Addressing long-term mortality risk in patients undergoing total pancreatectomy with islet autotransplant (TPIAT): causes of death and risk factors.

BACKGROUND: Total pancreatectomy with islet autotransplant (TPIAT) can improve quality of life for individuals with pancreatitis but creates health risks including diabetes, exocrine insufficiency, altered intestinal anatomy and function, and asplenia. METHODS: We studied survival and causes of death for 693 patients who underwent TPIAT between 2001 and 2020, using the National Death Index with medical records to ascertain survival after TPIAT, causes of mortality, and risk factors for death. We used Kaplan Meier curves to examine overall survival, and Cox regression and competing-risks methods to determine pre-TPIAT factors associated with all-cause and cause-specific post-TPIAT mortality. RESULTS: Mean age at TPIAT was 33.6 years (SD = 15.1). Overall survival was 93.1% (95% CI 91.2, 95.1%) 5 years after surgery, 85.2% (95% CI 82.0, 88.6%) at 10 years, and 76.2% (95% CI 70.8, 82.3%) at 15 years. Fifty-three of 89 deaths were possibly related to TPIAT; causes included chronic gastrointestinal complications, malnutrition, diabetes, liver failure, and infection/sepsis. In multivariable models, younger age, longer disease duration, and more recent TPIAT were associated with lower mortality. CONCLUSIONS: For patients undergoing TPIAT to treat painful pancreatitis, careful long-term management of comorbidities introduced by TPIAT may reduce risk for common causes of mortality.

Surgical approach and short-term outcomes in adults and children undergoing total pancreatectomy with islet autotransplantation: A report from the Prospective Observational Study of TPIAT.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a viable option for treating debilitating recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) in adults and children. No data is currently available regarding variation in approach to operation. METHODS: We evaluated surgical techniques, islet isolation and infusion approaches, and outcomes and complications, comparing children (n = 84) with adults (n = 195) enrolled between January 2017 and April 2020 by 11 centers in the United States in the Prospective Observational Study of TPIAT (POST), which was launched in 2017 to collect standard history and outcomes data from patients undergoing TPIAT for RAP or CP. RESULTS: Children more commonly underwent splenectomy (100% versus 91%, p = 0.002), pylorus preservation (93% versus 67%; p < 0.0001), Roux-en-Y duodenojejunostomy reconstruction (92% versus 35%; p < 0.0001), and enteral feeding tube placement (93% versus 63%; p < 0.0001). Median islet equivalents/kg transplanted was higher in children (4577; IQR 2816-6517) than adults (2909; IQR 1555-4479; p < 0.0001), with COBE purification less common in children (4% versus 15%; p = 0.0068). Median length of hospital stay was higher in children (15 days; IQR 14-22 versus 11 days; IQR 8-14; p < 0.0001), but 30-day readmissions were lower in children (13% versus 26%, p = 0.018). Rate of portal vein thrombosis was significantly lower in children than in adults (2% versus 10%, p = 0.028). There were no mortalities in the first 90 days post-TPIAT. CONCLUSIONS: Pancreatectomy techniques differ between children and adults, with islet yields higher in children. The rates of portal vein thrombosis and early readmission are lower in children.

Nonparametric estimation in an illness-death model with component-wise censoring.

In disease settings where study participants are at risk for death and a serious nonfatal event, composite endpoints defined as the time until the earliest of death or the nonfatal event are often used as the primary endpoint in clinical trials. In practice, if the nonfatal event can only be detected at clinic visits and the death time is known exactly, the resulting composite endpoint exhibits "component-wise censoring." The standard method used to estimate event-free survival in this setting fails to account for component-wise censoring. We apply a kernel smoothing method previously proposed for a marker process in a novel way to produce a nonparametric estimator for event-free survival that accounts for component-wise censoring. The key insight that allows us to apply this kernel method is thinking of nonfatal event status as an intermittently observed binary time-dependent variable rather than thinking of time to the nonfatal event as interval-censored. We also propose estimators for the probability in state and restricted mean time in state for reversible or irreversible illness-death models, under component-wise censoring, and derive their large-sample properties. We perform a simulation study to compare our method to existing multistate survival methods and apply the methods on data from a large randomized trial studying a multifactor intervention for reducing morbidity and mortality among men at above average risk of coronary heart disease.

