Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. INTERPRETATION: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

Prospective Study of Pain Outcomes Associated With Breast Surgery in Women With Nonhereditary Breast Cancer.

OBJECTIVE: To assess pain severity and interference with life in women after different types of breast cancer surgery and the demographic, treatment-related, and psychosocial variables associated with these pain outcomes. SUMMARY OF BACKGROUND DATA: Data are conflicting regarding pain outcomes and quality of life (QOL) among women who undergo different types of breast surgery. METHODS: Women with nonhereditary breast cancer completed the brief pain inventory before surgery and at 1, 6, 12, and 18 months postsurgery. We assessed associations between pain outcomes and CPM status and mastectomy status using multivariable repeated measures models. We assessed associations between pain outcome and QOL and decision satisfaction. RESULTS: Of 288 women (mean age 56 years, 58% non-Hispanic White), 50 had CPM, 75 had unilateral mastectomy, and 163 had BCS. Mean pain severity scores were higher at one (2.78 vs 1.9, P = 0.016) and 6 months (2.79 vs 1.96, P = 0.031) postsurgery in women who had CPM versus those who did not, but there was no difference at 12 and 18 months. Comparing mastectomy versus BCS, pain severity was higher at 1 and 12 months. There was a significant interaction between pain severity and time point for CPM ( P = 0.006), but not mastectomy status ( P = 0.069). Regardless of surgery type, Black women had higher pain severity ( P = 0.004) than White women. Higher pain interference was associated with lower QOL ( P < 0.001) and lower decision satisfaction ( P = 0.034). CONCLUSIONS: Providers should counsel women considering mastectomy about the potential for greater acute pain and its impact on overall well-being. Racial/ethnic disparities in pain exist and influence pain management in breast surgical patients.

Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein.

We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 µM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

Incorporating Baseline Breast Density When Screening Women at Average Risk for Breast Cancer : A Cost-Effectiveness Analysis.

BACKGROUND: Breast density classification is largely determined by mammography, making the timing of the first screening mammogram clinically important. OBJECTIVE: To evaluate the cost-effectiveness of breast cancer screening strategies that are stratified by breast density. DESIGN: Microsimulation model to generate the natural history of breast cancer for women with and those without dense breasts and assessment of the cost-effectiveness of strategies tailored to breast density and nontailored strategies. DATA SOURCES: Model parameters from the literature; statistical modeling; and analysis of Surveillance, Epidemiology, and End Results-Medicare data. TARGET POPULATION: Women aged 40 years or older. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: No screening; biennial or triennial mammography from age 50 to 75 years; annual mammography from age 50 to 75 years for women with dense breasts at age 50 years and biennial or triennial mammography from age 50 to 75 years for those without dense breasts at age 50 years; and annual mammography at age 40 to 75 years for women with dense breasts at age 40 years and biennial or triennial mammography at age 50 to 75 years for those without dense breasts at age 40 years. OUTCOME MEASURES: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. RESULTS OF BASE-CASE ANALYSIS: Baseline screening at age 40 years followed by annual screening at age 40 to 75 years for women with dense breasts and biennial screening at age 50 to 75 years for women without dense breasts was effective and cost-effective, yielding an incremental cost-effectiveness ratio of $36 200 per QALY versus the biennial strategy at age 50 to 75 years. RESULTS OF SENSITIVITY ANALYSIS: At a societal willingness-to-pay threshold of $100 000 per QALY, the probability that the density-stratified strategy at age 40 years was optimal was 56% compared with 6 other strategies. LIMITATION: Findings may not be generalizable outside the United States. CONCLUSION: The study findings advocate for breast density-stratified screening with baseline mammography at age 40 years. PRIMARY FUNDING SOURCE: National Cancer Institute.

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress.

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1ß. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.

Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models.

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

Multidisciplinary Management of Orbital Metastasis and Survival Outcomes.

