A Randomized Phase II Study of Sequential Eribulin Versus Paclitaxel Followed by FAC/FEC as Neoadjuvant Therapy in Patients with Operable HER2-Negative Breast Cancer.

LESSONS LEARNED: The combination of eribulin with 5-fluorouracil, either doxorubicin or epirubicin, and cyclophosphamide (FAC/FEC) was not superior to the combination of paclitaxel with FAC/FEC and was associated with greater hematologic toxicity. Eribulin followed by an anthracycline-based regimen is not recommended as a standard neoadjuvant therapy in nonmetastatic operable breast cancer. BACKGROUND: Neoadjuvant systemic therapy is the standard of care for locally advanced operable breast cancer. We hypothesized eribulin may improve the pathological complete response (pCR) rate compared with paclitaxel. METHODS: We conducted a 1:1 randomized open-label phase II study comparing eribulin versus paclitaxel followed by 5-fluorouracil, either doxorubicin or epirubicin, and cyclophosphamide (FAC/FEC) in patients with operable HER2-negative breast cancer. pCR and toxicity of paclitaxel 80 mg/m2 weekly for 12 doses or eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle for 4 cycles followed by FAC/FEC were compared. RESULTS: At the interim futility analysis, in March 2015, 51 patients (28 paclitaxel, 23 eribulin) had received at least one dose of the study drug and were thus evaluable for toxicity; of these, 47 (26 paclitaxel, 21 eribulin) had undergone surgery and were thus evaluable for efficacy. Seven of 26 (27%) in the paclitaxel group and 1 of 21 (5%) in the eribulin group achieved a pCR, and this result crossed a futility stopping boundary. In the paclitaxel group, the most common serious adverse events (SAEs) were neutropenic fever (grade 3, 3 patients, 11%). In the eribulin group, nine patients (39%) had neutropenia-related SAEs, and one died of neutropenic sepsis. The study was thus discontinued. For the paclitaxel and eribulin groups, the 5-year event-free survival (EFS) rates were 81.8% and 74.0% (hazard ratio [HR], 1.549; 95% confidence interval [CI], 0.817-2.938; p = .3767), and the 5-year overall survival (OS) rates were 100% and 84.4% (HR, 5.813; 95% CI, 0.647-52.208; p = .0752), respectively. CONCLUSION: We did not observe a higher proportion of patients undergoing breast conservation surgery in the eribulin group than in the paclitaxel group. The patients treated with eribulin were more likely to undergo mastectomy and less likely to undergo breast conservation surgery, but the difference was not statistically significant. As neoadjuvant therapy for operable HER2-negative breast cancer, eribulin followed by FAC/FEC is not superior to paclitaxel followed by FAC/FEC and is associated with a higher incidence of neutropenia-related serious adverse events.

ANETT: PhAse II trial of NEoadjuvant TAK-228 plus Tamoxifen in patients with hormone receptor-positive breast cancer.

INTRODUCTION: Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer. METHODS: In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed. RESULTS: Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p < 0.0001). There were no pathologic complete responses. CONCLUSION: Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.

G6PD deficiency and severity of COVID19 pneumonia and acute respiratory distress syndrome: tip of the iceberg?

The severe pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has inflicted heavy casualties, especially among the elderly and those with co-morbid illnesses irrespective of their age. The high mortality in African-Americans and males, in general, raises the concern for a possible X-linked mediated process that could affect the viral pathogenesis and the immune system. We hypothesized that G6PD, the most common X-linked enzyme deficiency, associated with redox status, may have a role in severity of pneumonia. Retrospective chart review was performed in hospitalized patients with COVID19 pneumonia needing supplemental oxygen. A total of 17 patients were evaluated: six with G6PD deficiency (G6PDd) and 11 with normal levels. The two groups (normal and G6PDd) were comparable in terms of age, sex, co-morbidities, and laboratory parameters-LDH, IL-6, CRP, and ferritin, respectively. Thirteen patients needed ventilatory support ; 8 in the normal group and 5 in the G6PDd group (72% vs.83%). The main differences indicating increasing severity in normal vs. G6PDd groups included G6PD levels (12.2 vs. 5.6, P = 0.0002), PaO2/FiO2 ratio (159 vs. 108, P = 0.05), days on mechanical ventilation (10.25 vs. 21 days P = 0.04), hemoglobin level (10 vs. 8.1 P = 0.03), and hematocrit (32 vs. 26 P = 0.015). Only one patient with G6PDd died; 16 were discharged home. Our clinical series ascribes a possible biological role for G6PDd in SARS-CoV2 viral proliferation. It is imperative that further studies are performed to understand the interplay between the viral and host factors in G6PDd that may lead to disparity in outcomes. KEY POINTS: • COVID19 studies show higher mortality in men, due to severe pneumonia and ARDS, indicating possible X-linked mediated differences • G6PD, the most common X-linked enzymopathy, highly prevalent in African Americans and Italians, maintains redox homeostasis. • Preclinical studies using G6PD deficient (G6PDd) cells infected with human coronavirus (hCoV), show impaired cellular responses, viral proliferation and worsening oxidative damage. • Retrospective chart review in hospitalized patients with COVID19 pneumonia needing supplemental oxygen shows differences between the two groups (Normal and G6PDd) in hematological indices; the G6PDdgroup demonstrated prolonged PaO2/FiO2 ratio, and longer days on mechanical ventilation indicating the severity of the pneumonia.

