Follow-up for human papillomavirus-related oropharynx cancer concentrated on unequal symptom change (FOCUS): Prospective patient-reported outcome collection.

BACKGROUND: Post-treatment surveillance recommendations for oropharyngeal cancer do not vary with p16 status despite the differences in outcomes. The optimal algorithm personalizing follow-up for these patients remains undefined. Here, we evaluate the feasibility and utility of incorporating electronic patient-reported outcomes (ePROs) and circulating tumor DNA (ctDNA) into routine surveillance for patients treated for p16+ oropharynx cancer. METHODS: A prospective registry was developed in which ePROs and ctDNA were incorporated into routine surveillance among patients with oropharynx cancer. ePROs were emailed monthly for 1 year and blood HPV ctDNA testing was performed every 3-6 months. The primary objective was to assess patient compliance with ePRO-based surveillance with adequate compliance defined as ≥85% of patients completing monthly ePROs. Sensitivity, specificity, and positive/negative predictive values to detect recurrence were calculated for ePROs, HPV ctDNA, or the combination. RESULTS: Of 122 patients who initially expressed interest, 76 completed the electronic consent process and 44/76 (58%) were compliant with monthly surveys over 1 year; thus adequate compliance was not achieved. Technical difficulties associated with ePRO receipt through email largely limited participation. Provider feedback was significantly associated with heightened ePRO compliance. One hundred and six patients had ctDNA testing with a mean number of three tests per patient. Sensitivity to detect recurrence was 75% for the combination of ePROs and ctDNA. CONCLUSION: Despite lower than anticipated compliance with ePROs, our findings show promise for incorporation of HPV ctDNA into surveillance paradigms for HPV-related oropharynx cancer with suggestions of methods to optimize ePRO formats for personalized surveillance.

Pneumonitis After Chemoradiotherapy and Adjuvant Durvalumab in Stage III Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant durvalumab after definitive chemoradiotherapy (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) is well-tolerated in clinical trials. However, pneumonitis rates outside of clinical trials remain poorly defined with CRT followed by durvalumab. We aimed to describe the influence of durvalumab on pneumonitis rates among a large cohort of patients with stage III NSCLC. METHODS AND MATERIALS: We studied patients with stage III NSCLC in the national Veterans Health Administration from 2015 to 2021 who received concurrent CRT alone or with adjuvant durvalumab. We defined pneumonitis as worsening respiratory symptoms with radiographic changes within 2 years of CRT and graded events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. We used Cox regression to analyze risk factors for pneumonitis and the effect of postbaseline pneumonitis on overall survival. RESULTS: Among 1994 patients (989 CRT alone, 1005 CRT followed by adjuvant durvalumab), the 2-year incidence of grade 2 or higher pneumonitis was 13.9% for CRT alone versus 22.1% for CRT plus durvalumab (unadjusted P < .001). On multivariable analysis, durvalumab was associated with higher risk of grade 2 pneumonitis (hazard ratio, 1.45; 95% CI, 1.09-1.93; P = .012) but not grade 3 to 5 pneumonitis (P = .2). Grade 3 pneumonitis conferred worse overall survival (hazard ratio, 2.51; 95% CI, 2.06-3.05; P < .001) but grade 2 pneumonitis did not (P = .4). CONCLUSIONS: Adjuvant durvalumab use was associated with increased risk of low-grade but not higher-grade pneumonitis. Reassuringly, low-grade pneumonitis did not increase mortality risk. We observed increased rates of high-grade pneumonitis relative to clinical trials; the reasons for this require further study.

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

The brain avidly consumes glucose to fuel neurophysiology. Cancers of the brain, such as glioblastoma (GBM), lose aspects of normal biology and gain the ability to proliferate and invade healthy tissue. How brain cancers rewire glucose utilization to fuel these processes is poorly understood. Here we perform infusions of 13 C-labeled glucose into patients and mice with brain cancer to define the metabolic fates of glucose-derived carbon in tumor and cortex. By combining these measurements with quantitative metabolic flux analysis, we find that human cortex funnels glucose-derived carbons towards physiologic processes including TCA cycle oxidation and neurotransmitter synthesis. In contrast, brain cancers downregulate these physiologic processes, scavenge alternative carbon sources from the environment, and instead use glucose-derived carbons to produce molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary modulation selectively alters GBM metabolism and slows tumor growth. Significance: This study is the first to directly measure biosynthetic flux in both glioma and cortical tissue in human brain cancer patients. Brain tumors rewire glucose carbon utilization away from oxidation and neurotransmitter production towards biosynthesis to fuel growth. Blocking these metabolic adaptations with dietary interventions slows brain cancer growth with minimal effects on cortical metabolism.

Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions.

Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at "one-size-fits-all" flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately $537 million. Combining weight-based dosing, dose rounding, and pharmacy-level vial sharing would generate expected annual VHA health system savings of $74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US.

Metabolomic Profiles of Human Glioma Inform Patient Survival.

Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal. 39, 942-956.

Cannabis Use in Patients Seen in an Academic Radiation Oncology Department.

PURPOSE: Cannabis use rates are increasing in the United States. Patients with cancer use cannabis for many reasons, even without high-quality supporting data. This study sought to characterize cannabis use among patients seen in radiation oncology in a state that has legalized adult nonmedical use cannabis and to identify key cannabis-related educational topics. METHODS AND MATERIALS: Cannabis history was documented by providers using a structured template at patient visits in an academic radiation oncology practice October 2020 to November 2021. Cannabis use data, including recency/frequency of use, reason, and mode of administration, were summarized, and logistic regression was used to explore associations between patient and disease characteristics and recent cannabis use. A multivariable model employed stepwise variable selection using the Akaike Information Criterion. RESULTS: Of 3143 patients total, 91 (2.9%) declined to answer cannabis use questions, and 343 (10.9%) endorsed recent use (≤1 month ago), 235 (7.5%) noted nonrecent use (>1 month ago), and 2474 (78.7%) denied history of cannabis use. In multivariable analyses, those ≥50 years old (odds ratio [OR], 0.409; 95% confidence interval [CI], 0.294-0.568; P < .001) or with history of prior courses of radiation (OR, 0.748; 95% CI, 0.572-0.979; P = .034) were less likely, and those with a mental health diagnosis not related to substance use (OR, 1.533; 95% CI, 1.171-2.005; P = .002) or who smoked tobacco (OR, 3.003; 95% CI, 2.098-4.299; P < .001) were more likely to endorse recent cannabis use. Patients reported pain, insomnia, and anxiety as the most common reasons for use. Smoking was the most common mode of administration. CONCLUSIONS: Patients are willing to discuss cannabis use with providers and reported recent cannabis use for a variety of reasons. Younger patients new to oncologic care and those with a history of mental illness or tobacco smoking may benefit most from discussions about cannabis given higher rates of cannabis use in these groups.

External beam management of stage I and II uterine cancer.

This review article highlights the treatment paradigms for early-stage endometrial cancer with a focus on the role of external beam radiation therapy. We aim for this review to serve as an introductory resource for gynecological oncologists, radiation oncologists, medical oncologists, and other practitioners to understand the treatments for this disease. The main treatment of endometrial cancer is surgical resection with total hysterectomy and bilateral salpingo-oophorectomy. The benefit of adjuvant radiation after surgery is primarily to prevent local recurrence. Patients with low risk of recurrence can be observed post-operatively. Vaginal cuff brachytherapy, which has been shown to be equally effective as pelvic radiation with fewer side effects, is typically recommended for high-intermediate risk patients (with characteristics such as lymphovascular space invasion, high grade, or significant myometrial invasion). In the adjuvant setting, pelvic radiation therapy is reserved for patients who have deeply invasive stage I grade 2 or 3 disease, stage II disease, and non-endometrioid histologies. In patients who are not medically operable, definitive treatment consists of brachytherapy±pelvic external beam radiation therapy. We have highlighted the main acute and long-term side effects of pelvic radiation as well as recommendations for symptom management and summarized promising evidence showing improved rates of toxicities with more conformal radiation techniques.

SIK2 kinase synthetic lethality is driven by spindle assembly defects in FANCA-deficient cells.