PURPOSE: To study the multidisciplinary management and survival outcomes of orbital metastasis (OM). METHODS: All patients with a diagnosis of OM treated during 1999-2019 were included. Clinical data were retrospectively collected and analyzed. RESULTS: The study included 118 patients, 71 females and 47 males, with a median age of 61 years. The most common primary tumor types were breast carcinoma (43 patients), melanoma (17), and lung (13), thyroid (7), renal cell (6), and neuroendocrine carcinoma (6). Ninety-six patients had a known history of cancer at OM diagnosis. The median time from diagnosis of primary cancer to OM was 31 months (range, 0-304). In 22 patients, OM was the first sign of cancer. In 47 patients, the orbit was the only site of metastasis. The most common presenting features were restricted by extraocular motility (77 patients) and proptosis (61). Eight patients had enophthalmos. OM was diagnosed based on clinical history and imaging studies in 81 patients and orbital biopsy in 37. One hundred nine patients were treated with chemotherapy and immunotherapy, 75 with radiation, and 21 with palliative surgical resection. Eighty-two patients died during follow up. The median overall survival (OS) time after diagnosis of OM was 17 months (95% CI: 12-28). OM from renal cell carcinoma was associated with the best and OM from thyroid cancer with the worst OS. Patients with breast cancer had longer median survival (28 months; 95% CI: 15-60) than patients with lung, melanoma, neuroendocrine, or thyroid cancer. CONCLUSION: In this large series, breast cancer and melanoma were the most common causes of OM. Most patients had a known history of cancer at OM diagnosis and did not require orbital biopsy to confirm the diagnosis. Patients with renal cell carcinoma and breast carcinoma had the best prognosis after diagnosis of OM.

Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation.

The presence of bulky disease in Hodgkin lymphoma (HL), traditionally defined with a 1-dimensional measurement, can change a patient's risk grouping and thus the treatment approach. We hypothesized that 3-dimensional measurements of disease burden obtained from baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), would more accurately risk-stratify patients. To test this hypothesis, we reviewed pretreatment PET-CT scans of patients with stage I-II HL treated at our institution between 2003 and 2013. Disease was delineated on prechemotherapy PET-CT scans by 2 methods: (1) manual contouring and (2) subthresholding of these contours to give the tumor volume with standardized uptake value ≥2.5. MTV and TLG were extracted from the threshold volumes (MTVt, TLGt) and from the manually contoured soft-tissue volumes. At a median follow-up of 4.96 years for the 267 patients evaluated, 27 patients were diagnosed with relapsed or refractory disease and 12 died. Both MTVt and TLGt were highly correlated with freedom from progression and were dichotomized with 80th percentile cutoff values of 268 and 1703, respectively. Consideration of MTV and TLG enabled restratification of early unfavorable HL patients as having low- and high-risk disease. We conclude that MTV and TLG provide a potential measure of tumor burden to aid in risk stratification of early unfavorable HL patients.

Assessing the Cost-Effectiveness of Updated Breast Cancer Screening Guidelines for Average-Risk Women.

BACKGROUND: Several specialty societies have recently updated their breast cancer screening guidelines in late 2015/early 2016. OBJECTIVES: To evaluate the cost-effectiveness of US-based mammography screening guidelines. METHODS: We developed a microsimulation model to generate the natural history of invasive breast cancer and capture how screening and treatment modified the natural course of the disease. We used the model to assess the cost-effectiveness of screening strategies, including annual screening starting at the age of 40 years, biennial screening starting at the age of 50 years, and a hybrid strategy that begins screening at the age of 45 years and transitions to biennial screening at the age of 55 years, combined with three cessation ages: 75 years, 80 years, and no upper age limit. Findings were summarized as incremental cost-effectiveness ratio (cost per quality-adjusted life-year [QALY]) and cost-effectiveness acceptability frontier. RESULTS: The screening strategy that starts annual mammography at the age of 45 years and switches to biennial screening between the ages of 55 and 75 years was the most cost-effective, yielding an incremental cost-effectiveness ratio of $40,135/QALY. Probabilistic analysis showed that the hybrid strategy had the highest probability of being optimal when the societal willingness to pay was between $44,000/QALY and $103,500/QALY. Within the range of commonly accepted societal willingness to pay, no optimal strategy involved screening with a cessation age of 80 years or older. CONCLUSIONS: The screening strategy built on a hybrid design is the most cost-effective for average-risk women. By considering the balance between benefits and harms in forming its recommendations, this hybrid screening strategy has the potential to optimize the health care system's investment in the early detection and treatment of breast cancer.

