MR-guided stereotactic radiation therapy for head and neck cancers.

Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT. Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients. Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality. Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity.

Monitoring Variations in the Use of Automated Contouring Software.

PURPOSE: Our purpose was to identify variations in the clinical use of automatically generated contours that could be attributed to software error, off-label use, or automation bias. METHODS AND MATERIALS: For 500 head and neck patients who were contoured by an in-house automated contouring system, Dice similarity coefficient and added path length were calculated between the contours generated by the automated system and the final contours after editing for clinical use. Statistical process control was used and control charts were generated with control limits at 3 standard deviations. Contours that exceeded the thresholds were investigated to determine the cause. Moving mean control plots were then generated to identify dosimetrists who were editing less over time, which could be indicative of automation bias. RESULTS: Major contouring edits were flagged for: 1.0% brain, 3.1% brain stem, 3.5% left cochlea, 2.9% right cochlea, 4.8% esophagus, 4.1% left eye, 4.0% right eye, 2.2% left lens, 4.9% right lens, 2.5% mandible, 11% left optic nerve, 6.1% right optic nerve, 3.8% left parotid, 5.9% right parotid, and 3.0% of spinal cord contours. Identified causes of editing included unexpected patient positioning, deviation from standard clinical practice, and disagreement between dosimetrist preference and automated contouring style. A statistically significant (P < .05) difference was identified between the contour editing practice of dosimetrists, with 1 dosimetrist editing more across all organs at risk. Eighteen percent (27/150) of moving mean control plots created for 5 dosimetrists indicated the amount of contour editing was decreasing over time, possibly corresponding to automation bias. CONCLUSIONS: The developed system was used to detect statistically significant edits caused by software error, unexpected clinical use, and automation bias. The increased ability to detect systematic errors that occur when editing automatically generated contours will improve the safety of the automatic treatment planning workflow.

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma.

Acral melanoma (AM) has distinct characteristics as compared with cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICIs). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3+CD8+PD1+ intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low versus high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared with responders across cancers, including AM, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma.

Background: Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results: 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. Conclusions: A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

Omitting cardiophrenic lymph nodes in the treatment of patients with Hodgkin lymphoma via modified involved-site radiation therapy.

Cardiophrenic lymph nodes (CPLNs) are occasionally involved in Hodgkin lymphoma (HL). We characterized the incidence of CPLN involvement among 169 HL patients and evaluated outcomes after treatment with omission of the CPLN region from the involved-site radiation therapy (ISRT) field. Three types of RT fields were used: standard (S)-ISRT, reduced-dose (RD)-ISRT (lower dose to CPLNs, standard to other sites), or modified (M)-ISRT (omission of CPLNs). CPLNs were involved at diagnosis in 29 patients (17%). Of the 20 patients who received RT after complete response to chemotherapy, 4(20%) received S-ISRT, 8(40%) RD-ISRT, and 8(40%) M-ISRT. The four-year progression-free survival was 94.7%. One relapse occurred at a non-CPLN site after RD-ISRT. The mean heart dose and volume of the heart that received 25 Gy was higher for S-ISRT patients compared to M-ISRT (p = .043 and p = .025, respectively). Re-planning the M-ISRT cases as S-ISRT resulted in significant increase in cardiac doses.

Oxytocin Receptors in the Anteromedial Bed Nucleus of the Stria Terminalis Promote Stress-Induced Social Avoidance in Female California Mice.

BACKGROUND: The neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT. METHODS: First, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior. RESULTS: A single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses. CONCLUSIONS: Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Duodenal toxicity after fractionated chemoradiation for unresectable pancreatic cancer.

