Penile-scrotal erythrodysesthesia among rectal cancer patients receiving fluoropyrimidine-based chemoradiation: a case report series.

BACKGROUND: Palmar-plantar erythrodysesthesia (PPE) is a slowly developing cutaneous reaction commonly experienced by patients treated with fluoropyrimidines. While erythrodysesthesia normally presents in a palmar-plantar distribution, it can also present with genital involvement, but this presentation is likely underreported and incorrectly attributed to an acute reaction from radiation therapy. This article aims to define erythrodysesthesia of the penis and scrotum as a rare but significant side effect of capecitabine. CASE PRESENTATION: We identified five cases of moderate to severe penis and scrotal erythrodysesthesia over a 2-year period at a large tertiary cancer center, representing an estimated incidence of 3.6% among male patients with rectal cancer who were treated with fluoropyrimidine-based chemoradiation within our institution. CONCLUSIONS: Improved understanding of erythrodysesthesia involving the penis and scrotum can facilitate early identification and treatment of symptoms, and possibly prevent the discontinuation or delay of cancer treatment in patients treated with capecitabine and similar drugs. These clinical advances would improve and prolong patient quality of life during cancer treatment and prevent complications that result in hospitalization.

Multicenter registry and test bed for extended outpatient hemodynamic monitoring: the hemodynamic frontiers in heart failure (HF2) initiative.

Background: Hemodynamic Frontiers in Heart Failure (HF2) is a multicenter academic research consortium comprised of 14 US institutions with mature remote monitoring programs for ambulatory patients with heart failure (HF). The consortium developed a retrospective and prospective registry of patients implanted with a wireless pulmonary artery pressure (PAP) sensor. Goals/aims: HF2 registry collects demographic, clinical, laboratory, echocardiographic (ECHO), and hemodynamic data from patients with PAP sensors. The aims of HF2 are to advance understanding of HF and to accelerate development of novel diagnostic and therapeutic innovations. Methods: HF2 includes adult patients implanted with a PAP sensor as per FDA indications (New York Heart Association (NYHA) Class III HF functional class with a prior hospitalization, or patients with NYHA Class II or brain natriuretic peptide (BNP) elevation without hospitalization) at a HF2 member site between 1/1/19 to present. HF2 registry is maintained at University of Kansas Medical Center (KUMC). The registry was approved by the institutional review board (IRB) at all participating institutions with required data use agreements. Institutions report data into the electronic registry database using REDCap, housed at KUMC. Results: This initial data set includes 254 patients implanted from the start of 2019 until May 2023. At time of device implant, the cohort average age is 73 years old, 59.8% are male, 72% have NYHA Class III HF, 40% have left ventricular ejection fraction (LVEF) < 40%, 35% have LVEF > 50%, mean BNP is 560 pg/ml, mean N-Terminal pro-BNP (NTproBNP) is 5,490 pg/ml, mean creatinine is 1.65 mg/dl. Average baseline hemodynamics at device implant are right atrial pressure (RAP) of 11 mmHg, pulmonary artery systolic pressure (PASP) of 47 mmHg, pulmonary artery diastolic pressure (PADP) 21 mmHg, mean pulmonary artery pressure (mPAP) of 20 mmHg, pulmonary capillary wedge pressure (PCWP) of 19 mmHg, cardiac output (CO) of 5.3 L/min, and cardiac index (CI) of 2.5 L/min/m2. Conclusion: A real-world registry of patients implanted with a PAP sensor enables long-term evaluation of hemodynamic and clinic outcomes in highly-phenotyped ambulatory HF patients, and creates a unique opportunity to validate and test novel diagnostic and therapeutic approaches to HF.

KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios-KLRG1+ subset of tumor-infiltrating regulatory T cells was associated with tumor progression from immune equilibrium to escape and was also lost in tumors responding to ICB. Validation studies confirmed KLRG1 signatures in human tumor-infiltrating CD4 T cells associate with disease progression in renal cancer. These findings nominate KLRG1+ CD4 T cell populations as subsets for further investigation in cancer immunity and demonstrate the utility of longitudinal spectral flow profiling as an engine of dynamic biomarker discovery.

Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators.

Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive immuno-oncology targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate master regulators (MRs) as mechanistic determinants of TI-Treg transcriptional state. Pooled CRISPR-Cas9 screening in vivo, using a chimeric hematopoietic stem cell transplant model, confirmed the essentiality of eight MRs in TI-Treg recruitment and/or retention without affecting other T cell subtypes, and targeting one of the most significant MRs (Trps1) by CRISPR KO significantly reduced ectopic tumor growth. Analysis of drugs capable of inverting TI-Treg MR activity identified low-dose gemcitabine as the top prediction. Indeed, gemcitabine treatment inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased anti-PD-1 efficacy, and depleted MR-expressing TI-Tregs in vivo. This study provides key insight into Treg signaling, specifically in the context of cancer, and a generalizable strategy to systematically elucidate and target MR proteins in immunosuppressive subpopulations.

Impact of exercise on pulmonary artery pressure in patients with heart failure using an ambulatory pulmonary artery pressure monitor.

Background: In this multicenter prospective study, we explored the relationship between pulmonary artery pressure (PAP) at rest and in response to a 6-min walk test (6MWT) in ambulatory patients with heart failure (HF) with an implantable PAP sensor (CardioMEMS, Abbott). Methods: Between 5/2019 and 2/2021, HF patients with a CardioMEMS sensor were recruited from seven sites. PAP was recorded in the supine and seated position at rest and in the seated position immediately post-exercise. Results: In our cohort of 66 patients, mean age was 70 ± 12 years, 67% male, left ventricular ejection fraction (LVEF) < 50% in 53%, mean 6MWT distance was 277 ± 95 meters. Resting seated PAPs were 31 ± 15 mmHg (systolic), 13 ± 8 mmHg (diastolic), and 20 ± 11 mmHg (mean). The pressures were lower in the seated rather than the supine position. After 6MWT, the pressures increased to PAP systolic 37 ± 19 mmHg (p < 0.0001), diastolic 15 ± 10 mmHg (p = 0.006), and mean 24 ± 13 mmHg (p < 0.0001). Patients with elevated PAP diastolic at rest (>15 mmHg) demonstrated a greater increase in post-exercise PAP. Conclusion: The measurement of PAP with CardioMEMS is feasible immediately post-exercise. Despite being well-managed, patients had severely limited functional capacity. We observed a significant increase in PAP with ambulation which was greater in patients with higher baseline pressures.

KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response.

Current methods for biomarker discovery and target identification in immuno-oncology rely on static snapshots of tumor immunity. To thoroughly characterize the temporal nature of antitumor immune responses, we developed a 34-parameter spectral flow cytometry panel and performed high-throughput analyses in critical contexts. We leveraged two distinct preclinical models that recapitulate cancer immunoediting (NPK-C1) and immune checkpoint blockade (ICB) response (MC38), respectively, and profiled multiple relevant tissues at and around key inflection points of immune surveillance and escape and/or ICB response. Machine learning-driven data analysis revealed a pattern of KLRG1 expression that uniquely identified intratumoral effector CD4 T cell populations that constitutively associate with tumor burden across tumor models, and are lost in tumors undergoing regression in response to ICB. Similarly, a Helios - KLRG1 + subset of tumor-infiltrating regulatory T cells (Tregs) was associated with tumor progression from immune equilibrium to escape, and were also lost in tumors responding to ICB. Validation studies confirmed KLRG1 signatures in human tumorinfiltrating CD4 T cells associate with disease progression in renal cancer. These findings nominate KLRG1 + CD4 T cell populations as subsets for further investigation in cancer immunity and demonstrate the utility of longitudinal spectral flow profiling as an engine of dynamic biomarker and/or target discovery.

Quantifying clinical severity of physics errors in high-dose rate prostate brachytherapy using simulations.