American Society of Breast Surgeons' Practice Patterns After Publication of the SSO-ASTRO-ASCO DCIS Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation.

BACKGROUND: The SSO-ASTRO-ASCO consensus guideline on margins for breast-conserving surgery with whole breast irradiation in ductal carcinoma in situ (DCIS) recommended a 2-mm margin. We sought to determine the impact of guideline publication on clinician practice. METHODS: A total of 3081 members of the American Society of Breast Surgeons (ASBrS) received a survey. Respondents' clinical practice type and duration, guideline familiarity, and margin width preferences before and after publication were assessed. Clinical practice pattern differences before and after publication were investigated using McNemar's test. RESULTS: A total of 767 (24.9%) of those surveyed responded. Most (92.4%) indicated guideline familiarity. Of those familiar, re-excision preference for DCIS and a positive margin remained the same before (94.4%) and after (94.3%) publication (McNemar's test p = 1.0). Following publication, surgeons were more likely to avoid re-excision to achieve margins wider than 2-mm (82.3% pre versus 87.5% post, p = 0.002). More surgeons performed re-excision for a close margin with pure DCIS (25.9% pre versus 36.5% post, p < 0.001) and with DCIS with microinvasion (DCIS-M) (40.7% pre versus 52.3% post, p < 0.001). For patients with invasive disease with extensive intraductal component (EIC) and a close margin, preference to avoid re-excision was similar (51.2% per versus 55.2% post, p = 0.071). CONCLUSION: Since guideline publication, surgeons are less likely to perform re-excision to obtain a margin greater than 2-mm and more likely to perform re-excision to obtain a 2-mm margin for both pure DCIS and DCIS-M. Preference to avoid re-excision with a close margin and EIC was similar before and after publication.

Compliance with Opioid Therapy: Distinguishing Clinical Characteristics and Demographics Among Patients with Cancer Pain.

Background: Because an increase of patients who misuse opioids has been identified in our cancer clinical setting through urine drug testing (UDT) and the Screener and Opioid Assessment for Patient's with Pain-Short Form (SOAPP-SF), we conducted this retrospective cohort study to identify patient characteristics that are associated with UDT that indicates noncompliance. Methods: Over a two-year period, 167 of 8,727 patients (2.4%) seen in the pain clinic and who underwent UDT were evaluated to determine compliance with prescribed opioid regimens. Descriptive clinical and demographic data were collected, and group differences based on compliance with opioid therapy were evaluated. Results: Fifty-eight percent of the patients were noncompliant with their prescribed opioid therapy. Noncompliant patients were younger than compliant patients, with a median age of 46 vs 49 years (P = 0.0408). Noncompliant patients were more likely to have higher morphine equivalent daily doses; however, the difference was not statistically significant. Patients with a history of alcohol (ETOH) (P = 0.0332), illicit drug use (P = 0.1014), and smoking (P = 0.4184) were more likely noncompliant. Univariate regression analysis showed that a history of ETOH use (P = 0.034), a history of anxiety (P = 0.027), younger age (P = 0.07), and a SOAPP-SF score of 4 or higher (P = 0.05) were associated with an abnormal UDT. Conclusions: History of ETOH use, anxiety, high SOAPP-SF score, and younger age were associated with UDT that indicates noncompliance. Given the very small percentage of UDT testing, it is quite likely that a significant number of patients who did not undergo UDT were also nonadherent with treatment recommendations.

Early-stage Hodgkin lymphoma outcomes after combined modality therapy according to the post-chemotherapy 5-point score: can residual pet-positive disease be cured with radiotherapy alone?

