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PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

We use establishment-level data from the US Census Bureau's Annual Survey of Manufactures to study the characteristics and geographic locations of investments in robots. We find that the distribution of robots is highly skewed across locations. Some locations, which we call Robot Hubs, have far more robots than one would expect even after accounting for industry and manufacturing employment. We characterize these Robot Hubs along several industry, demographic, and institutional dimensions. The presences of robot integrators, which specialize in helping manufacturers install robots, and of higher levels of union membership are positively correlated with being a Robot Hub.

Human learning and decision-making are supported by multiple systems operating in parallel. Recent studies isolating the contributions of reinforcement learning (RL) and working memory (WM) have revealed a trade-off between the two. An interactive WM/RL computational model predicts that although high WM load slows behavioral acquisition, it also induces larger prediction errors in the RL system that enhance robustness and retention of learned behaviors. Here, we tested this account by parametrically manipulating WM load during RL in conjunction with EEG in both male and female participants and administered two surprise memory tests. We further leveraged single-trial decoding of EEG signatures of RL and WM to determine whether their interaction predicted robust retention. Consistent with the model, behavioral learning was slower for associations acquired under higher load but showed parametrically improved future retention. This paradoxical result was mirrored by EEG indices of RL, which were strengthened under higher WM loads and predictive of more robust future behavioral retention of learned stimulus–response contingencies. We further tested whether stress alters the ability to shift between the two systems strategically to maximize immediate learning versus retention of information and found that induced stress had only a limited effect on this trade-off. The present results offer a deeper understanding of the cooperative interaction between WM and RL and show that relying on WM can benefit the rapid acquisition of choice behavior during learning but impairs retention.SIGNIFICANCE STATEMENTSuccessful learning is achieved by the joint contribution of the dopaminergic RL system and WM. The cooperative WM/RL model was productive in improving our understanding of the interplay between the two systems during learning, demonstrating that reliance on RL computations is modulated by WM load. However, the role of WM/RL systems in the retention of learned stimulus–response associations remained unestablished. Our results show that increased neural signatures of learning, indicative of greater RL computation, under high WM load also predicted better stimulus–response retention. This result supports a trade-off between the two systems, where degraded WM increases RL processing, which improves retention. Notably, we show that this cooperative interplay remains largely unaffected by acute stress.

Background Prior evidence indicates that negative symptom severity and cognitive deficits, in people with schizophrenia (PSZ), relate to measures of reward-seeking and loss-avoidance behavior (implicating the ventral striatum/VS), as well as uncertainty-driven exploration (reliant on rostrolateral prefrontal cortex/rlPFC). While neural correlates of reward-seeking and loss-avoidance have been examined in PSZ, neural correlates of uncertainty-driven exploration have not. Understanding neural correlates of uncertainty-driven exploration is an important next step that could reveal insights to how this mechanism of cognitive and negative symptoms manifest at a neural level. Methods We acquired fMRI data from 29 PSZ and 36 controls performing the Temporal Utility Integration decision-making task. Computational analyses estimated parameters corresponding to learning rates for both positive and negative reward prediction errors (RPEs) and the degree to which participates relied on representations of relative uncertainty. Trial-wise estimates of expected value, certainty, and RPEs were generated to model fMRI data. Results Behaviorally, PSZ demonstrated reduced reward-seeking behavior compared to controls, and negative symptoms were positively correlated with loss-avoidance behavior. This finding of a bias toward loss avoidance learning in PSZ is consistent with previous work. Surprisingly, neither behavioral measures of exploration nor neural correlates of uncertainty in the rlPFC differed significantly between groups. However, we showed that trial-wise estimates of relative uncertainty in the rlPFC distinguished participants who engaged in exploratory behavior from those who did not. rlPFC activation was positively associated with intellectual function. Conclusions These results further elucidate the nature of reinforcement learning and decision-making in PSZ and healthy volunteers.