PURPOSE: Improving local control is critical to improving survival and quality of life for patients with locally advanced unresectable pancreatic cancer (LAPC). However, previous attempts at radiation dose escalation have been limited by duodenal toxicity. In order to guide future studies, we analyzed the clinical and dosimetric factors associated with duodenal toxicity in patients undergoing fractionated chemoradiation for LAPC. METHODS AND MATERIALS: Medical records and treatment plans of 106 patients with LAPC who were treated with chemoradiation between July 2005 and June 2010 at our institution were reviewed. All patients received neoadjuvant and concurrent chemotherapy. Seventy-eight patients were treated with conventional radiation to 50.4 Gy in 28 fractions; 28 patients received dose-escalated radiation therapy (range, 57.5-75.4 Gy in 28-39 fractions). Treatment-related toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. Univariate and multivariate analyses were performed to assess prognostic influence of clinical, pathologic, and treatment-related factors by using Kaplan-Meier and Cox regression methods. RESULTS: Twenty patients had treatment-related duodenal toxicity events, such as duodenal inflammation, ulceration, and bleeding. Four patients had grade 1 events, 8 had grade 2, 6 had grade 3, 1 had grade 4, and 1 had grade 5. On univariate analysis, a toxicity grade ≥2 was associated with tumor location, low platelet count, an absolute volume (cm(3)) receiving a dose of at least 55 Gy (V(55 Gy) > 1 cm(3)), and a maximum point dose >60 Gy. Of these factors, only V(55 Gy) ≥1 cm(3) was associated with duodenal toxicity on multivariate analysis (hazard ratio, 6.7; range, 2.0-18.8; P=.002). CONCLUSIONS: This study demonstrates that a duodenal V(55 Gy) >1 cm(3) is an important dosimetric predictor of grade 2 or greater duodenal toxicity and establishes it as a dosimetric constraint when treating patients with unresectable pancreatic cancer with concurrent chemoradiation.

Use of infliximab in the treatment of peripheral ulcerative keratitis in Crohn disease.

PURPOSE: To report the effectiveness of infliximab in the treatment of peripheral ulcerative keratitis (PUK) associated with Crohn disease. DESIGN: Retrospective, interventional case series. SETTING: Institutional, academic referral setting. patient or study population: Six eyes of 3 patients with PUK associated with Crohn disease that failed or were intolerant to traditional immunosuppression such as oral prednisone and cyclophosphamide. INTERVENTION OR OBSERVATION PROCEDURE(S): Infliximab intravenous infusion 5 mg/kg every 2 to 8 weeks. MAIN OUTCOME MEASURE(S): Subjective outcome such as pain improvement and objective outcomes such as visual acuity, signs of inflammation, and progression of corneal thinning. RESULTS: Symptom of pain improved in all patients. Visual acuity remained stable in 4 of 6 eyes, improved in 1 of 6 eyes, and worsened in 1 of 6 eyes (secondary to stromal scar). Rapid resolution of inflammation and arrest of further thinning were observed in all 6 eyes. Similar effects were observed on recurrence treated with repeat dosing of infliximab in 5 of 6 eyes. CONCLUSIONS: Infliximab produced a rapid, dramatic, repeatable suppression of corneal inflammation, pain, and keratolysis in PUK associated with Crohn disease. Although the effect of long-term therapy with these agents is unknown, infliximab should be considered in patients with Crohn-associated PUK not amenable to traditional therapy. Larger prospective studies are needed to determine the efficacy of infliximab in this aggressive disease entity.

Effect of brain stem and dorsal vagus complex dosimetry on nausea and vomiting in head and neck intensity-modulated radiation therapy.