The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here, we performed a kinome-wide synthetic lethality screen in FANCA-/- fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA. We found that FANCA colocalizes with SIK2 at multiple mitotic structures and regulates the activity of SIK2 at centrosomes. Furthermore, we found that loss of FANCA exacerbates cell cycle defects induced by pharmacological inhibition of SIK2, including impaired G2-M transition, delayed mitotic progression, and cytokinesis failure. In addition, we showed that inhibition of SIK2 abrogates nocodazole-induced prometaphase arrest, suggesting a novel role for SIK2 in the spindle assembly checkpoint. Together, these findings demonstrate that FANCA-deficient cells are dependent upon SIK2 for survival, supporting a preclinical rationale for targeting of SIK2 in FA-disrupted cancers.

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia.

Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.

SOX11 Inhibitors Are Cytotoxic in Mantle Cell Lymphoma.

PURPOSE: Mantle cell lymphoma (MCL) is a fatal subtype of non-Hodgkin lymphoma. SOX11 transcription factor is overexpressed in the majority of nodal MCL. We have previously reported that B cell-specific overexpression of SOX11 promotes MCL pathogenesis via critically increasing BCR signaling in vivo. SOX11 is an attractive target for MCL therapy; however, no small-molecule inhibitor of SOX11 has been identified to date. Although transcription factors are generally considered undruggable, the ability of SOX11 to bind to the minor groove of DNA led us to hypothesize that there may exist cavities at the protein-DNA interface that are amenable to targeting by small molecules. EXPERIMENTAL DESIGN: Using a combination of in silico predictions and experimental validations, we report here the discovery of three structurally related compounds (SOX11i) that bind SOX11, perturb its interaction with DNA, and effect SOX11-specific anti-MCL cytotoxicity. RESULTS: We find mechanistic validation of on-target activity of these SOX11i in the inhibition of BCR signaling and the transcriptional modulation of SOX11 target genes, specifically, in SOX11-expressing MCL cells. One of the three SOX11i exhibits relatively superior in vitro activity and displays cytotoxic synergy with ibrutinib in SOX11-expressing MCL cells. Importantly, this SOX11i induces cytotoxicity specifically in SOX11-positive ibrutinib-resistant MCL patient samples and inhibits Bruton tyrosine kinase phosphorylation in a xenograft mouse model derived from one of these subjects. CONCLUSIONS: Taken together, our results provide a foundation for therapeutically targeting SOX11 in MCL by a novel class of small molecules.

PAK1 inhibition reduces tumor size and extends the lifespan of mice in a genetically engineered mouse model of Neurofibromatosis Type 2 (NF2).

Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.

Impact of Lung Parenchymal-Only Failure on Overall Survival in Early-Stage Lung Cancer Patients Treated With Stereotactic Ablative Radiotherapy.

INTRODUCTION: The impact of lung parenchymal-only failure on patient survival after stereotactic ablative body radiotherapy (SABR) for early-stage non-small-cell lung cancer (NSCLC) remains unclear. PATIENTS AND METHODS: The study population included 481 patients with early-stage NSCLC who were treated with 3- to 5-fraction SABR between 2000 and 2016. The primary study objective was to assess the impact of out-of-field lung parenchymal-only failure (OLPF) on overall survival (OS). RESULTS: At a median follow-up of 5.9 years, the median OS was 2.7 years for all patients. Patients with OLPF did not have a significantly different OS compared to patients without failure (P = .0952, median OS 4.1 years with failure vs. 2.6 years never failure). Analysis in a 1:1 propensity score-matched cohort for Karnofsky performance status, comorbidity score, and smoking status showed no differences in OS between patients without failure and those with OLPF (P = .8). In subgroup analyses exploring the impact of time of failure on OS, patients with OLPF 6 months or more after diagnosis did not have significantly different OS compared to those without failure, when accounting for immortal time bias (P = .3, median OS 4.3 years vs. 3.5 years never failure). Only 7 patients in our data set experienced failure within 6 months of treatment, of which only 4 were confirmed to be true failures; therefore, limited data are available in our cohort on the impact of OLPF for ≤ 6 months on OS. CONCLUSION: OLPF after SABR for early-stage NSCLC does not appear to adversely affect OS, especially if occurring at least 6 months after SABR. More studies are needed to understand if OLPF within 6 months of SABR is associated with adverse OS. These data are useful when discussing prognosis of lung parenchymal failures after initial SABR.

Predictors of Nodal and Metastatic Failure in Early Stage Non-small-cell Lung Cancer After Stereotactic Body Radiation Therapy.