Analysis of composite endpoints with component-wise censoring in the presence of differential visit schedules.

Composite endpoints are very common in clinical research, such as recurrence-free survival in oncology research, defined as the earliest of either death or disease recurrence. Because of the way data are collected in such studies, component-wise censoring is common, where, for example, recurrence is an interval-censored event and death is a right-censored event. However, a common way to analyze such component-wise censored composite endpoints is to treat them as right-censored, with the date at which the non-fatal event was detected serving as the date the event occurred. This approach is known to introduce upward bias when the Kaplan-Meier estimator is applied, but has more complex impact on semi-parametric regression approaches. In this article we compare the performance of the Cox model estimators for right-censored data and the Cox model estimators for interval-censored data in the context of component-wise censored data where the visit process differs across levels of a covariate of interest, a common scenario in observational data. We additionally examine estimators of the cause-specific hazard when applied to the individual components of such component-wise censored composite endpoints. We found that when visit schedules differed according to levels of a covariate of interest, the Cox model estimators for right-censored data and the estimators for cause-specific hazards were increasingly biased as the frequency of visits decreased. The Cox model estimator for interval-censored data with censoring at the last disease-free date is recommended for use in the presence of differential visit schedules.

Designing clinical trials with (restricted) mean survival time endpoint: Practical considerations.

BACKGROUND/AIMS: The difference in mean survival time, which quantifies the treatment effect in terms most meaningful to patients and retains its interpretability regardless of the shape of the survival distribution or the proportionality of the treatment effect, is an alternative endpoint that could be used more often as the primary endpoint to design clinical trials. The underuse of this endpoint is due to investigators' lack of familiarity with the test comparing the mean survival times and the lack of tools to facilitate trial design with this endpoint. The aim of this article is to provide investigators with insights and software to design trials with restricted mean survival time as the primary endpoint. METHODS: A closed-form formula for the asymptotic power of the test of restricted mean survival time difference is presented. The effects of design parameters on power were evaluated for the mean survival time test and log-rank test. An R package which calculates the power or the sample size for user-specified parameter values and provides power plots for each design parameter is provided. The R package also calculates the probability that the restricted mean survival time is estimable for user-defined trial designs. RESULTS: Under proportional hazards and late differences in survival, the power of the mean survival time test can approach that of the log-rank test if the restriction time is late. Under early differences, the power of the restricted mean survival time test is higher than that of the log-rank test. Duration of accrual and follow-up have little influence on the power of the restricted mean survival time test. The choice of restriction time, on the other hand, has a large impact on power. Because the power depends on the interplay among the design factors, plotting the relationship between each design parameter and power allows the users to select the designs most appropriate for their trial. When modification is necessary to ensure the difference in restricted mean survival time is estimable, the three available modifications all perform adequately in the scenarios studied. CONCLUSION: The restricted mean survival time is a survival endpoint that is meaningful to investigators and to patients and at the same time requires less restrictive assumptions. The biggest challenge with this endpoint is selection of the restriction time. We recommend selecting a restriction time that is clinically relevant to the disease and the clinical setting of the trial of interest. The practical considerations and the R package provided in this work are readily available tools that researchers can use to design trials with restricted mean survival time as the primary endpoint.

A win ratio approach to the re-analysis of Multiple Risk Factor Intervention Trial.