Evaluation of efficacy and safety of pegfilgrastim when given less than two weeks from dose-dense chemotherapy regimens.

INTRODUCTION: In clinical practice, waiting 14 days between the administration of pegfilgrastim and subsequent chemotherapy cycle (as recommended by the prescribing information) is sometimes not feasible with multi-cycle dose-dense regimens. This study evaluated the practice related to the use of pegfilgrastim in oncology patients at a multi-hospital health system. METHODS: Patients who received pegfilgrastim as primary prophylaxis following dose-dense chemotherapy scheduled every 14 days were included. The primary endpoint was the impact of <14 elapsed days between pegfilgrastim administration and next chemotherapy cycle on the change in mean absolute neutrophil counts (ANC). A generalized linear mixed-effects model with fixed effects for pegfilgrastim delivery method, elapsed days between pegfilgrastim and chemotherapy (fixed categorical effect for 12, 13, 14 days), and ANC at subsequent cycle was fitted to the change in ANC between chemotherapy cycles. RESULTS: One hundred and sixty four patients with breast cancer who received pegfilgrastim support for dose dense doxorubicin and cyclophosphamide (ddAC) qualified for the model. The mean age was 52 ± 12 years. Eighty-eight percent received pegfilgrastim on-body injector while 13% received pegfilgrastim injection. The mean number of elapsed days between pegfilgrastim and subsequent chemotherapy was 13 ± 0.5 days. The method of pegfilgrastim delivery and elapsed days between pegfilgrastim and chemotherapy administration had no significant effect on the change in ANC (p = 0.8663 and p = 0.8434 respectively); however, patient's age (p = 0.0125) had a significant effect on the change in ANC. CONCLUSION: The study findings suggest safety and efficacy when chemotherapy is administered 12-14 days from pegfilgrastim.

A randomized, controlled phase II trial of neoadjuvant ado-trastuzumab emtansine, lapatinib, and nab-paclitaxel versus trastuzumab, pertuzumab, and paclitaxel in HER2-positive breast cancer (TEAL study).

BACKGROUND: Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. METHODS: Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. RESULTS: The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms. CONCLUSION: In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. TRIAL REGISTRATION: Clinicaltrials.gov NCT02073487 , February 27, 2014.

Detection of breast cancer stem cell gene mutations in circulating free DNA during the evolution of metastases.

PURPOSE: Limited knowledge exists on the detection of breast cancer stem cell (BCSC)-related mutations in circulating free DNA (cfDNA) from patients with advanced cancers. Identification of new cancer biomarkers may allow for earlier detection of disease progression and treatment strategy modifications. METHODS: We conducted a prospective study to determine the feasibility and prognostic utility of droplet digital polymerase chain reaction (ddPCR)-based BCSC gene mutation analysis of cfDNA in patients with breast cancer. RESULTS: Detection of quantitative BCSC gene mutation in cfDNA by ddPCR mirrors disease progression and thus may represent a valuable and cost-effective measure of tumor burden. We have previously shown that hematological and neurological expressed 1-like (HN1L), ribosomal protein L39 (RPL39), and myeloid leukemia factor 2 (MLF2) are novel targets for BCSC self-renewal, and targeting these genetic alterations could be useful for personalized genomic-based therapy. CONCLUSION: BCSC mutation detection in cfDNA may have important implications for diagnosis, prognosis, and serial monitoring.