INTRODUCTION/BACKGROUND: Many patients with early stage non-small-cell lung cancer (ES-NSCLC) undergoing stereotactic body radiation therapy (SBRT) develop metastases, which is associated with poor outcomes. We sought to identify factors predictive of metastases after lung SBRT and created a risk stratification tool. MATERIALS AND METHODS: We included 363 patients with ES-NSCLC who received SBRT; the median follow-up was 5.8 years. The following patient and tumor factors were retrospectively analyzed for their association with metastases (defined as nodal and/or distant failure): gender; age; lobe involved; centrality; previous NSCLC; smoking status; gross tumor volume (GTV); T-stage; histology; dose; minimum, maximum, and mean GTV dose; and parenchymal lung failure. A metastasis risk-score linear-model using beta coefficients from a multivariate Cox model was built. RESULTS: A total of 111 (27.3%) of 406 lesions metastasized. GTV and dose were significantly associated with metastases on univariate and multivariate Cox proportional hazards modeling (P < .001 and hazard ratio [HR], 1.02 per mL; P < .05 and HR, 0.99 per Gy, respectively). Histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not associated with development of metastasis. A metastasis risk-score model using GTV and prescription dose was built: risk score = (0.01611 × GTV) - (0.00525 × dose [BED10]). Two risk-score cutoffs separating the cohort into low-, medium-, and high-risk subgroups were examined. The risk score identified significant differences in time to metastases between low-, medium-, and high-risk patients (P < .001), with 3-year estimates of 81.1%, 63.8%, and 38%, respectively. CONCLUSION: GTV and radiation dose are associated with time to metastasis and may be used to identify patients at higher risk of metastasis after lung SBRT.

A proteasome-resistant fragment of NIK mediates oncogenic NF-κB signaling in schwannomas.

Schwannomas are common, highly morbid and medically untreatable tumors that can arise in patients with germ line as well as somatic mutations in neurofibromatosis type 2 (NF2). These mutations most commonly result in the loss of function of the NF2-encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells (SCs). Here, we identify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis. Using a genomic approach to profile aberrant tumor signaling pathways, we describe multiple upregulated NF-κB signaling elements in human and murine schwannomas, leading us to identify a caspase-cleaved, proteasome-resistant NIK kinase domain fragment that amplifies pathogenic NF-κB signaling. Lentiviral-mediated transduction of this NIK fragment into normal SCs promotes proliferation, survival, and adhesion while inducing schwannoma formation in a novel in vivo orthotopic transplant model. Furthermore, we describe an NF-κB-potentiated hepatocyte growth factor (HGF) to MET proto-oncogene receptor tyrosine kinase (c-Met) autocrine feed-forward loop promoting SC proliferation. These innovative studies identify a novel signaling axis underlying schwannoma formation, revealing new and potentially druggable schwannoma vulnerabilities with future therapeutic potential.

Whole-exome sequencing enables correct diagnosis and surgical management of rare inherited childhood anemia.

Correct diagnosis of inherited bone marrow failure syndromes is a challenge because of the significant overlap in clinical presentation of these disorders. Establishing right genetic diagnosis is crucial for patients' optimal clinical management and family counseling. A nondysmorphic infant reported here developed severe transfusion-dependent anemia and met clinical criteria for diagnosis of Diamond-Blackfan anemia (DBA). However, whole-exome sequencing demonstrated that the child was a compound heterozygote for a paternally inherited pathogenic truncating variant (SPTA1c.4975 C>T) and a novel maternally inherited missense variant of uncertain significance (SPTA1c.5029 G>A) within the spectrin gene, consistent with hereditary hemolytic anemia due to disruption of red blood cell (RBC) cytoskeleton. Ektacytometry demonstrated abnormal membrane flexibility of the child's RBCs. Scanning electron microscopy revealed morphological aberrations of the patient's RBCs. Both parents were found to have mild hereditary elliptocytosis. Importantly, patients with severe RBC membrane defects may be successfully managed with splenectomy to minimize peripheral destruction of misshapen RBCs, whereas patients with DBA require lifelong transfusions, steroid therapy, or hematopoietic stem cell transplantation. As suggested by the WES findings, splenectomy rendered our patient transfusion-independent, improving the family's quality of life and preventing transfusion-related iron overload. This case illustrates the utility of whole-exome sequencing in clinical care of children with genetic disorders of unclear presentation.