Intensity-modulated radiation therapy (IMRT) is becoming the treatment of choice for many head and neck cancer patients. IMRT reduces some toxicities by reducing radiation dose to uninvolved normal tissue near tumor targets; however, other tissues not irradiated using previous 3D techniques may receive clinically significant doses, causing undesirable side effects including nausea and vomiting (NV). Irradiation of the brainstem, and more specifically, the area postrema and dorsal vagal complex (DVC), has been linked to NV. We previously reported preliminary hypothesis-generating dose effects associated with NV in IMRT patients. The goal of this study is to relate brainstem dose to NV symptoms. We retrospectively studied 100 consecutive patients that were treated for oropharyngeal cancer with IMRT. We contoured the brainstem, area postrema, and DVC with the assistance of an expert diagnostic neuroradiologist. We correlated dosimetry for the 3 areas contoured with weekly NV rates during IMRT. NV rates were significantly higher for patients who received concurrent chemotherapy. Post hoc analysis demonstrated that chemoradiation cases exhibited a trend towards the same dose-response relationship with both brainstem mean dose (p = 0.0025) and area postrema mean dose (p = 0.004); however, both failed to meet statistical significance at the p ≤ 0.002 level. Duration of toxicity was also greater for chemoradiation patients, who averaged 3.3 weeks with reported Common Terminology Criteria for Adverse Events (CTC-AE), compared with an average of 2 weeks for definitive RT patients (p = 0.002). For definitive RT cases, no dose-response trend could be ascertained. The mean brainstem dose emerged as a key parameter of interest; however, no one dose parameter (mean/median/EUD) best correlated with NV. This study does not address extraneous factors that would affect NV incidence, including the use of antiemetics, nor chemotherapy dose schedule specifics before and during RT. A prospective study will be required to depict exactly how IMRT dose affects NV.

Increased impulsivity associated with severity of suicide attempt history in patients with bipolar disorder.

BACKGROUND: Impulsivity is a prominent and measurable characteristic of bipolar disorder that can contribute to risk for suicidal behavior. The purpose of this study was to investigate the relationship between impulsivity and severity of past suicidal behavior, a potential predictor of eventual suicide, in patients with bipolar disorder. METHOD: In bipolar disorder subjects with either a definite history of attempted suicide or no such history, impulsivity was assessed with both a questionnaire (Barratt Impulsiveness Scale) and behavioral laboratory performance measures (immediate memory/delayed memory tasks). Diagnosis was determined with the Structured Clinical Interview for DSM-IV. Interviews of patients and review of records were used to determine the number of past suicide attempts and the medical severity of the most severe attempt. RESULTS: Subjects with a history of suicide attempts had more impulsive errors on the immediate memory task and had shorter response latencies, especially for impulsive responses. Impulsivity was highest in subjects with the most medically severe suicide attempts. Effects were not accounted for by presence of depression or mania at the time of testing. Barratt Impulsiveness Scale scores were numerically, but not significantly, higher in subjects with suicide attempts. A history of alcohol abuse was associated with greater probability of a suicide attempt. Multivariate analysis showed that ethanol abuse history and clinical state at the time of testing did not have a significant effect after impulsivity was taken into account. DISCUSSION: These results suggest that a history of severe suicidal behavior in patients with bipolar disorder is associated with impulsivity, manifested as a tendency toward rapid, unplanned responses.

Impulsivity: a link between bipolar disorder and substance abuse.

BACKGROUND: Substance abuse is present in most patients with bipolar disorder and associated with poor treatment outcome and increased risk of suicide. Increased impulsivity may be a link between bipolar disorder and substance abuse. METHODS: First, we compared impulsivity as a stable trait (Barratt Impulsiveness Scale, BIS) and as state-dependent behavioral laboratory performance (Immediate Memory-Delayed Memory task, derived from the Continuous Performance Task) in interepisode bipolar and non-bipolar subjects with and without substance abuse. Secondly, we compared impulsivity in interepisode and manic bipolar subjects with and without substance abuse. RESULTS: The BIS scores were increased in interepisode bipolar disorder and in subjects with histories of substance abuse, and were increased further in interepisode bipolar subjects with substance abuse. Performance impulsivity was increased in subjects with substance abuse, regardless of whether they had bipolar disorder. Among subjects with bipolar disorder, after correction for age, BIS scores were increased in those with substance abuse. Performance impulsivity was increased in manic compared with interepisode subjects, regardless of substance abuse history, and was increased in interepisode subjects with substance abuse similarly to manic subjects without substance abuse. These differences could not be accounted for by age, gender, or course of illness. CONCLUSIONS: Trait impulsivity is increased additively in bipolar disorder and substance abuse. Performance impulsivity is increased in interepisode bipolar disorder only if a history of substance abuse is present. This increased predisposition to impulsivity when not manic may contribute to the decrement in treatment outcome and compliance, and increased risk for suicide and aggression, in bipolar disorder with substance abuse.