Nomogram Predicting Bladder Cancer-specific Mortality After Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-invasive Bladder Cancer: Results of an International Consortium.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy.

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

Evidence of Disseminated Intravascular Coagulation in a Porcine Model Following Radiation Exposure.

Recent evidence has suggested that disseminated intravascular coagulation (DIC) plays an integral role in death at the LD50 dose of either gamma or solar particle event (SPE)-like proton radiation in ferrets. In these studies, Yucatan minipigs were evaluated to determine whether they were susceptible to the development of radiation induced DIC. Yucatan minipigs were exposed to a dose of 2.5 Gray (Gy) with x-rays and monitored over the course of 30 days. Evidence of DIC was evaluated by way of thromboelastometry parameters, platelet counts, fibrinogen concentration, and the d-dimer assay. Pigs exposed to x-rays developed signs of DIC within 2 days post-irradiation. The development of DIC was exacerbated over the course of the studies, and one of the pigs died at day 14 and another had to be euthanized on day 16 post-irradiation. For both of these pigs, DIC was evident at the time of death. The following observations were indicated or were suggestive of DIC: whole blood clotting was impaired (as evidenced by thromboelastometry alterations), there were decreased platelet counts, elevated d-dimer concentrations in the blood, and/or hemorrhaging and the presence of fibrin in tissues observed during post-mortem examination. The extrapolation of data from these studies, in combination with other published data, have led to the hypothesis that there could be a correlation between the propensity to develop DIC, as indicated by hemorrhaging at death at relatively low doses of radiation, and the LD50 for a particular species. Our data suggest that the development of DIC may contribute to death at the LD50 dose in large mammals.

Wound Measurement Techniques: Comparing the Use of Ruler Method, 2D Imaging and 3D Scanner.

The statistics on the growing number of non-healing wounds is alarming. In the United States, chronic wounds affect 6.5 million patients. An estimated US $25 billion is spent annually on treatment of chronic wounds and the burden is rapidly growing due to increasing health care costs, an aging population and a sharp rise in the incidence of diabetes and obesity worldwide.(1) Accurate wound measurement techniques will help health care personnel to monitor the wounds which will indirectly help improving care.(7,9) The clinical practice of measuring wounds has not improved even today.(2,3) A common method like the ruler method to measure wounds has poor interrater and intrarater reliability.(2,3) Measuring the greatest length by the greatest width perpendicular to the greatest length, the perpendicular method, is more valid and reliable than other ruler based methods.(2) Another common method like acetate tracing is more accurate than the ruler method but still has its disadvantages. These common measurement techniques are time consuming with variable inaccuracies. In this study, volumetric measurements taken with a non-contact 3-D scanner are benchmarked against the common ruler method, acetate grid tracing, and 2-D image planimetry volumetric measurement technique. A liquid volumetric fill method is used as the control volume. Results support the hypothesis that the 3-D scanner consistently shows accurate volumetric measurements in comparison to standard volumetric measurements obtained by the waterfill technique (average difference of 11%). The 3-D scanner measurement technique was found more reliable and valid compared to other three techniques, the ruler method (average difference of 75%), acetate grid tracing (average difference of 41%), and 2D planimetric measurements (average difference of 52%). Acetate tracing showed more accurate measurements compared to the ruler method (average difference of 41% (acetate tracing) compared to 75% (ruler method)). Improving the accuracy in measuring chronic wounds might improve overall care of patients with non-healing wounds. This study consistently shows that the 3-D scanner is a more accurate, quicker, and safer method for measuring wounds.

Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis.

Caspases mediate apoptosis and have also been implicated in stem-cell biology. How caspases are linked to stem-cell biology is not known. Here, we show that the apoptotic blebs of cancer cells fuse together to form novel structures called 'blebbishields'. Blebbishields form spheres by fusion. Both blebbishield formation and sphere formation involve active caspases and N-linked glycosylation. Sphere formation is enhanced by acidic pH and is counteracted by inhibitors of proton pump, caspases, and cholesterol. The blebbishields from VEGFR2(High) cells are capable of enhanced sphere formation. Blebbishields express transiently downregulated stem-cell markers and the sphere-forming blebbishield-derived cells are tumorigenic. Our study demonstrates that the cancer stem cells can survive after apoptosis by blebbishield formation and subsequent sphere formation.

