosed in 37.3% (60/161) of patients receiving brachytherapy plus 3DCRT, and 9.3% (19/204) of patients receiving brachytherapy plus IMRT (P < .0005). Logistic regression analysis found a decreased association between UTI and stage III endometrial cancer (odds ratio [OR], 0.51, 95% confidence interval [CI], 0.26, 0.99; P = .048). When compared with brachytherapy, both types of external beam radiation therapy were associated with an increased risk of UTI, though adjuvant 3DCRT (OR, 47.52, 95% CI, 14.81, 152.47; P < .001) had a more dramatic risk increase than IMRT (7.89, 95% CI, 2.26, 27.62; P = .001). CONCLUSIONS: When compared with IMRT, 3DCRT is associated with a significantly increased risk of UTI, supporting the use of IMRT as the less toxic external beam radiation therapy for endometrial cancer.

Frequency-selective exocytosis by ribbon synapses of hair cells in the bullfrog's amphibian papilla.

The activity of auditory afferent fibers depends strongly on the frequency of stimulation. Although the bullfrog's amphibian papilla lacks the flexible basilar membrane that effects tuning in mammals, its afferents display comparable frequency selectivity. Seeking additional mechanisms of tuning in this organ, we monitored the synaptic output of hair cells by measuring changes in their membrane capacitance during sinusoidal electrical stimulation at various frequencies. Using perforated-patch recordings, we found that individual hair cells displayed frequency selectivity in synaptic exocytosis within the frequency range sensed by the amphibian papilla. Moreover, each cell's tuning varied in accordance with its tonotopic position. Using confocal imaging, we observed a tonotopic gradient in the concentration of proteinaceous Ca(2+) buffers. A model for synaptic release suggests that this gradient maintains the sharpness of tuning. We conclude that hair cells of the amphibian papilla use synaptic tuning as an additional mechanism for sharpening their frequency selectivity.

Activity-independent specification of synaptic targets in the posterior lateral line of the larval zebrafish.

The development of functional neural circuits requires that connections between neurons be established in a precise manner. The mechanisms by which complex nervous systems perform this daunting task remain largely unknown. In the posterior lateral line of larval zebrafish, each afferent neuron forms synaptic contacts with hair cells of a common hair-bundle polarity. We investigated whether afferent neurons distinguish hair-cell polarities by analyzing differences in the synaptic signaling between oppositely polarized hair cells. By examining two mutant zebrafish lines with defects in mechanoelectrical transduction, and by blocking transduction during the development of wild-type fish, we found that afferent neurons could form specific synapses in the absence of stimulus-evoked patterns of synaptic release. Asking next whether this specificity arises through intrinsically generated patterns of synaptic release, we found that the polarity preference persisted in two mutant lines lacking essential synaptic proteins. These results indicate that lateral-line afferent neurons do not require synaptic activity to distinguish hair-cell polarities and suggest that molecular labels of hair-cell polarity guide prepatterned afferents to form the appropriate synapses.