Early-stage classical Hodgkin lymphoma (HL) patients are evaluated by an end-of-chemotherapy positron emission tomography-computed tomography (eoc-PET-CT) after doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) and before radiation therapy (RT). We determined freedom from progression (FFP) in patients treated with ABVD and RT according to the eoc-PET-CT 5-point score (5PS). Secondarily, we assessed whether patients with a positive eoc-PET-CT (5PS of 4-5) can be cured with RT alone. The cohort comprised 174 patients treated for stage I-II HL with ABVD and RT alone. ABVD was given with a median of four cycles and RT with a median dose of 30·6 Gy. Five-year FFP was 97%. Five-year FFP was 100% (0 relapses/98 patients) for patients with a 5PS of 1-2, 97% (2/65) for a 5PS of 3, 83% (1/8) for a 5PS of 4, and 67% (1/3) for a 5PS of 5 (P < 0·001). Patients with positive eoc-PET-CT scans who were selected for salvage RT alone had experienced a very good partial response to ABVD. Risk factors for recurrence in this subgroup included a small reduction in tumour size and a 'bounce' in ≥1 PET-CT parameter (reduction then rise from interim to final scan). Thus, a positive eoc-PET-CT is associated with inferior FFP; however, appropriately selected patients can be cured with RT alone.

General Anesthesia Imposes Negative Effects on Heart Rate and Blood Pressure Regulation in Patients With a History of Head and Neck Radiation Therapy.

BACKGROUND: Head and neck radiation therapy (HNRT) impairs baroreflex sensitivity, and it may potentiate the effects of anesthetics on heart rate (HR) and blood pressure (BP) regulation. Currently, the impacts of HNRT on HR and BP under anesthesia remain unclear. METHODS: In this study, 472 patients with primary oral cavity or oropharyngeal cancer at all stages were examined. Half of the patients underwent HNRT plus surgery. The other half underwent surgery only and was matched with the treatment patients according to age, sex, and body mass index at a 1:1 ratio. The HRs and BPs in the 2 groups during anesthetic induction, skin incision, and emergence were compared retrospectively. A multivariable model of repeated measures with unstructured covariance structure was used to examine the associations of HNRT with intraoperative HRs and BPs after adjusting for baseline HR and BP, time, use of ß-blockers, history of chemotherapy, and American Society of Anesthesiologists physical status score. BPs and HRs were collected every 5 minutes. The baseline HR and BP measurements were not included in the outcome vector and were only used as adjustment for baselines. RESULTS: Compared with corresponding baseline values in controls, the baseline HR was significantly higher (P = .0012) and the baseline systolic BP was lower (P < .0001) in the treatment group. The baseline diastolic BP levels did not differ significantly (P = .6411). Fewer patients receiving HNRT than controls took ß-blockers daily (17% vs 28%; P = .0041). Comparing the corresponding values in control and treatment groups, multivariable analysis revealed significant associations of HNRT with decreases in HR during anesthesia induction (-2.21 [95% confidence interval {CI}, -4.42 to -0.01]; P = .0492) and skin incision (-2.66 [95% CI, -5.16 to -0.16]; P = .0373) and of HNRT with decreases in systolic BP during anesthesia induction (-6.88 [95% CI, -10.99 to -2.78]; P = .0011) and skin incision (-15.87 [95% CI, -20.45 to -11.29]; P < .001). However, we observed a significant association of HNRT with decrease in diastolic BP only during skin incision (-6.50 [95% CI, -9.47 to -3.53]; P < .0001). CONCLUSIONS: The significant finding in the study was that general anesthesia imposed a negative chronotropic effect on HR in the group given HNRT. Therefore, one should be watchful for bradycardia in these patients; particularly those with low BPs. Their hemodynamics may rapidly progress into an unstable status when bradycardia and hypotension develop altogether.

Prospective Study of Surgical Decision-making Processes for Contralateral Prophylactic Mastectomy in Women With Breast Cancer.