What Are the Effects of Irreversible Electroporation on a Staphylococcus aureus Rabbit Model of Osteomyelitis?

BACKGROUND: The treatment of osteomyelitis can be challenging because of poor antibiotic penetration into the infected bone and toxicities associated with prolonged antibiotic regimens to control infection. Irreversible electroporation (IRE), a percutaneous image-guided ablation technology in which the targeted delivery of high-voltage electrical pulses permanently damages the cell membrane, has been shown to effectively control bacterial growth in various settings. However, IRE for the management of bone infections has yet to be evaluated. QUESTIONS/PURPOSES: We aimed to evaluate IRE for treating osteomyelitis by assessing (1) the efficacy of IRE to suppress the in vitro growth of a clinical isolate of S. aureus, alone or combined with cefazolin; and (2) the effects of IRE on the in vivo treatment of a rabbit model of osteomyelitis. METHODS: S. aureus strain UAMS-1 expanded in vitro to the log phase was subjected to an electric field of 2700 V/cm, which was delivered in increasing numbers of pulses. Immediately after electroporation, bacteria were plated on agar plates with or without cefazolin. The number of colony-forming units (CFUs) was scored the following day. ANOVA tests were used to analyze in vitro data. In a rabbit osteomyelitis model, we inoculated the same bacterial strain into the radius of adult male New Zealand White rabbits. Three weeks after inoculation, all animals (n = 32) underwent irrigation and débridement, as well as wound culture of the infected forelimb. Then, they were randomly assigned to one of four treatment groups (n = eight per group): untreated control, cefazolin only, IRE only, or combined IRE + cefazolin. Serial radiography was performed to assess disease progression using a semiquantitative grading scale. Bone and soft-tissue specimens from the infected and contralateral forelimbs were collected at 4 weeks after treatment for bacterial isolation and histologic assessment using a semiquantitative scale. RESULTS: The in vitro growth of S. aureus UAMS-1 was impaired by IRE in a pulse-dependent fashion; the number of CFUs/mL was different among seven pulse levels, namely 0, 10, 30, 60, 90, 120, and 150 pulses. With the number of CFUs/mL observed in untreated controls set as 100%, 10 pulses rendered a median of 50.2% (range 47.1% to 58.2%), 30 pulses rendered a median of 2.7% (range 2.5% to 2.8%), 60 pulses rendered a median of 0.014% (range 0.012% to 0.015%), 90 pulses rendered a median of 0.004% (range 0.002% to 0.004%), 120 pulses rendered a median of 0.001% (range 0.001% to 0.001%), and 150 pulses rendered a median of 0.001% (range 0.000% to 0.001%) (Kruskal-Wallis test: p = 0.003). There was an interaction between the effect of the number of pulses and the concentration of cefazolin (two-way ANOVA: F [8, 30] = 17.24; p < 0.001), indicating that combining IRE with cefazolin is more effective than either treatment alone at suppressing the growth of S. aureus UAMS-1. Likewise, the clinical response in the rabbit model (the percentage of animals without detectable residual bacteria in the bone and surrounding soft tissue after treatment) was better in the combination group than in the other groups: control, 12.5% (one of eight animals); IRE only, 12.5% (one of eight animals); cefazolin only, 25% (two of eight animals); and IRE + cefazolin, 75% (six of eight animals) (two-sided Fisher's exact test: p = 0.030). CONCLUSIONS: IRE effectively suppressed the growth of S. aureus UAMS-1 and enhanced the antibacterial effect of cefazolin in in vitro studies. When translated to a rabbit osteomyelitis model, the addition of IRE to conventional parenteral antibiotic treatment produced the strongest response, which supports the in vitro findings. CLINICAL RELEVANCE: Our results show that IRE may improve the results of standard parenteral antibiotic treatment, thus setting the stage for models with larger animals and perhaps trials in humans for validation.

Development of an Electroporation and Nanoparticle-based Therapeutic Platform for Bone Metastases.