PURPOSE: To quantitatively evaluate through automated simulations the clinical significance of potential high-dose rate (HDR) prostate brachytherapy (HDRPB) physics errors selected from our internal failure-modes and effect analysis (FMEA). METHODS AND MATERIALS: A list of failure modes was compiled and scored independently by 8 brachytherapy physicists on a one-to-ten scale for severity (S), occurrence (O), and detectability (D), with risk priority number (RPN) = SxOxD. Variability of RPNs across observers (standard deviation/average) was calculated. Six idealized HDRPB plans were generated, and error simulations were performed: single (N = 1722) and systematic (N = 126) catheter shifts (craniocaudal; -1cm:1 cm); single catheter digitization errors (tip and connector needle-tips displaced independently in random directions; 0.1 cm:0.5 cm; N = 44,318); and swaps (two catheters swapped during digitization or connection; N = 528). The deviations due to each error in prostate D90%, urethra D20%, and rectum D1cm3 were analyzed using two thresholds: 5-20% (possible clinical impact) and >20% (potentially reportable events). RESULTS: Twenty-nine relevant failure modes were described. Overall, RPNs ranged from 6 to 108 (average ± 1 standard deviation, 46 ± 23), with responder variability ranging from 19% to 184% (average 75% ± 30%). Potentially reportable events were observed in the simulations for systematic shifts >0.4 cm for prostate and digitization errors >0.3 cm for the urethra and >0.4 cm for rectum. Possible clinical impact was observed for catheter swaps (all organs), systematic shifts >0.2 cm for prostate and >0.4 cm for rectum, and digitization errors >0.2 cm for prostate and >0.1 cm for urethra and rectum. CONCLUSIONS: A high variability in RPN scores was observed. Systematic simulations can provide insight in the severity scoring of multiple failure modes, supplementing typical FMEA approaches.

Demographic diversity of participants in Pfizer sponsored clinical trials in the United States.

The approval of new medicinal agents requires robust efficacy and safety clinical trial data demonstrated to be applicable to population subgroups. Limited data have previously been reported by drug sponsors on the topic of clinical trial diversity. In order to establish a baseline of diversity in our clinical trials that can be used by us and other sponsors, an analysis of clinical trial diversity was conducted covering race, ethnicity, sex, and age. This analysis includes Pfizer interventional clinical trials that initiated enrollment between 2011 through 2020. The data set comprises 213 trials with 103,103 US participants. The analysis demonstrated that overall trial participation of Black or African American individuals was at the US census level (14.3% vs 13.4%), participation of Hispanic or Latino individuals was below US census (15.9% vs 18.5%), and female participation was at US census (51.1% vs 50.8%). The analysis also examined the percentage of trials that achieved racial and ethnic distribution levels at or above census levels. Participant levels above census were achieved in 56.1% of Pfizer trials for Black or African American participants, 51.4% of trials for White participants, 16.0% of trials for Asian participants, 14.2% of trials for Native Hawaiian and Pacific Islander participants, 8.5% of trials for American Indian and Alaska Native participants, and 52.3% of trials for Hispanic or Latino participants. The results presented here provide a baseline upon which we can quantify the impact of our ongoing efforts to improve racial and ethnic diversity in clinical trials.

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain.

Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. Furthermore, we found that in murine cerebral cortical neurons and induced pluripotent stem cell (iPSC)-derived neurons prepared from healthy human donors, most of this uPA is associated with pre-synaptic vesicles. Our in vivo experiments revealed that in both, the gyrencephalic cortex of the non-human primate and the lissecephalic murine brain, cerebral ischemia decreases the number of intact synaptic contacts and the expression of uPA and NCAD in a band of tissue surrounding the necrotic core. Additionally, our in vitro data show that uPA induces the synthesis of NCAD in cerebral cortical neurons, and in line with these observations, intravenous treatment with recombinant uPA three hours after the onset of cerebral ischemia induces NCAD-mediated repair of synaptic contacts in the area surrounding the necrotic core.

A 75-Year-Old Woman with COVID-19 Pneumonia and Wellens Syndrome Diagnosed by Electrocardiography.