OBJECTIVE: We prospectively examined the psychosocial predictors and the decision-making process regarding contralateral prophylactic mastectomy (CPM) among women with sporadic breast cancer. BACKGROUND: Increasing numbers of women with breast cancer are seeking CPM. Data are limited about the surgical decision-making process and the psychosocial factors that influence interest in CPM. METHODS: Women with early-stage unilateral breast cancer (n = 117) were recruited before their first surgical visit at MD Anderson and completed questionnaires assessing knowledge of and interest in CPM and associated psychosocial factors. After the appointment, women and their surgeons completed questions about the extent that various surgical options (including CPM) were discussed; also, the women rated their perceived likelihood of having CPM and the surgeons rated the appropriateness of CPM. RESULTS: Before their first visit, 50% of women were moderately to extremely interested in CPM and 12 (10%) of women had CPM at the time of their primary breast cancer surgery. Less knowledge about breast cancer (P = 0.02) and greater cancer worry (P = 0.03) predicted interest in CPM. Greater cancer worry predicted who had CPM (P = 0.02). Interest in CPM before surgical visit and the likelihood of having CPM after the visit differed (P ≤ 0.001). Surgeons' rating of the appropriateness of CPM and the patient's reported likelihood of having CPM were not significantly different (P = 0.49). CONCLUSIONS: Interest in CPM is common among women with sporadic breast cancer. The informational and emotional aspects of CPM may affect the decision to have CPM and should be addressed when discussing surgical options.

Analysis of Charges Associated with Definitive Nonsurgical Therapy for Early-Stage Lateralized Tonsil Cancer.

OBJECTIVE: The cost of treatment as it affects comparative effectiveness is becoming increasingly more important. Because cost data are not readily available, we evaluated the charges associated with definitive nonsurgical therapy for early-stage lateralized tonsil cancers. METHODS: Patients treated with unilateral radiation therapy (RT) for T1 or T2 tonsil cancer between 1995 and 2007 were retrospectively reviewed. Total and radiation-specific charges, from 3 months before to 4 months after radiation, were adjusted for inflation. All facets of treatment were evaluated for significant associations with total billing. RESULTS: Eighty-four patients were identified. Three-year overall survival, disease-specific survival, and recurrence-free survival were 97 % [95 % confidence interval (CI) 0.88-0.99], 98 % (95 % CI 0.89-1), and 96 % (95 % CI 0.88-0.99), respectively. The median for radiation-specific charges was $60,412 (range $16,811-$84,792). The median for total charges associated with treatment was $109,917 (range $36,680-$231,895). Total billing for treatment was significantly associated with the year of diagnosis (p = 0.008), intensity-modulated radiation therapy versus wedge pair RT (p = 0.005), preradiation direct laryngoscopy (p < 0.0001), chemotherapy (p < 0.0001), gastrostomy tube placement (p = 0.004), and postradiation neck dissection (p = 0.005). CONCLUSIONS: Although cost data for treatment are not readily available, historically, the recovery rate is approximately 30 %. The charges associated with definitive nonsurgical therapy for early-stage lateralized tonsil cancer have a wide range likely due to treatment-related procedures, the use of chemotherapy, and evolving RT technologies. These benchmark data are important given renewed interested in primary surgery for tonsil cancer. Cost of care, disease control, and functional outcomes will be critical for comparisons of effectiveness when selecting treatment modalities.

Sorafenib in metastatic thyroid cancer: a systematic review.