Purpose To assess for nanopore formation in bone marrow cells after irreversible electroporation (IRE) and to evaluate the antitumoral effect of IRE, used alone or in combination with doxorubicin (DOX)-loaded superparamagnetic iron oxide (SPIO) nanoparticles (SPIO-DOX), in a VX2 rabbit tibial tumor model. Materials and Methods All experiments were approved by the institutional animal care and use committee. Five porcine vertebral bodies in one pig underwent intervention (IRE electrode placement without ablation [n = 1], nanoparticle injection only [n = 1], and nanoparticle injection followed by IRE [n = 3]). The animal was euthanized and the vertebrae were harvested and evaluated with scanning electron microscopy. Twelve rabbit VX2 tibial tumors were treated, three with IRE, three with SPIO-DOX, and six with SPIO-DOX plus IRE; five rabbit VX2 tibial tumors were untreated (control group). Dynamic T2*-weighted 4.7-T magnetic resonance (MR) images were obtained 9 days after inoculation and 2 hours and 5 days after treatment. Antitumor effect was expressed as the tumor growth ratio at T2*-weighted MR imaging and percentage necrosis at histologic examination. Mixed-effects linear models were used to analyze the data. Results Scanning electron microscopy demonstrated nanopores in bone marrow cells only after IRE (P , .01). Average volume of total tumor before treatment (503.1 mm3 ± 204.6) was not significantly different from those after treatment (P = .7). SPIO-DOX was identified as a reduction in signal intensity within the tumor on T2*-weighted images for up to 5 days after treatment and was related to the presence of iron. Average tumor growth ratios were 103.0% ± 75.8 with control treatment, 154.3% ± 79.7 with SPIO-DOX, 77% ± 30.8 with IRE, and -38.5% ± 24.8 with a combination of SPIO-DOX and IRE (P = .02). The percentage residual viable tumor in bone was significantly less for combination therapy compared with control (P = .02), SPIO-DOX (P , .001), and IRE (P = .03) treatment. The percentage residual viable tumor in soft tissue was significantly less with IRE (P = .005) and SPIO-DOX plus IRE (P = .005) than with SPIO-DOX. Conclusion IRE can induce nanopore formation in bone marrow cells. Tibial VX2 tumors treated with a combination of SPIO-DOX and IRE demonstrate enhanced antitumor effect as compared with individual treatments alone. © RSNA, 2017 Online supplemental material is available for this article.

Correlating mammographic and pathologic findings in clinical decision support using natural language processing and data mining methods.

BACKGROUND: A key challenge to mining electronic health records for mammography research is the preponderance of unstructured narrative text, which strikingly limits usable output. The imaging characteristics of breast cancer subtypes have been described previously, but without standardization of parameters for data mining. METHODS: The authors searched the enterprise-wide data warehouse at the Houston Methodist Hospital, the Methodist Environment for Translational Enhancement and Outcomes Research (METEOR), for patients with Breast Imaging Reporting and Data System (BI-RADS) category 5 mammogram readings performed between January 2006 and May 2015 and an available pathology report. The authors developed natural language processing (NLP) software algorithms to automatically extract mammographic and pathologic findings from free text mammogram and pathology reports. The correlation between mammographic imaging features and breast cancer subtype was analyzed using one-way analysis of variance and the Fisher exact test. RESULTS: The NLP algorithm was able to obtain key characteristics for 543 patients who met the inclusion criteria. Patients with estrogen receptor-positive tumors were more likely to have spiculated margins (P = .0008), and those with tumors that overexpressed human epidermal growth factor receptor 2 (HER2) were more likely to have heterogeneous and pleomorphic calcifications (P = .0078 and P = .0002, respectively). CONCLUSIONS: Mammographic imaging characteristics, obtained from an automated text search and the extraction of mammogram reports using NLP techniques, correlated with pathologic breast cancer subtype. The results of the current study validate previously reported trends assessed by manual data collection. Furthermore, NLP provides an automated means with which to scale up data extraction and analysis for clinical decision support. Cancer 2017;114-121. © 2016 American Cancer Society.

Utility of Appendiceal Calcifications Detected on Computed Tomography as a Predictor for an Underlying Appendiceal Epithelial Neoplasm.