SOX11 augments BCR signaling to drive MCL-like tumor development.

Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (Eµ-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell-specific IgH-Eµ enhancer. The overexpression of SOX11 exclusively in B cells exhibits oligoclonal B-cell hyperplasia in the spleen, bone marrow, and peripheral blood, with an immunophenotype (CD5+CD19+CD23-) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation of pBTK and other molecules in the BCR signaling pathway, and serial bone marrow transplant from transgenic donors produces lethality with decreasing latency. We report here that overexpression of SOX11 in B cells promotes BCR signaling and a disease phenotype that mimics human MCL.

PRL­3 increases the aggressive phenotype of prostate cancer cells in vitro and its expression correlates with high-grade prostate tumors in patients.

The increased expression of phosphatase of regenerating liver-3 (PRL­3) has been shown to be associated with the aggressive and metastatic phenotype of different solid tumors. However, it is not known whether PRL­3 plays a similar role in the progression of prostate cancer (PCa). In this study, immunoblot analysis of androgen receptor (AR)-positive PCa lines (LNCaP and LNCaP­SF) revealed the constitutive cytoplasmic expression of PRL­3, and stimulation with R1881 (AR agonist) rapidly increased the nuclear translocation of PRL­3. The AR-negative cell lines exhibited negligible PRL­3 expression, and the ectopic overexpression of PRL­3 increased both the proliferative and invasive potential of PC3 and DU145 cells. In addition, we measured PRL­3 protein expression in human prostate tumor sections. A high-density prostate tumor microarray (TMA) was immunostained to assess whether PRL­3 expression and its subcellular localization (cytoplasmic and nuclear levels) is associated with the Gleason score (GS), Gleason grade (GG) and tumor stage (T-stage). Digital image analysis (DIA) revealed that PRL­3 expression was significantly higher in the malignant cores, as compared to the non­malignant areas. Increases in both total and nuclear PRL­3 levels were also associated with a higher GS and GG. Metastatic tumors (T4­stage) had lower cytoplasmic, but higher nuclear PRL­3 levels. Furthermore, the nuclear/cytoplasmic ratio for PRL­3 in the tumors graded as GS7 could effectively distinguish between indolent (3+4) and aggressive (4+3) disease. Thus, our experiments using PCa lines suggested that PRL­3 is an AR-regulated gene and its androgen-induced nuclear localization may increase the aggressive behavior of PCa cells. Furthermore, the digital analysis of immunostained tumor sections suggested that PRL­3 may be an effective biomarker of high-grade PCa, and its nuclear/cytoplasmic ratio may be used to distinguish between indolent vs. aggressive tumors.

Caregiver stress and burnout in an oncology unit.

PURPOSE: Caring for patients with cancer can be taxing for front-line health care providers. The growing intensity of treatment protocols, in conjunction with staff shortages, reduced hospital stays, and broader pressures on the health care system may exacerbate these challenges, leading to increased risk for burnout. This article reviews the research literature regarding the prevalence of burnout and psychosocial distress among oncology providers, examines multifactorial occupational and personal determinants of risk, and considers intervention strategies to enhance resilience. METHODS: Literature review of empirical peer-reviewed studies focusing on prevalence and correlates of burnout among oncology physicians and nurses. RESULTS: Findings from a number of studies using validated measures and large samples suggest that prevalence rates for burnout and psychosocial distress are high among oncology staff, though not necessarily higher than in non-cancer-practice settings. A growing database has examined occupational (e.g., workload) and demographic (e.g., gender) factors that may contribute to risk, but there is less information about personal (e.g., coping) or organizational (e.g., staffing, physician-nurse relations) determinants or multilevel interactions among these factors. Oncologist burnout may adversely affect anticipated staff turnover. Other important endpoints (biological stress markers, health status, patient satisfaction, quality-of-care indices) have yet to be examined in the oncology setting. Intervention research is at a more rudimentary phase of development. CONCLUSIONS: Burnout and distress affect a significant proportion of oncology staff. There is a need for additional conceptually based, longitudinal, multivariate studies regarding burnout and its associated risk factors and consequences.

Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib.

PURPOSE: To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma. PATIENTS AND METHODS: Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression. RESULTS: Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities. CONCLUSION: The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.