BACKGROUND: Sorafenib was recently approved by the U.S. Food and Drug Administration for radioiodine-resistant metastatic differentiated thyroid cancer (DTC). In addition, two drugs (vandetanib and cabozantinib) have received U.S. Food and Drug Administration approval for use in medullary thyroid cancer (MTC). Several published phase II trials have investigated the efficacy of sorafenib in thyroid cancers, but to date, results from those studies have not been compared. METHODS: A systematic review of the literature was performed to assess response rate, median progression-free survival, and adverse events associated with sorafenib therapy for metastatic thyroid cancers. RESULTS: This review included seven trials involving 219 patients: 159 with DTC (papillary, follicular, and poorly differentiated), 52 with MTC, and 8 with anaplastic thyroid cancer. No study reported complete responses to treatment. Overall partial response, stable disease, and progressive disease rates were 21%, 60%, and 20%, respectively. The median progression-free survival was 18 months for patients with all subtypes of thyroid cancer. Drug was discontinued in 16% of patients because of toxicities or intolerance, and the dose was reduced in a further 56%. Side effects with an incidence ≥ 50% were hand-foot syndrome (74%), diarrhea (70%), skin rash (67%), fatigue (61%), and weight loss (57%). Deaths not related to progressive disease occurred in nearly 4% of patients. CONCLUSION: Treatment with sorafenib in patients with progressive DTC and MTC is a promising strategy, but the adverse event rate is high, leading to a high rate of dose reduction or discontinuation. Consequently, sorafenib use in patients with metastatic thyroid cancer requires careful selection of patients and careful management of side effects.

First do no harm: population-based study shows non-evidence-based trastuzumab prescription may harm elderly women with breast cancer.

Trastuzumab, although cardiotoxic, is associated with improved survival in HER2-positive breast cancer. Non-compliance with HER2 testing guidelines before prescribing trastuzumab occurs in practice; however, the clinical consequences are unclear. Using SEER-Medicare database (2000-2009), we assessed differences in baseline characteristics between women ≥ 65 with breast cancer who received and did not receive HER2 testing prior to trastuzumab prescription. We used propensity score matched-pair analysis to balance the confounders between these two groups. We assessed the differences in overall survival and 3-year rates of avoiding congestive heart failure (CHF) between women who received trastuzumab without HER2 testing (trastuzumab group) and women who had chemotherapy but did not receive trastuzumab (irrespective of testing) (chemo-only group). Based on the matched data, we used Cox regression in these assessments with double robust estimation or with stratification. Among women who received trastuzumab, 140 (4.7 %) had no documentation of HER2 testing. Breast surgery, south residential region, and an earlier year of diagnosis were predictive of no HER2 testing in multivariate logistic regression. Women in the chemo-only group had similar overall survival (HR = 1.28; P = 0.108) over an 8-year follow-up post-diagnosis and significantly higher likelihood of avoiding CHF over 3 years after the first administration of chemotherapy or trastuzumab (HR = 1.66, P = 0.036) compared to women in the trastuzumab group, using the propensity score-matched data. Non-evidence-based prescription of trastuzumab is associated with increased rates of CHF with no additional survival benefit among older women with breast cancer. Inappropriate prescriptions of targeted therapies agent can lead to detrimental health and financial consequences.

Cost of contralateral prophylactic mastectomy.

PURPOSE: To compare the healthcare costs of women with unilateral breast cancer who underwent contralateral prophylactic mastectomy (CPM) with those of women who did not. METHODS: We conducted a retrospective study of 904 women treated for stage I-III breast cancer with or without CPM. Women were matched according to age, year at diagnosis, stage, and receipt of chemotherapy. We included healthcare costs starting from the date of surgery to 24 months. We identified whether care was immediate or delayed (CPM within 6 months or 6-24 months after initial surgery, respectively). Costs were converted to approximate Medicare reimbursement values and adjusted for inflation. Multivariable regression analysis was performed to evaluate the effect of CPM on total breast cancer care costs adjusting for patient characteristics and accounting for matched pairs. RESULTS: The mean difference between the CPM and no-CPM matched groups was $3,573 (standard error [SE] $455) for professional costs, $4,176 (SE $1,724) for technical costs, and $7,749 (SE $2,069) for total costs. For immediate and delayed CPM, the mean difference for total costs was $6,528 (SE $2,243) and $16,744 (SE $5,017), respectively. In multivariable analysis, the CPM group had a statistically significant increase of 16.9 % in mean total costs compared with the no-CPM group (p < 0.0001). Human epidermal growth factor receptor 2/neu-positive status, receipt of radiation, and reconstruction were associated with increases in total costs. CONCLUSIONS: CPM significantly increases short-term healthcare costs for women with unilateral breast cancer. These patient-level cost results can be used for future studies that evaluate the influence of costs of CPM on decision making.