BACKGROUND: Composite outcomes, which combine multiple types of clinical events into a single outcome, are common in clinical trials. The usual analysis considers the time to first occurrence of any event in the composite. The major criticisms of such an approach are (1) this implicitly treats the outcomes as if they were of equal importance, but they often vary in terms of clinical relevance and severity, (2) study participants often experience more than one type of event, and (3) often less severe events occur before more severe ones, but the usual analysis disregards any information beyond that first event. METHODS: A novel approach, referred to as the win ratio, which addresses the aforementioned criticisms of composite outcomes, is illustrated with a re-analysis of data on fatal and non-fatal cardiovascular disease time-to-event outcomes reported for the Multiple Risk Factor Intervention Trial. In this trial, 12,866 participants were randomized to a special intervention group (n = 6428) or a usual care (n = 6438) group. Non-fatal outcomes were ranked by risk of cardiovascular disease death up to 20 years after trial. In one approach, participants in the special intervention and usual care groups were first matched on coronary heart disease risk at baseline and time of enrollment. Each matched pair was categorized as a winner or loser depending on which one experienced a cardiovascular disease death first. If neither died of cardiovascular disease causes, they were evaluated on the most severe non-fatal outcome. This process continued for all the non-fatal outcomes. A second win ratio statistic, obtained from Cox partial likelihood, was also estimated. This statistic provides a valid estimate of the win ratio using multiple events if the marginal and conditional survivor functions of each outcome satisfy proportional hazards. Loss ratio statistics (inverse of win ratios) are compared to hazard ratios from the usual first event analysis. A larger 11-event composite was also considered. RESULTS: For the 7-event cardiovascular disease composite, the previously reported first event analysis based on 581 events in the special intervention group and 652 events in the usual care group yielded a hazard ratio (95% confidence interval) of 0.89 (0.79-0.99), compared to 0.86 (0.77-0.97) and 0.91 (0.81-1.02) for the severity ranked estimates. Results for the 11-event composite also confirmed the findings of the first event analysis. CONCLUSION: The win ratio analysis was able to leverage information collected past the first experienced event and rank events by severity. The results were similar to and confirmed previously reported traditional first event analysis. The win ratio statistic is a useful adjunct to the traditional first event analysis for trials with composite outcomes.

Endoscopic versus percutaneous drainage of post-operative peripancreatic fluid collections following pancreatic resection.

BACKGROUND: Post-operative peripancreatic fluid collection (PFC) is a common complication following pancreatic resection which can be managed with endoscopic or percutaneous drainage. METHODS: Patients who underwent either endoscopic or percutaneous drainage of post-operative PFC were extracted from a prospectively-maintained database. The two groups were matched for surgery type, presence of a surgical drain and timing of drainage. RESULTS: Thirty-nine matched patients were identified in each group with a median age of 62 years. For primary drainage, technical success was achieved in almost all patients in both endoscopic and percutaneous groups (100% and 97%, p = NS); clinical success was achieved in 67% and 59%, respectively (p = 0.63). At least one "salvage" drainage procedure was required in 13 endoscopic patients versus 16 in the percutaneous group. Clinical success was achieved following the first salvage. Procedure in 85% of the endoscopic patients and 88% of the percutaneous patients (p = 0.62). Stent/drain duration (59 vs 33 days, p < 0.001) and number of post-procedural CT studies (2 vs 1, p = 0.02) were significantly higher in the endoscopic group. There was no difference in length of stay, complication, or recurrence between the two groups. CONCLUSION: Endoscopic drainage of post-operative PFC appears to be safe and effective with comparable success rates and outcomes to percutaneous drainage.

Development and Validation of a Multi-institutional Preoperative Nomogram for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasms (IPMNs) of the Pancreas: A Report from The Pancreatic Surgery Consortium.

OBJECTIVE: Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA: IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS: Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS: We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS: For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease.

Multi-institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-risk Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72-4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.

Influence of Age on the Clinical Outcome of Breast Cancer for Men and the Development of Second Primary Cancers.