Patients with interstitial lung disease (ILD), especially those with pulmonary fibrosis, are at increased risk of developing lung cancer. Management of lung cancer in patients with ILD is particularly challenging. Diagnosis can be complicated by difficulty differentiating lung nodules from areas of focal fibrosis, and percutaneous biopsy approaches confer an increased risk of complications in those with pulmonary fibrosis. Lung cancer treatment in these patients pose several specific considerations. The degree of lung function impairment may preclude lobectomy or surgical resection of any type. Surgical resection can trigger an acute exacerbation of the underlying ILD. The presence of ILD confers an increased risk of pneumonitis with radiotherapy, and many of the systemic therapies also carry an increased risk of pneumonitis in this population. The safety of immunotherapy in the setting of ILD remains to be fully elucidated and concerns remain as to triggering pneumonitis. The purpose of this review is to summarize the evidence regarding consideration for tissue diagnosis, chemotherapy and immunotherapy, radiotherapy, and surgery, in this patient population and discuss emerging areas of research. We also propose a multidisciplinary approach and practical considerations for monitoring for ILD progression during lung cancer treatment.

BACKGROUND: The Visual Vertigo Analogue Scale (VVAS) assesses visual vertigo. Instead of the original scoring methods (positive VVAS > 1), we propose categorizing patients as having No (0), Mild (0.1–40), Moderate (40.01–70), or Severe (70.01–100) symptoms. OBJECTIVE: Our primary aim was to validate an alternative interpretation of the VVAS by exploring the relationship between categories of visual vertigo symptoms and measures of activity and participation, dizziness handicap, anxiety, and depression. We aimed to describe the severity of visual vertigo reported by patients in different vestibular diagnostic categories. METHODS: Participants with vestibular disorders (n = 250) completed the VVAS, Vestibular Activities and Participation (VAP) Measure, Dizziness Handicap Inventory (DHI), and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Patients with central disorders were more symptomatic than those with peripheral vestibular disorders. As evaluated by one-way ANOVA, the scores on the VAP, HADS, and DHI significantly differed among mild, moderate, severe, and no visual vertigo categories (p

Background Psychiatric diagnosis and treatment have historically taken a symptom-based approach, with less attention on identifying underlying symptom-producing mechanisms. Recent efforts have illuminated the extent to which different underlying circuitry can produce phenotypically similar symptomatology (e.g., psychosis in bipolar disorder vs. schizophrenia). Computational modeling makes it possible to identify and mathematically differentiate behaviorally unobservable, specific reinforcement learning differences in patients with schizophrenia versus other disorders, likely owing to a higher reliance on prediction error–driven learning associated with basal ganglia and underreliance on explicit value representations associated with orbitofrontal cortex. Methods We used a well-established probabilistic reinforcement learning task to replicate those findings in individuals with schizophrenia both on (n = 120) and off (n = 44) antipsychotic medications and included a patient comparison group of bipolar patients with psychosis (n = 60) and healthy control subjects (n = 72). Results Using accuracy, there was a main effect of group (F3,279 = 7.87, p Conclusions Both medicated and unmedicated patients showed overreliance on prediction error–driven learning as well as significantly higher noise and value-related memory decay, compared with the healthy control subjects and the patients with bipolar disorder. Additionally, the computational model parameters capturing these processes can significantly improve patient/control classification, potentially providing useful diagnosis insight.

Cognitive theories of depression, and mindfulness theories of well-being, converge on the notion that self-judgment plays a critical role in mental health. However, these theories have rarely been tested via tasks and computational modeling analyses that can disentangle the information processes operative in self-judgments. We applied a drift-diffusion computational model to the self-referential encoding task (SRET) collected before and after an 8-week mindfulness intervention (n = 96). A drift-rate regression parameter representing positive-relative to negative-self-referential judgment strength positively related to mindful awareness and inversely related to depression, both at baseline and over time; however, this parameter did not significantly relate to the interaction between mindful awareness and nonjudgmentalness. At the level of individual depression symptoms, at baseline, a spectrum of symptoms (inversely) correlated with the drift-rate regression parameter, suggesting that many distinct depression symptoms relate to valenced self-judgment between subjects. By contrast, over the intervention, changes in only a smaller subset of anhedonia-related depression symptoms showed substantial relationships with this parameter. Both behavioral and model-derived measures showed modest split-half and test-retest correlations. Results support cognitive theories that implicate self-judgment in depression and mindfulness theories, which imply that mindful awareness should lead to more positive self-views.