BACKGROUND: Mucinous appendiceal neoplasms can contain radiopaque calcifications. Whether appendiceal radiographic calcifications indicate the presence of an appendiceal epithelial neoplasm is unknown. This study aimed to determine whether appendiceal calcifications detected by computed tomography (CT) correlate with the presence of appendiceal epithelial neoplasms. METHODS: From prospective appendiceal and pathology databases, 332 cases of appendiceal neoplasm and 136 cases of control appendectomy were identified, respectively. Only cases with preoperative CT scans available for review were included in the study. Images were reviewed by two abdominal radiologists. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated, and the kappa statistic was used to determine agreement between the radiologists' interpretations. RESULTS: Interobserver agreement between the radiologists was substantial, with a kappa of 0.74. Appendiceal mural calcifications were identified on CT scans in 106 appendiceal neoplasm cases (32%) and in 1 control case (1%) (P = 0.0001). In the appendiceal neoplasm subgroup, the presence of radiographic calcifications was associated with mucinous histology (35% vs 17%; P = 0.006; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.78) and with well-differentiated histologic grade (40% vs 24%; P = 0.002; OR, 0.47; 95% CI, 0.29-0.76). The findings showed a sensitivity of 31.9% (95% CI, 26.9-37.2%), a specificity of 99.3% (95% CI, 96-100%), a PPV of 99.1% (95% CI, 94.9-100%), and an NPV of 37.4% (95% CI, 32.4-42.6%). CONCLUSION: This case-control study showed that appendiceal mural calcifications detected on CT are associated with underlying appendiceal epithelial neoplasms and that the identification of incidental mural appendiceal calcifications may have an impact on decisions regarding surgical intervention.

Prognostic value of incidental hypervascular micronodules detected on cone-beam computed tomography angiography of patients with liver metastasis.

PURPOSE: To determine the clinical relevance of incidentally-found hypervascular micronodules (IHM) on cone-beam computed tomography angiography (CBCTA) in patients with liver metastasis undergoing transarterial (chemo)embolization (TACE/TAE). MATERIAL AND METHODS: This was a HIPAA-compliant institutional review board-approved single-institution retrospective review of 95 non-cirrhotic patients (52 men; mean age, 60 years) who underwent CBCTA prior to (chemo)embolic delivery. IHM were defined by the presence of innumerable subcentimetre hepatic parenchymal hypevascular foci not detected on pre-TACE/TAE contrast-enhanced cross-sectional imaging. Multivariate analysis was performed to compare time to tumour progression (TTP) between patients with and without IHM. RESULTS: IHM were present in 21 (22%) patients. Patients with IHM had a significantly shorter intrahepatic TTP determined by a higher frequency of developing new liver metastasis (hazard ratio [HR]: 1.99; 95% confidence interval [CI] 1.08-3.67, P= 0.02). Patients with IHM trended towards a shorter TTP of the tumour(s) treated with TACE/TAE (HR: 1.72; 95% CI: 0.98-3.01, P= 0.056). Extrahepatic TTP was not significantly different between the two cohorts (P= 0.27). CONCLUSION: Patients with IHM on CBCTA have worse prognosis due to a significantly higher risk of developing new hepatic tumours. Further work is needed to elucidate its underlying mechanisms of pathogenesis. KEY POINTS: • 21% of liver metastasis patients undergoing TACE/TAE have IHM on CBTA. • IHM are associated with a high risk of developing new hepatic tumours. • IHA are also associated with a trend toward poorer response to TACE/TAE.

Development of a predictive model for 6 month survival in patients with venous thromboembolism and solid malignancy requiring IVC filter placement.

PURPOSE: Our purpose was to develop a predictive model for short-term survival (i.e. <6 months) following inferior vena cava filter placement in patients with venous thromboembolism (VTE) and solid malignancy. METHODS: Clinical and laboratory parameters were retrospectively reviewed for patients with solid malignancy who received a filter between January 2009 and December 2011 at a tertiary care cancer center. Multivariate Cox proportional hazards modeling was used to assess variables associated with 6 month survival following filter placement in patients with VTE and solid malignancy. Significant variables were used to generate a predictive model. RESULTS: 397 patients with solid malignancy received a filter during the study period. Three variables were associated with 6 month survival: (1) serum albumin [hazard ratio (HR) 0.496, P < 0.0001], (2) recent or planned surgery (<30 days) (HR 0.409, P < 0.0001), (3) TNM staging (stage 1 or 2 vs. stage 4, HR 0.177, P = 0.0001; stage 3 vs. stage 4, HR 0.367, P = 0.0002). These variables were used to develop a predictive model to estimate 6 month survival with an area under the receiver operating characteristic curve of 0.815, sensitivity of 0.782, and specificity of 0.715. CONCLUSIONS: Six month survival in patients with VTE and solid malignancy requiring filter placement can be predicted from three patient variables. Our predictive model could be used to help physicians decide whether a permanent or retrievable filter may be more appropriate as well as to assess the risks and benefits for filter retrieval within the context of survival longevity in patients with cancer.