BACKGROUND: Low incidence of breast cancer in men (BCM) (< 1% of all breast cancers) has led to a paucity of outcome data. This study evaluated the impact of age on BCM outcomes. METHODS: For this study, BCM patients treated between 2000 and 2011 were stratified by age (≤ 65 or > 65 years). Kaplan-Meier methods were used to compare overall survival (OS) and breast cancer-specific survival (BCSS). Competing-risk methods analyzed time to second primary cancers (SPCs), with any-cause death treated as a competing risk. RESULTS: The study identified 152 BCM patients with a median age of 64 years (range 19-96 years). The median body mass index (BMI) was 28 kg/m2. Men age 65 years or younger (n = 78, 51%) were more overweight/obese than men older than 65 years (n = 74, 49%) (89% vs 74%, respectively; P = 0.008). Both groups had similar nodal metastases rates (P = 0.4), estrogen receptor positivity (P = 1), and human epidermal growth factor receptor 2 (HER2)neu overexpression (P = 0.6). Men 65 years of age or younger were more likely to receive chemotherapy (P = 0.002). The median follow-up period was 5.8 years (range 0.1-14.4 years). The 5-year OS was 86% (95% confidence interval [CI] 80-93%), whereas the 5-year BCSS was 95% (95% CI 91-99%). The BCM patients 65 years of age and younger had better OS (P = 0.003) but not BCSS (P = 0.8). The 5-year cumulative incidence of SPC was 8.4% (95% CI 3.4-13.4%). The prior SPC rate was higher for men older than 65 years (n = 20, 31%) than for those age 65 years or younger (n = 7, 11%) (P = 0.008). This did not account for differences in life years at risk. No difference was observed in SPC cumulative incidence stratified by age (P = 0.3). CONCLUSIONS: Men 65 years of age or younger received more chemotherapy and had improved OS, but not BCSS, compared with men older than 65 years. For all BCM, SPC is a risk, and appropriate screening may be warranted.

Progression Patterns in the Remnant Pancreas after Resection of Non-Invasive or Micro-Invasive Intraductal Papillary Mucinous Neoplasms (IPMN).

BACKGROUND: Although IPMN are thought to represent a whole-gland disease, segmental resection remains the most frequently performed treatment. We sought to determine the rates, patterns, and predictors of IPMN progression in the pancreatic remnant following segmental resection of noninvasive or microinvasive IPMN. METHODS: A prospectively maintained database was queried to identify all patients who underwent resection of noninvasive or microinvasive IPMN (≤ 10 mm of invasive component) between 1989 and 2015. Progression (recurrence) was defined as either the development of cancer, a new IPMN cystic lesion > 1 cm or ≥ 50% increase in the diameter of residual IPMN lesions in the remnant. Univariate and multivariate cox regression models were created to determine predictors of progression. RESULTS: A total of 319 patients underwent resection for noninvasive and microinvasive IPMN. The median age was 68, 53% had branch-duct (BD) IPMN, and 6% had microinvasive disease. After a median follow-up of 42 months, 71 patients (22%) experienced IPMN progression. Within this group of 71 patients, 11 (16% of recurrence) developed invasive cancer in the pancreatic remnant after a median of 28 months. Twelve patients (17%) experienced progression > 5 years following initial resection. On multivariate analysis, a distal location of the initial lesion was associated with an increased risk of progression (multivariate hazards ratio = 2.43, confidence interval 1.47-4.0, p < 0.001). CONCLUSIONS: In this study, 22% of patients had disease progression following resection of noninvasive or microinvasive IPMN; 16% of these progressions represented invasive disease. These patients represent a high-risk group and should undergo long-term radiographic surveillance.

Cardiac Safety of Dual Anti-HER2 Therapy in the Neoadjuvant Setting for Treatment of HER2-Positive Breast Cancer.