The goal of this study was to evaluate disease, survival, and toxic effects after unilateral radiation therapy treatment for tonsillar cancer.A retrospective study was performed of patients treated at our institution within the period from 2000 to 2018. Summary statistics were used to assess the cohort by patient characteristics and treatments delivered. The Kaplan-Meier method was used to determine survival outcomes.The cohort comprised 403 patients, including 343 (85%) with clinical and/or radiographic evidence of ipsilateral cervical nodal disease and 181 (45%) with multiple involved nodes. Human papillomavirus was detected in 294 (73%) tumors. Median follow-up time was 5.8 years. Disease relapse was infrequent with local recurrence in 9 (2%) patients, neck recurrence in 13 (3%) patients, and recurrence in the unirradiated contralateral neck in 9 (2%) patients. Five- and 10-year overall survival rates were 94% and 89%, respectively. Gastrostomy tubes were needed in 32 (9%) patients, and no patient had a feeding tube 6 months after therapy.For patients with well-lateralized tonsillar tumors and no clinically evident adenopathy of the contralateral neck, unilateral radiation therapy offers favorable rates of disease outcomes and a relatively low toxicity profile.

OBJECTIVE The Affordable Care Act mandates that primary preventive services have no out-of-pocket costs but does not exempt secondary prevention from out-of-pocket costs. Most commercially insured patients with diabetes have high-deductible health plans (HDHPs) that subject key microvascular disease–related services to high out-of-pocket costs. Brief treatment delays can significantly worsen microvascular disease outcomes. RESEARCH DESIGN AND METHODS This cohort study used a large national commercial (and Medicare Advantage) health insurance claims data set to examine matched groups before and after an insurance design change. The study group included 50,790 patients with diabetes who were continuously enrolled in low-deductible (≤$500) health plans during a baseline year, followed by up to 4 years in high-deductible (≥$1,000) plans after an employer-mandated switch. HDHPs had low out-of-pocket costs for nephropathy screening but not retinopathy screening. A matched control group included 335,178 patients with diabetes who were contemporaneously enrolled in low-deductible plans. Measures included time to first detected microvascular disease screening, severe microvascular disease diagnosis, vision loss diagnosis/treatment, and renal function loss diagnosis/treatment. RESULTS HDHP enrollment was associated with relative delays in retinopathy screening (0.7 months [95% CI 0.4, 1.0]), severe retinopathy diagnosis (2.9 months [0.5, 5.3]), and vision loss diagnosis/treatment (3.8 months [1.2, 6.3]). Nephropathy-associated measures did not change to a statistically significant degree among HDHP members relative to control subjects at follow-up. CONCLUSIONS People with diabetes in HDHPs experienced delayed retinopathy diagnosis and vision loss diagnosis/treatment of up to 3.8 months compared with low-deductible plan enrollees. Findings raise concerns about visual health among HDHP members and call attention to discrepancies in Affordable Care Act cost sharing exemptions.

Purpose Transarterial radioembolization (TARE) is a treatment for liver tumours based on injection of radioactive microspheres in the hepatic arterial system. It is crucial to achieve a maximum tumour dose for an optimal treatment response, while minimizing healthy liver dose to prevent toxicity. There is, however, no intraprocedural feedback on the dose distribution, as nuclear imaging can only be performed after treatment. As holmium-166 (166Ho) microspheres can be quantified with MRI, we investigate the feasibility and safety of performing 166Ho TARE within an MRI scanner and explore the potential of intraprocedural MRI-based dosimetry. Methods Six patients were treated with 166Ho TARE in a hybrid operating room. Per injection position, a microcatheter was placed under angiography guidance, after which patients were transported to an adjacent 3-T MRI system. After MRI confirmation of unchanged catheter location, 166Ho microspheres were injected in four fractions, consisting of 10%, 30%, 30% and 30% of the planned activity, alternated with holmium-sensitive MRI acquisition to assess the microsphere distribution. After the procedures, MRI-based dose maps were calculated from each intraprocedural image series using a dedicated dosimetry software package for 166Ho TARE. Results Administration of 166Ho microspheres within the MRI scanner was feasible in 9/11 (82%) injection positions. Intraprocedural holmium-sensitive MRI allowed for tumour dosimetry in 18/19 (95%) of treated tumours. Two CTCAE grade 3–4 toxicities were observed, and no adverse events were attributed to treatment in the MRI. Towards the last fraction, 4/18 tumours exhibited signs of saturation, while in 14/18 tumours, the microsphere uptake patterns did not deviate from the linear trend. Conclusion This study demonstrated feasibility and preliminary safety of a first in-human application of TARE within a clinical MRI system. Intraprocedural MRI-based dosimetry enabled dynamic insight in the microsphere distribution during TARE. This proof of concept yields unique possibilities to better understand microsphere distribution in vivo and to potentially optimize treatment efficacy through treatment personalization. Registration Clinicaltrials.gov, identifier NCT04269499, registered on February 13, 2020 (retrospectively registered).