BACKGROUND There are increasing reports of cardiovascular complications associated with coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2. Wellens syndrome, or left anterior descending T-wave syndrome, is diagnosed by a pattern of electrocardiographic (ECG) changes that include inverted or biphasic T waves in leads V2-V3. CASE REPORT A 75-year-old woman presented to the emergency department with a 1-week history of fatigue and progressive shortness of breath who acutely decompensated, necessitating mechanical ventilator support. Initial lab workup revealed COVID-19 positivity, which was confirmed by repeat testing. A routine ECG obtained during her hospitalization and compared with her baseline revealed diffuse T-wave inversions of her precordial leads, which was highly suggestive of Wellens syndrome. Cardiac enzymes obtained were slightly elevated and an echocardiogram did not demonstrate wall motion abnormalities. The patient was initiated on non-ST segment elevation myocardial infarction protocol with heparin infusion for 48 hours and dual antiplatelet therapy, in addition to beta blockade. Repeat ECGs showed complete resolution of Wellens syndrome shortly after therapy. CONCLUSIONS Although rare, Wellens syndrome is a significant indicator of left anterior descending artery stenosis and is commonly associated with acute medical illness. COVID-19 pneumonia has been associated with many adverse cardiovascular outcomes, with ischemia and arrhythmia becoming increasingly more common. Diagnosis of Wellens often includes coronary angiography; however, during the current pandemic, many authorities have recommended medical management alone during the acute phase of care, depending on the severity of concomitant illness.

Hypofractionated spinal stereotactic body radiation therapy for high-grade epidural disease.

OBJECTIVE: To characterize the clinical outcomes when stereotactic body radiation therapy (SBRT) alone is used to treat high-grade epidural disease without prior surgical decompression, the authors conducted a retrospective cohort study of patients treated at the Memorial Sloan Kettering Cancer Center between 2014 and 2018. The authors report locoregional failure (LRF) for a cohort of 31 cases treated with hypofractionated SBRT alone for grade 2 epidural spinal cord compression (ESCC) with radioresistant primary cancer histology. METHODS: High-grade epidural disease was defined as grade 2 ESCC, which is notable for radiographic deformation of the spinal cord by metastatic disease. Kaplan-Meier survival curves and cumulative incidence functions were generated to examine the survival and incidence experiences of the sample level with respect to overall survival, LRF, and subsequent requirement of vertebral same-level surgery (SLS) due to tumor progression or fracture. Associations with dosimetric analysis were also examined. RESULTS: Twenty-nine patients undergoing 31 episodes of hypofractionated SBRT alone for grade 2 ESCC between 2014 and 2018 were identified. The 1-year and 2-year cumulative incidences of LRF were 10.4% (95% CI 0-21.9) and 22.0% (95% CI 5.5-38.4), respectively. The median survival was 9.81 months (95% CI 8.12-18.54). The 1-year cumulative incidence of SLS was 6.8% (95% CI 0-16.0) and the 2-year incidence of SLS was 14.5% (95% CI 0.6-28.4). All patients who progressed to requiring surgery had index lesions at the thoracic apex (T5-7). CONCLUSIONS: In carefully selected patients, treatment of grade 2 ESCC disease with hypofractionated SBRT alone offers a 1-year cumulative incidence of LRF similar to that in low-grade ESCC and postseparation surgery adjuvant hypofractionated SBRT. Use of SBRT alone has a favorable safety profile and a low cumulative incidence of progressive disease requiring open surgical intervention (14.5%).

Urokinase-Type Plasminogen Activator Protects Cerebral Cortical Neurons from Soluble Aß-Induced Synaptic Damage.

Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aß and correlates with the development of cognitive deficits better than the number of plaques. The mammalian plasminogen activation (PA) system catalyzes the generation of plasmin via two activators: tissue-type (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of Aß plaques in advanced stages of AD. In contrast, it is unknown whether uPA and its receptor (uPAR) contribute to the pathogenesis of this disease. Neuronal cadherin (NCAD) plays a pivotal role in the formation of synapses and dendritic branches, and Aß decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aß on the synapse. In line with these observations, the synaptic abundance of uPA, but not uPAR, is decreased in the frontal cortex of AD patients and 5xFAD mice, and in cerebral cortical neurons incubated with soluble Aß. We found that uPA treatment increases the synaptic expression of NCAD by a uPAR-mediated plasmin-independent mechanism, and that uPA-induced formation of NCAD dimers protects the synapse from the harmful effects of soluble Aß oligomers. These data indicate that Aß-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.SIGNIFICANCE STATEMENT Soluble amyloid ß (Aß)-induced synaptic dysfunction is an early event in the pathogenesis of cognitive deficits in Alzheimer's disease (AD). We found that neuronal urokinase-type (uPA) protects the synapse from the deleterious effects of soluble Aß. However, Aß-induced inactivation of the eukaryotic initiation factor 2α decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Aß on the synapse. In line with these observations, the synaptic expression of uPA is decreased in the frontal cortex of AD brains and 5xFAD mice, and uPA treatment abrogates the deleterious effects of Aß on the synapse. These results unveil a novel mechanism of Aß-induced synaptic dysfunction in AD patients, and indicate that recombinant uPA is a potential therapeutic strategy to protect the synapse before the development of irreversible brain damage.

Internal Jugular Vein as Alternative Access for Implantation of a Wireless Pulmonary Artery Pressure Sensor.

BACKGROUND: A wireless pulmonary artery pressure sensor (CardioMEMS) is approved for implantation via the femoral vein. The internal jugular vein (IJ) is an attractive alternative access route commonly used in pulmonary artery catheterization. METHODS AND RESULTS: Retrospective chart review was performed for all sensor implants from 10 providers at 4 centers from September 2016 to June 2018. To compare procedural outcomes and discharge efficiency between groups, multivariate analyses incorporating potential confounders were performed. Seventy-three (28%) patients had femoral access, and 189 (72%) had IJ access; demographics were similar between the groups. Complications, including one case of hematoma and 4 cases of mild hemoptysis, and 30-day mortality (2%-3%) did not differ between groups. Provider preference for IJ access substantially increased over time, with IJ accounting for 90% of cases in 2018. After risk-adjustment, IJ cases had 20% (5%-33%) shorter fluoroscopy time (P=0.01) and 24% (7%-38%) lower contrast volume (P=0.008). Compared with outpatient femoral cases, outpatient IJ cases had 62% (52%-69%) faster needle-to-door time and were 34 times (6-235) more likely to have same-day discharge (P<0.001 for both). CONCLUSIONS: IJ access for CardioMEMS implant is a safe alternative associated with superior procedural and discharge outcomes. Implanters at 4 high-volume centers adopted IJ access as the preferred implant approach.

Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal.

Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin-dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35 (also known as Cdk5r1), a membrane-anchored protein that is rapidly degraded by the proteasome. Here, we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-methyl-D-aspartate (NMDA) receptors. We show that tPA treatment increases the abundance of p35 and its binding to Cdk5 in the postsynaptic density (PSD). Furthermore, our data indicate that tPA-induced p35-mediated Cdk5 activation does not induce cell death, but instead prevents NMDA-induced ubiquitylation of postsynaptic density protein-95 (PSD-95; also known as Dlg4) and the removal of GluR1 (also known as Gria1)-containing α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors from the PSD. These results show that the interaction between tPA and synaptic NMDA receptors regulates the expression of AMPA receptor subunits in the PSD via p35-mediated Cdk5 activation. This is a novel role for tPA as a regulator of Cdk5 activation in cerebral cortical neurons.

A prospective study of ¹8FDG-PET with CT coregistration for radiation treatment planning of lymphomas and other hematologic malignancies.