Determination of ideal PtcO2 measurement time in evaluation of hypoxic wound patients.

OBJECTIVE: Evaluation of ideal time for baseline PtcO2 readings in air, elevation test, and oxygen challenge during evaluation of hypoxic wound patients. DESIGN: Retrospective analysis. IRB APPROVAL: Western IRB deemed this study exempt from requiring IRB approval. PATIENTS: 202 patients with lower extremity wounds. METHOD: Patients had PtcO2 measurements using 6 electrodes positioned in 3 paired locations along the limb (above the knee: AK; below the knee: BK; and foot). Measurements were made from each electrode at 7 different time-event occasions: position of limb (supine or elevated), type of breathing gas (sea level air or oxygen), and time of measurement. A total of 8,484 measurements were analyzed by first examining each electrode's data, and then pooling the data for each location pair. MAIN RESULTS: PtcO2 readings for air (10 minutes) were less than air at 20 minutes. Maximal readings were close to the 20-minute mark for AK and BK measurements, and closer to 30 minutes for the foot. Elevation test at 3 versus 5 minutes showed a continuing decline in PtcO2 values. Oxygen challenge readings at 5 and 10 minutes were significantly different: the latter always larger than the former. CONCLUSION: Ideal times for baseline readings, leg elevation test, and oxygen challenge test are at least 20, 5, and 10 minutes, respectively.

Umbilical artery catheters and blood flow velocities in the superior mesenteric artery: effect of insertion, removal, aspiration, and bolus infusion.

PURPOSE: We studied whether umbilical artery catheters (UACs) affect blood flow in the superior mesenteric artery (SMA) of neonates. METHODS: Noninvasive duplex pulsed Doppler sonography was used to measure peak systolic velocity, end-diastolic velocity, and mean flow velocity in the SMA. The resistance index and pulsatility index were calculated from these data. Thirty-two infants weighing 450-2,520 g at birth were enrolled in the study. Gestational age at birth was 24-37 weeks. Eighteen infants were studied before and after UAC insertion. Twenty infants were studied before and after UAC removal. Eleven infants with UACs were studied before and during aspiration of blood from the UAC and during bolus infusion of 5% dextrose solution into the UAC. Data were compared before and after UAC insertion; before and after UAC removal; and before and during aspiration and during bolus infusion. RESULTS: Blood flow velocities and vascular resistance were similar in all comparisons except for increases in end-diastolic and mean velocities after UAC insertion. CONCLUSIONS: Insertion and removal of UACs, aspiration of blood from UACs, and bolus infusion of fluids into UACs do not diminish blood flow velocity or increase vascular resistance in the SMA.

Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome.

OBJECTIVE: To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome (ARDS). DESIGN: A prospective, double-blind, placebo-controlled, randomized, parallel, multicenter pilot clinical trial. PATIENTS: A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome. INTERVENTION: Patients were randomized into four treatment groups in a 2:1:2:1 ratio, as follows: 12 hours of surfactant per day, 12 hours of 0.6% saline per day, 24 hours of surfactant per day, and 24 hours of 0.6% saline per day. Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration. MAIN OUTCOME MEASURES: Ventilatory data, arterial blood gases, and hemodynamic parameters were measured at baseline, every 4 or 8 hours during the 5 days of treatment, 24 hours after treatment, and 30 days after treatment, at which time mortality was also assessed. Safety was evaluated throughout the 30 days of the study. RESULTS: Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system. Although there were no differences in any physiological parameters between the treatment groups, there was a dose-dependent trend in reduction of mortality from 47% in the combined placebo group to 41% and 35% in the groups treated with 12 hours and 24 hours of surfactant per day, respectively. CONCLUSIONS: Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days; however, at the doses given, it did not result in significant improvements in patients with sepsis-induced ARDS.

Extracorporeal membrane oxygenation in the successful treatment of traumatic adult respiratory distress syndrome: case report and review.

We present the case of a 25-year-old, 28-week pregnant woman with two gunshot wounds to the chest. Extracorporeal membrane oxygenation (ECMO) was begun within 12 hours, despite poor results in prior studies and the need for anticoagulation postoperatively, since oxygenation was rapidly deteriorating despite aggressive treatment. The patient ultimately made a full recovery.