Quantifying the interobserver variability (IoV) of prostate and periprostatic anatomy delineation on prostate MRI is necessary to inform its use for treatment planning, treatment delivery, and treatment quality assessment.Twenty five prostate cancer patients underwent MRI-based low-dose-rate prostate brachytherapy (LDRPBT). The patients were scanned with a 3D T2-weighted sequence for treatment planning and a 3D T2/T1-weighted sequence for quality assessment. Seven observers involved with the LDRPBT workflow delineated the prostate, external urinary sphincter (EUS), seminal vesicles, rectum, and bladder on all 50 MRIs. IoV was assessed by measuring contour similarity metrics, differences in organ volumes, and differences in dosimetry parameters between unique observer pairs. Measurements from a group of 3 radiation oncologists (G1) were compared against those from a group consisting of the other 4 clinical observers (G2).IoV of the prostate was lower for G1 than G2 (Matthew's correlation coefficient [MCC], G1 vs. G2: planning-0.906 vs. 0.870, p 0.001; postimplant-0.899 vs. 0.861, p 0.001). IoV of the EUS was highest of all the organs for both groups, but was lower for G1 (MCC, G1 vs. G2: planning-0.659 vs. 0.402, p 0.001; postimplant-0.684 vs. 0.398, p 0.001). Large differences in prostate dosimetry parameters were observed (G1 maximum absolute prostate ΔD90: planning-76.223 Gy, postimplant-36.545 Gy; G1 maximum absolute prostate ΔV100: planning-13.927%, postimplant-8.860%).While MRI is optimal in the management of prostate cancer with radiation therapy, significant interobserver variability of the prostate and external urinary sphincter still exist.

Purpose/ObjectivesDetermining the optimal postoperative reirradiation volume following salvage surgery for recurrent head and neck squamous cell cancer (HNSCC) is critical given the significant risk of severe reirradiation toxicity and need to provide durable local control. The purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT.Materials/MethodsPatterns of LRR for 61 patients treated consecutively between 2003-2014 who received post-operative IMRT reirradiation to ≥60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR.ResultsA total of 55 patients were eligible for analysis and 23 (42%) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the only significant predictor of LRR after post-operative reirradiation (p = 0.037). Physician classification of LRR yielded 14 (61%) in-field failures, 3 (13%) marginal failures, and 6 (26%) out-of-field failures, while DIR yielded 10 (44%) in-field failures, 4 (17%) marginal failures, and 9 (39%) out-of-field failures. Most failures (57%) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56% of failures occurred within 1 cm of the surgical flap.ConclusionThe majority of locoregional recurrences after surgical salvage and adjuvant reirradiation for recurrent HNSCC occurred marginally or in-field, often in or near the anastomotic site.

We examined the meaning of metabolically active lesions on 1 month restaging nuclear imaging of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving axicabtagene ciloleucel (axi-cel) by assessing the relationship between total metabolic tumor volume (MTV) on positron emission tomography (PET) scans and circulating tumor DNA (ctDNA) in the plasma. In this prospective multicenter sample collection study, MTV was retrospectively calculated via commercial software at baseline, 1 and 3 months post chimeric antigen receptor (CAR) T-cell therapy; ctDNA was available pre and post axi-cel. Spearman correlation coefficient (rs) was used to study the relationship between the variables and a mathematical model was constructed to describe tumor dynamics 1 month post CAR T-cell therapy. The median time between baseline scan and axi-cel infusion was 33 (range, 1-137) days for all 57 patients. For 41 of the patients with imaging within 33 days of axi-cel or imaging before that time but no bridging therapy, the correlation at baseline became stronger (rs 0.61, P< 0.0001) compared to all patients (rs 0.38, P= 0.004). Excluding patients in complete remission with no measurable residual disease, ctDNA and MTV at 1 month did not correlate (rs 0.28, P= 0.11), but did correlate at 3 months (rs 0.79, P= 0.0007). Modeling of tumor dynamics, which incorporated ctDNA and inflammation as part of MTV, recapitulated outcomes of patients with positive radiologic 1-month scans. Our results suggested that non-progressing hypermetabolic lesions on 1 month PET represent ongoing treatment response and their composition may be elucidated by concurrent ctDNA.