PURPOSE: This prospective single-institution study examined the impact of positron emission tomography (PET) with the use of 2-[(18)F] fluoro-2-deoxyglucose and computed tomography (CT) scan radiation treatment planning (TP) on target volume definition in lymphoma. METHODS AND MATERIALS: 118 patients underwent PET/CT TP during June 2007 to May 2009. Gross tumor volume (GTV) was contoured on CT-only and PET/CT studies by radiation oncologists (ROs) and nuclear medicine physicians (NMPs) for 95 patients with positive PET scans. Treatment plans and dose-volume histograms were generated for CT-only and PET/CT for 95 evaluable sites. Paired t test statistics and Pearson correlation coefficients were used for analysis. RESULTS: 70 (74%) patients had non-Hodgkin lymphoma, 10 (11%) had Hodgkin lymphoma, 12 (10%) had plasma-cell neoplasm, and 3 (3%) had other hematologic malignancies. Forty-three (45%) presented with relapsed/refractory disease. Forty-five (47%) received no prior chemotherapy. The addition of PET increased GTV as defined by ROs in 38 patients (median, 27%; range, 5%-70%) and decreased GTV in 41 (median, 39.5%; range, 5%-80%). The addition of PET increased GTV as defined by NMPs in 27 patients (median, 26.5%; range, 5%-95%) and decreased GTV in 52 (median, 70%; range, 5%-99%). The intraobserver correlation between CT-GTV and PET-GTV was higher for ROs than for NMPs (0.94, P<.01 vs 0.89, P<.01). On the basis of Bland-Altman plots, the PET-GTVs defined by ROs were larger than those defined by NMPs. On evaluation of clinical TPs, only 4 (4%) patients had inadequate target coverage (D95 <95%) of the PET-GTV defined by NMPs. CONCLUSIONS: Significant differences between the RO and NMP volumes were identified when PET was coregistered to CT for radiation planning. Despite this, the PET-GTV defined by ROs and NMPs received acceptable prescription dose in nearly all patients. However, given the potential for a marginal miss, consultation with an experienced PET reader is highly encouraged when PET/CT volumes are delineated, particularly for questionable lesions and to assure complete and accurate target volume coverage.

Correlation of Planned Dose to Area Postrema and Dorsal Vagal Complex with Clinical Symptoms of Nausea and Vomiting in Oropharyngeal Cancer (OPC) patients treated with radiation alone using IMRT.

OBJECTIVE: To correlate the planned dose to the nausea center (NC) - area postrema (AP) and dorsal vagal complex (DVC) - with nausea and vomiting symptoms in OPC patients treated with IMRT without chemotherapy. We also investigated whether it was possible to reduce doses to the NC without significant degradation of the clinically accepted treatment plan. METHODS: From 11/04 to 4/09, 37 OPC patients were treated with definitive or adjuvant IMRT without chemotherapy. Of these, only 23 patients had restorable plans and were included in this analysis. We contoured the NC with the assistance of an expert board-certified neuroradiologist. We searched for correlation between the delivered dose to the NC and patient-reported nausea and vomiting during IMRT. We used one-paired t-test: two-sample assuming equal variances to compare differences in dose to NC between symptomatic and asymptomatic patients. We then replanned each case to determine if reduced dose to the NC could be achieved without compromising coverage to target volumes, increasing unwarranted hotspots or increasing dose to surrounding critical normal tissues. RESULTS: Acute symptoms of nausea were as follows: Grade 0 (n=6), Grade 1 (n=13), Grade 2 (n=3), and Grade 3 (n=1). Patients with no complaints of nausea had a median dose to the DVC of 34.2 Gy (range 4.6-46.6 Gy) and AP of 32.6 Gy (range 7.0-41.4Gy); whereas those with any complaints of nausea had a median DVC dose of 40.4 Gy (range 19.3-49.4 Gy) and AP dose of 38.7 Gy (range 16.7-46.8 Gy) (p=0.04). Acute vomiting was as follows: Grade 0 (n=17), Grade 1 (n=4), Grade 2 (n=1), and Grade 3 (n=1). There was no significant difference in DVC or AP dose among those with and without vomiting symptoms (p=0.28).Upon replanning of each case to minimize dose to the NC, we were, on average, able to reduce the radiation dose to AP by 18% and DVC by 17%; while the average dose variations to the PTV coverage, brainstem, cord, temporal lobes, and cochlea were never greater than 3%. Hotspots increased by 2% for 3 patients while hotspots for remaining patients were less than 2% variation. CONCLUSION: For OPC cancer patients treated with IMRT without chemotherapy, dose to AP and DVC may be associated with development of nausea. We were able to show that reducing doses substantially to the NC is achievable without significant alteration of the clinically accepted plan and may reduce the incidence and grade of nausea. As symptoms of nausea can be devastating to patients, one can consider routine contouring and constraining of the NC to minimize chances of having this complication.