BACKGROUND: Trastuzumab and pertuzumab are approved for the neoadjuvant treatment of human epidermal growth receptor 2 (HER2)-positive breast cancer, but cardiac safety data is limited. We report the cardiac safety of dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel, trastuzumab, and pertuzumab (THP) in the neoadjuvant setting followed by adjuvant trastuzumab-based therapy. METHODS: Fifty-seven patients treated with neoadjuvant dose-dense AC-THP followed by adjuvant trastuzumab-based therapy between September 1, 2013, and March 1, 2015, were identified. The primary outcome was cardiac event rate, defined by heart failure (New York Heart Association [NYHA] class III/IV) or cardiac death. Patients underwent left ventricular ejection fraction (LVEF) monitoring at baseline, after AC, and serially during 1 year of anti-HER2 therapy. RESULTS: The median age was 46 years (range 26-68). Two (3.5%) patients developed NYHA class III/IV heart failure 5 and 9 months after initiation of trastuzumab-based therapy, leading to permanent discontinuation of anti-HER2 treatment. Seven (12.3%) patients developed a significant LVEF decline (without NYHA class III/IV symptoms). The median LVEF was 65% (range 55%-75%) at baseline and 64% (range 53%-72%) after AC, and decreased to 60% (range 35%-70%), 60% (range 23%-73%), 61% (range 25%-73%), and 58% (range 28%-66%) after 3, 6, 9, and 12 months (± 6 weeks) of trastuzumab-based therapy. CONCLUSION: The incidence of NYHA class III/IV heart failure after neoadjuvant AC-THP (followed by adjuvant trastuzumab-based therapy) is comparable to rates reported in trials of sequential doxorubicin and trastuzumab. Our findings do not suggest an increased risk of cardiotoxicity from trastuzumab plus pertuzumab following a doxorubicin-based regimen. IMPLICATIONS FOR PRACTICE: Dual anti-human epidermal growth receptor 2 (HER2) therapy with trastuzumab and pertuzumab combined with standard chemotherapy has received accelerated approval for the neoadjuvant treatment of stage II-III HER2-positive breast cancer. Cardiac safety data for trastuzumab and pertuzumab in this setting are limited to clinical trials that utilized epirubicin-based chemotherapy. Formalized investigations into the cardiac safety of trastuzumab and pertuzumab with doxorubicin- (rather than epirubicin) based regimens are important because these regimens are widely used for the adjuvant and neoadjuvant treatment of breast cancer. The known role of HER2 signaling in the physiological adaptive responses of the heart provides further rationale for study on the potential cardiotoxicity of dual anti-HER2 blockade. Findings from this retrospective study provide favorable preliminary data on the cardiac safety of trastuzumab and pertuzumab in combination with a regimen of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel, one of the preferred breast cancer treatment regimens, according to the National Comprehensive Cancer Network.

Estimating the OncotypeDX score: validation of an inexpensive estimation tool.

BACKGROUND: OncotypeDX, a multi-gene expression assay, has been incorporated into clinical practice as a prognostic and predictive tool. However, its use in resource-constrained international healthcare systems is limited. Here we develop and validate a simplified model using clinicopathologic criteria to predict OncotypeDX score. METHODS: Patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive and HER2-negative invasive ductal carcinoma for whom the OncotypeDX test was successfully performed between 09/2008 and 12/2011 were retrospectively identified. Tumor size, nuclear and histologic grade, lymphovascular invasion, and ER and PR status were extracted from pathology reports. Data were split into a training dataset comprising women tested 09/2008-04/2011, and a validation dataset comprising women tested 04/2011-12/2011. Using the training dataset, linear regression analysis was used to identify factors associated with OncotypeDX score, and to create a simplified risk score and identify risk cutoffs. RESULTS: Estrogen and progesterone receptors, tumor size, nuclear and histologic grades, and lymphovascular involvement were independently associated with OncotypeDX. The full model explained 39% of the variation in the test data, and the simplified risk score and cutoffs assigned 57% of patients in the test data to the correct risk category (OncotypeDX score <18, 18-30, >30). 41% of patients were predicted to have OncotypeDX score <18, of these 83, 16, and 2% had true scores of <18, 18-30, and >30, respectively. CONCLUSIONS: Awaiting an inexpensive test that is prognostic and predictive, our simplified tool allows clinicians to identify a fairly large group of patients (41%) with very low chance of having high-risk disease (2%).

Is Routine Axillary Imaging Necessary in Clinically Node-Negative Patients Undergoing Neoadjuvant Chemotherapy?