Synergy between B02 and AZD1775 is associated with impaired Rad51-mediated homologous recombination repair in HPV-positive HNSCC cells

Supplementary Table S1

Supplementary Materials and Methods

Supplemental Tables T1-T3, and Supplemental Figures S1-S5

Despite advances in surgery, chemotherapy, and radiation, there are limited treatment options for advanced head and neck squamous cell carcinoma (HNSCC) and survival remains very poor. Therefore, effective therapies are desperately needed. Recently, selective exploitation of DNA damage and replication stress responses has become a novel approach for cancer treatment. Wee1 kinase and Rad51 recombinase are two proteins involved in regulating replication stress and homologous recombination repair in cancer cells. In this study, we investigated the combined effect of Rad51 inhibitor (B02) and Wee1 inhibitor (AZD1775) in vitro and in vivo in various HNSCC cell lines. Clonogenic survival assays demonstrated that B02 synergized with AZD1775 in vitro in all HNSCC cell lines tested. The synergy between these drugs was associated with forced CDK1 activation and reduced Chk1 phosphorylation leading to induction of excessive DNA damage and replication stress, culminating in aberrant mitosis and apoptosis. Our results showed that elevated Rad51 mRNA expression correlated with worse survival in HNSCC patients with HPV-positive tumors. The combination of B02 and AZD1775 significantly inhibited tumor growth in vivo in mice bearing HPV-positive HNSCC tumors as compared to HPV-negative HNSCC. This differential sensitivity appears to be linked to HPV-positive tumors having more in vivo endogenous replication stress owing to transformation by E6 and E7 oncogenes. Furthermore, addition of B02 radiosensitized the HPV-negative HNSCC tumors in vitro and in vivo. In conclusion, our data implicate that a novel rational combination with Rad51 and Wee1 inhibitors holds promise as synthetic lethal therapy, particularly in high-risk HPV-positive HNSCC.

Single agent activity of B02 in HNSCC cell lines, Cell growth assay in HNSCC cells, Cell growth assay in HNSCC cells, and Synergy between B02 and AZD1775 is mediated in part through forced activation of CDK1 and inhibition of Chk1 associated with impaired Rad51-mediated homologous recombination repair in HNSCC cells.

INTRODUCTION Integrated quality improvement (QI) and cost reduction strategies can help increase value in cancer care. Time-driven activity-based costing (TDABC) is a bottom-up costing tool that measures resource use over the full care cycle. We applied standard QI and TDABC methods to improve workflow efficiency and reduce costs for MRI-guided prostate brachytherapy. METHODS AND MATERIALS We constructed process maps of the baseline prostate brachytherapy workflow from initial consultation through one year after treatment. Process maps reflected resources and time required at each step. TDABC costs were calculated by multiplying each process time by the cost per min of the resource(s) used at that step. We then used plan-do-study-act methodology to identify workflow inefficiencies and implement solutions to reduce resource consumption. RESULTS The highest cost components at baseline were the operating room (OR) (40%), imaging (8.7%), and consultation (7.6%). Higher-than-expected costs (3%) were incurred during surgery scheduling. After targeted QI initiatives, OR time was reduced from 90 to 70 min, which reduced overall cost by 5%. Personnel task downshifting reduced costs by 10% at consultation and 77% at surgery scheduling. Re-engineering of follow-up protocols reduced costs by 8.4%. Costs under the new workflow decreased by 18.2%. CONCLUSIONS TDABC complements traditional QI initiatives by quantifying the highest cost steps and focusing QI initiatives to reduce costs and improve efficiency. As payment reform evolves toward bundled payments, TDABC and QI initiatives will help providers understand, communicate, and improve the value of cancer care.

Purpose Brachytherapy is an essential technique to deliver radiation therapy and is involved in the treatment of multiple disease sites as monotherapy or as an adjunct to external beam radiation therapy. With a growing focus on the cost and value of cancer treatments as well new payment models, it is essential that standardized quality measures and metrics exist to allow for straightforward assessment of brachytherapy quality and for the development of clinically significant and relevant clinical data elements. We present the American Brachytherapy Society consensus statement on quality measures and metrics for brachytherapy as well as suggested clinical data elements. Methods and Materials Members of the American Brachytherapy Society with expertise in disease site specific brachytherapy created a consensus statement based on a literature review and clinical experience. Results Key quality measures (ex. workup, clinical indications), dosimetric metrics, and clinical data elements for brachytherapy were evaluated for each modality including breast cancer, cervical cancer, endometrial cancer, prostate cancer, keratinocyte carcinoma, soft tissue sarcoma, and uveal melanoma. Conclusions This consensus statement provides standardized quality measures and dosimetric quality metrics as well as clinical data elements for each disease site to allow for standardized assessments of brachytherapy quality. Moving forward, a similar paradigm can be considered for external beam radiation therapy as well, providing comprehensive radiation therapy quality measures, metrics, and clinical data elements that can be incorporated into new payment models.