Cell-free DNA as a molecular tool for monitoring disease progression and response to therapy in breast cancer patients.

Due to the spatial and temporal genomic heterogeneity of breast cancer, genomic sequencing obtained from a single biopsy may not capture the complete genomic profile of tumors. Thus, we propose that cell-free DNA (cfDNA) in plasma may be an alternate source of genomic information to provide comprehensive data throughout a patient's clinical course. We performed a retrospective chart review of 100 patients with stage 4 or high-risk stage 3 breast cancer. The degree of agreement between genomic alterations found in tumor DNA (tDNA) and cfDNA was determined by Cohen's Kappa. Clinical disease progression was compared to mutant allele frequency using a two-sided Fisher's exact test. The presence of mutations and mutant allele frequency was correlated with progression-free survival (PFS) using a Cox proportional hazards model and a log-rank test. The most commonly found genomic alterations were mutations in TP53 and PIK3CA, and amplification of EGFR and ERBB2. PIK3CA mutation and ERBB2 amplification demonstrated robust agreement between tDNA and cfDNA (Cohen's kappa = 0.64 and 0.77, respectively). TP53 mutation and EGFR amplification demonstrated poor agreement between tDNA and cfDNA (Cohen's kappa = 0.18 and 0.33, respectively). The directional changes of TP53 and PIK3CA mutant allele frequency were closely associated with response to therapy (p = 0.002). The presence of TP53 mutation (p = 0.0004) and PIK3CA mutant allele frequency [p = 0.01, HR 1.074 (95 % CI 1.018-1.134)] was excellent predictors of PFS. Identification of selected cancer-specific genomic alterations from cfDNA may be a noninvasive way to monitor disease progression, predict PFS, and offer targeted therapy.

Irreversible Electroporation in the Epidural Space of the Porcine Spine: Effects on Adjacent Structures.

Purpose To determine the effects of irreversible electroporation (IRE) on the neural tissues after ablation in the epidural space of the porcine spine. Materials and Methods The institutional animal care and use committee approved this study. With the IRE electrode positioned in the right lateral recess of the spinal epidural space, 20 IRE ablations were performed with computed tomographic (CT) guidance by using different applied voltages in four animals that were euthanized immediately after magnetic resonance (MR) imaging of the spine, performed 6 hours after IRE (terminal group). Histopathologic characteristics of the neural tissues were assessed and used to select a voltage for a survival study. Sixteen CT-guided IRE ablations in the epidural space were performed by using 667 V in four animals that were survived for 7 days (survival group). Clinical characteristics, MR imaging findings (obtained 6 hours after IRE and before euthanasia), histopathologic characteristics, and simulated electric field strengths were assessed. A one-way analysis of variance was used to compare the simulated electric field strength to histologic findings. Results The mean distance between the IRE electrode and the spinal cord and nerve root was 1.71 mm ± 0.90 and 8.47 mm + 3.44, respectively. There was no clinical evidence of paraplegia after IRE ablation. MR imaging and histopathologic examination showed no neural tissue lesions within the spinal cord; however, five of 16 nerve roots (31.2%) demonstrated moderate wallerian degeneration in the survival group. The severity of histopathologic injury in the survival group was not significantly related to either the simulated electric field strength or the distance between the IRE electrode and the neural structure (P > .05). Conclusion Although the spinal cord appears resistant to the toxic effects of IRE, injury to the nerve roots may be a limiting factor for the use of IRE ablation in the epidural space. © RSNA, 2016 Online supplemental material is available for this article.

Two Decades of ICU Utilization and Hospital Outcomes in a Comprehensive Cancer Center.

OBJECTIVE: To investigate ICU utilization and hospital outcomes of oncological patients admitted to a comprehensive cancer center. DESIGN: Observational cohort study. SETTING: The University of Texas MD Anderson Cancer Center. PATIENTS: Consecutive adults with cancer discharged over a 20-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The Cochran-Armitage test for trend was used to evaluate ICU utilization and hospital mortality rates by primary service over time. A negative binomial log linear regression model was fitted to the data to investigate length of stay over time. Among 387,306 adult hospitalized patients, the ICU utilization rate was 12.9%. The overall hospital mortality rate was 3.6%: 16.2% among patients with an ICU stay and 1.8% among non-ICU patients. Among those admitted to the ICU, the mean (SD) admission Sequential Organ Failure Assessment score was 6.1 (3.8) for all ICU patients: 7.3 (4.4) for medical ICU patients and 4.9 (2.8) for surgical ICU patients. Hematologic disorders were associated with the highest hospital mortality rate in ICU patients (42.8%); metastatic disease had the highest mortality rate in non-ICU patients (4.2%); sepsis, pneumonia, and other infections had the highest mortality rate for all inpatients (8.5%). CONCLUSIONS: This study provides a longitudinal view of ICU utilization rates, hospital and ICU length of stay, and severity-adjusted mortality rates. Although the data arise from a single institution, it encompasses a large number of hospital admissions over two decades and can serve as a point of comparison for future oncological studies at similar institutions. More studies of this nature are needed to determine whether consolidation of cancer care into specialized large-volume facilities may improve outcomes, while simultaneously sustaining appropriate resource utilization and reducing unnecessary healthcare costs.