Supplementary Data: Tables S1-S2; Figures S1-S4

1 supplementary method, 3 supplementary tables and 7 supplementary figures

Purpose:Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy.Experimental Design:We analyzed 2,688 patients with stage III–IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat.Results:Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57–0.94; P = 0.016] than those with ω score P = 0.69; P = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression.Conclusions:Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.

Purpose:Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications.Experimental Design:RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation.Results:Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH-activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype.Conclusions:Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.

Background: Previous surveys reported declining cervical cancer screening rates from 2000 to 2010, but trends by key demographic and age groups are less clear.Methods: We examined 3-year Papanicolaou (Pap) test rates among 4.2 million women enrolled in a large national health plan during 2001 to 2010. We calculated and plotted adjusted 3-year rates stratified by age and key neighborhood-level socioeconomic characteristics including poverty level and race/ethnicity (white, black, Hispanic, and mixed ethnicity neighborhood). We fitted trends in 2001–2010 screening rates and socioeconomic disparities as annual percentage changes (APC) using joinpoint analysis.Results: Women ages 21 to 29 years had estimated 3-year Pap testing rates of 81.3% to 81.4% over the decade. Estimated disparities by low–high poverty level were 3.1% and 2.0% in 2001–2003 and 2008–2010, respectively, a nonsignificant decline. Initial white–black disparities were 4.0% and declined significantly from 2005–2007 to 2008–2010 to 2.8% at an APC of −0.65% (P = 0.021). White–Hispanic disparities declined from 4.3% to 0.8% over the decade, a −0.50% APC (P = 0.024). Among women ages 30 to 64 years, estimated 3-year Pap testing rates trended down from 76.1% to 71.8% over the decade [−0.94% APC (P < 0.001) until 2005–2007]. This pattern was similar among women from most categories of poverty and race/ethnicity.Conclusions: Among commercially insured women ages 21 to 29 years, 3-year Pap testing rates remained stable at 81% over the decade; disparities were small and improved for Hispanic women to a greater degree than for black women. Among women ages 30 to 64 years, 3-year Pap testing rates declined from 2001 to 2010.Impact: Cervical cancer screening should be promoted to achieve Healthy People 2020 goals. Cancer Epidemiol Biomarkers Prev; 23(11); 2366–73. ©2014 AACR.

Supplementary Table 1: Claims-based codes used to define numerator events and exclude women from the denominator. Supplementary Table 2: Adjusted 3-year cervical cancer screening rates and disparities among women age 21-29 from 2001 to 2010. Supplementary Table 3: Adjusted 3-year cervical cancer screening rates and disparities among women age 30-64 from 2001 to 2010.

Pituitary tumors are a diverse group of neoplasms that are classified based on clinical manifestations, hormone excess, and histomorphologic features. Those that cause growth hormone (GH) excess and acromegaly are subdivided into morphologic variants that have not yet been shown to have pathogenetic significance or predictive value for therapy and outcome. Here, we identify a selective somatic histidine-to-leucine substitution in codon 49 of the extracellular domain of the GH receptor (GHR) in a morphologic subtype of human GH-producing pituitary tumors that is characterized by the presence of cytoskeletal aggresomes. This GHR mutation significantly impairs glycosylation-mediated receptor processing, maturation, ligand binding, and signaling. Pharmacologic GH antagonism recapitulates the morphologic phenotype of pituitary tumors from which this mutation was identified, inducing the formation of cytoskeletal keratin aggresomes. This novel GHR mutation provides evidence for impaired hormone autofeedback in the pathogenesis of these pituitary tumors. It explains the lack of responsiveness to somatostatin analogue therapy of this tumor type, in contrast to the exquisite sensitivity of tumors that lack aggresomes, and has therapeutic implications for the safety of GH antagonism as a therapeutic modality in acromegaly. [Cancer Res 2007;67(15):7505–11]