Performance and prognostic utility of the 92-gene assay in the molecular subclassification of ampullary adenocarcinoma.

BACKGROUND: Ampullary adenocarcinoma is a rare gastrointestinal cancer associated with diverse outcomes due to clinical and pathological heterogeneity. Standardized methods to better prognosticate and inform therapeutic selection for ampullary adenocarcinoma are needed. This study explored the novel use and potential prognostic utility of a 92-gene cancer classifier in ampullary adenocarcinomas. METHODS: In this prospectively-defined, blinded study of ampullary adenocarcinoma [N =54; stage T3 or higher (57 %); Grade III (44 %); Node positive (55 %)], the performance of a 92-gene classifier was examined to predict the ampullary subtype that was derived from histomorphological examination of resected ampullary samples. Outcome data for relapse-free survival (RFS) and overall survival (OS) were plotted to compare the prognostic utility of histological subtyping, histomolecular phenotyping, and the 92-gene classifier. Multivariate analysis was used to determine clinicopathological variables that were independently associated with overall survival. RESULTS: The 92-gene classifier demonstrated sensitivities and specificities of 85 % [95 % CI, 66-94] and 68 % [95 % CI, 48-84] and 64 % [95 % CI, 46-79] and 88 % [95 % CI, 70-98] for the pancreaticobiliary and intestinal histological subtypes, respectively. For the 92-gene classifier, improved outcomes were observed for the intestine versus the pancreaticobiliary prediction (median OS 108.1 v 36.4 months; HR, 2.17; 95 % CI, 0.98 to 4.79; P = 0.05). Similar results were seen for ampullary adenocarcinoma stratification by histological subtype (P = 0.04) and histomolecular phenotype (P = 0.02). Within poorly differentiated ampullary adenocarcinomas only the 92-gene classifier demonstrated statistically significant differences in RFS and OS (P < 0.05). CONCLUSIONS: Prognostic stratification of ampullary adenocarcinoma was similar for the 92-gene classifier, histological subtype, and histomolecular phenotype. The 92-gene classifier provides an unbiased standardized molecular-based approach to stratify ampullary tumors.

Prognosis for patients with metastatic breast cancer who achieve a no-evidence-of-disease status after systemic or local therapy.

BACKGROUND: This study sought to determine outcomes for patients with metastatic breast cancer (MBC) with no evidence of disease (NED) after treatment and to identify factors predictive of outcomes once the status of NED was attained. METHODS: This study reviewed 570 patients with MBC who were consecutively treated between January 2003 and December 2005. Ninety patients (16%) attained NED, which was defined as a complete metabolic response on positron emission tomography or sclerotic healing of bone metastases on computed tomography or magnetic resonance imaging. The median follow-up for patients attaining NED was 100 months (range, 14-134 months). RESULTS: The 3- and 5-year overall survival (OS) rates were 44% and 24%, respectively, for the entire group and 96% and 78%, respectively, for those attaining NED. According to a landmark analysis, NED status was significantly associated with survival at 2 (P < .001; hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34) and 3 years (P < .001; HR, 0.20; 95% CI, 0.14-0.30). From the time of NED, the median survival was 102 months (range, 14-134 months) with 5-year OS and progression-free survival (PFS) rates of 77% and 40%, respectively. According to a multivariate analysis, human epidermal growth factor receptor 2 positivity was significantly associated with OS in comparison with estrogen receptor positivity (P = .02; HR, 0.44; 95% CI, 0.21-0.90), and trastuzumab use was significantly associated with PFS (P = .007; HR, 0.48; 95% CI, 0.28-0.82). Thirty-one patients (34%) with NED remained in remission at the last follow-up. CONCLUSIONS: MBC patients who attain the status of NED have significantly prolonged survival with a durable response to therapy. Ultimately, this study provides essential outcome data for clinicians and patients living with MBC.

Safety and diagnostic accuracy of percutaneous biopsy in upper tract urothelial carcinoma.

OBJECTIVE: To assess the diagnostic accuracy and safety of percutaneous biopsy for upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: From 2002 to 2013, 26 upper tract lesions in 24 patients (20 men; median [range] age 67.8 [51.7-85.9] years) were percutaneously biopsied. Analysis was separated based on lesion appearance: (i) mass infiltrating renal parenchyma, (ii) filling defect in the collecting system, (iii) urothelial wall thickening. We tracked immediate complications and tract seeding on follow-up imaging. RESULTS: Of the 26 upper tract lesions, 15 (58%) were masses infiltrating the renal parenchyma (mean [range] size 5.4 [1.1-14.0] cm), six (23%) were urothelial wall thickenings (mean [range] size 0.8 [0.4-1.1] cm), and five (19%) were filling defects within the renal pelvis or calyx (mean [range] size 2.7 [1.0-4.6] cm). Definitive diagnosis of UTUC was made by biopsy in 22 of 26 lesions (85%). Biopsy characterised 14 of 15 infiltrative masses and five of five filling defects; biopsy characterised three of six cases of urothelial wall thickening. CT follow-up was available for 19 patients (73%) at a median (range) of 13.6 (1.0-98.9) months. Three patients (11%) developed recurrence in the nephrectomy bed at 5.6, 9.7, and 29.0 months after biopsy; none were attributed to tract seeding after independent review, because recurrence was remote from the biopsy site. CONCLUSION: Percutaneous biopsy is effective for diagnosis of UTUC, providing tissue diagnosis in 85% of cases. While case reports cite a risk of tract seeding, no cases of recurrence were definitely attributable to percutaneous biopsy. Thus, for upper tract urothelial lesions, which are not amenable to endoscopic biopsy, percutaneous biopsy is a safe and effective technique.

JOURNAL CLUB: Standardizing CT-Guided Biopsy Procedures: Patient Dose and Image Noise.

OBJECTIVE: The objective of this study was to standardize our image acquisition protocol for CT-guided biopsy procedures. MATERIALS AND METHODS: The records of consecutive patients who underwent CT-guided biopsy 3 months before (n = 598 biopsies) and 3 months after (n = 540 biopsies) standardization of our image acquisition protocol were retrospectively reviewed. CT technical parameters were individualized on the basis of the sum of the anteroposterior and transverse dimensions of the patient. Information on patient demographic characteristics, biopsy site, complications associated with the procedure, and diagnostic yield was collected. The radiation dose metrics that were evaluated included the volume CT dose index, dose-length product, and size-specific dose estimate. Image noise was quantified using the SD of the CT number measured in subcutaneous fat. Fisher exact test and one-way ANOVA were used to evaluate statistical significance. RESULTS: The mean dose-length product decreased by 72.3% (from 699.7 to 193.9 mGy × cm; p < 0.0001), and statistically significant decreases in dose-length product were observed when data were stratified according to biopsy site (i.e., lung, solid organ, lymph node, or bone; for all sites, p < 0.0001). The mean size-specific dose estimate decreased by 58.9% (from 125 to 51.4 mGy), which was statistically significant (p < 0.001). Image noise increased during the study period, but this increase was not statistically significantly different among the four biopsy sites (p = 0.46). CONCLUSION: Standardization of the image acquisition protocol used in CT-guided biopsy procedures significantly reduced patient radiation dose and decreased variability in image noise.

Biomarker validation: common data analysis concerns.

Biomarker validation, like any other confirmatory process based on statistical methodology, must discern associations that occur by chance from those reflecting true biological relationships. Validity of a biomarker is established by authenticating its correlation with clinical outcome. Validated biomarkers can lead to targeted therapy, improve clinical diagnosis, and serve as useful prognostic and predictive factors of clinical outcome. Statistical concerns such as confounding and multiplicity are common in biomarker validation studies. This article discusses four major areas of concern in the biomarker validation process and some of the proposed solutions. Because present-day statistical packages enable the researcher to address these common concerns, the purpose of this discussion is to raise awareness of these statistical issues in the hope of improving the reproducibility of validation study findings.