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend axillary imaging prior to neoadjuvant chemotherapy (NAC) in breast cancer patients who are clinically node negative (cN0) by physical examination. However, the benefit of this approach remains uncertain. The purpose of this study was to determine whether abnormal axillary imaging pre-NAC predicts nodal metastases post-NAC (ypN+) in cN0 patients. METHODS: cN0 patients undergoing NAC followed by axillary surgery were identified. Rates of ypN+ were compared among patients with abnormal pre-treatment axillary imaging vs. normal or no pre-treatment imaging using Fisher's exact test. RESULTS: From May 2008 to March 2016, 402 eligible cN0 patients were identified. The median age of the patients was 49.5 years, and the median tumor size was 4 cm. Of these patients, 38% were estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-), 30% were HER2+ , and 32% were triple negative. All had pre-NAC mammograms, 40% axillary ultrasound, 83% MRI, and 51% PET. Abnormal nodes on imaging were seen in 208 patients (52%); 128 had pre-NAC node biopsy, and 75 were positive. Overall, 28% of the patients (n = 111) were ypN+ post-NAC. Although the incidence of ypN+ was significantly higher in patients with abnormal nodes on pre-NAC imaging (p = 0.001), 54% did not require axillary lymph node dissection (ALND) post-NAC. Among the patients with normal nodes on pre-NAC imaging, 20% were ypN+ post-NAC. CONCLUSIONS: Half of patients with abnormal nodes on pre-NAC imaging did not require ALND post-NAC, while 20% of those with normal pre-NAC nodes had disease post-NAC, indicating that in cN0 patients already selected for NAC, axillary imaging pre-NAC does not predict the need for axillary surgery post-NAC with sufficient accuracy to be clinically useful.

Percutaneous Peritoneal Lavage for the Rapid Staging of Gastric and Pancreatic Cancer.

BACKGROUND: Positive peritoneal cytology is classified as M1 disease in gastric and pancreatic cancer. While peritoneal cytology is typically obtained by laparoscopic peritoneal lavage, this study sought to examine the feasibility and safety of performing this percutaneously, with monitored anesthesia care and in combination with other diagnostic procedures to condense and expedite the staging process. METHODS: Patients with gastric or pancreatic cancer scheduled for laparoscopy with peritoneal lavage were prospectively enrolled to undergo intraoperative percutaneous peritoneal lavage prior to laparoscopic peritoneal lavage. Saline was infused through a percutaneously-inserted catheter and fluid was collected for peritoneal cytology. Three-quadrant washings collected during laparoscopy were also sent for peritoneal cytology. The primary outcome was to evaluate the sensitivity and specificity of percutaneous peritoneal lavage for detecting positive peritoneal cytology compared with the gold standard of laparoscopic peritoneal lavage, while the secondary outcome was to determine safety. RESULTS: Percutaneous peritoneal lavage was successfully performed in 70 of 76 patients (92%). Ten of 48 gastric cancer patients (21%) and three of 22 pancreatic cancer patients (14%) had positive percutaneous and laparoscopic peritoneal cytology. Two additional gastric cancer patients had positive laparoscopic peritoneal cytology only. Sensitivity and specificity of percutaneous peritoneal lavage compared with laparoscopic peritoneal lavage were 87% and 100%, respectively. No complications occurred with percutaneous peritoneal lavage. CONCLUSIONS: Percutaneous peritoneal lavage is a safe and effective minimally invasive alternative to laparoscopic peritoneal lavage for the diagnosis of metastatic gastric and pancreatic cancer. It is possible this can be utilized in an outpatient setting, such as during endoscopy, to allow for earlier diagnosis of M1 disease and decreased time to appropriate treatment.

Evaluation of Local and Distant Recurrence Patterns in Patients with Triple-Negative Breast Cancer According to Age.

BACKGROUND: Triple-negative breast cancer (TNBC) subtype and young patient age are both associated with an increased risk of local recurrence (LR) and distant recurrence (DR). In young women with TNBC, it is unclear whether subtype or patient age is driving prognosis. METHODS: Patients treated for primary TNBC from 1998 to 2011 were identified from the breast surgery database. Clinicopathologic characteristics, treatment, and outcomes were compared between patients <40 and ≥40 years of age at diagnosis. Multivariate models were used to identify factors independently associated with LR and DR. RESULTS: Among 1930 patients with TNBC, 289 (15 %) were <40 and 1641 (85 %) were ≥40 years of age at diagnosis. Younger patients were more likely to present with higher stage disease and more likely to receive mastectomy (p < 0.01), axillary node dissection (p < 0.01), and chemotherapy (p < 0.01). At a median follow-up of 74 (0-201.1) months, there was no difference in LR or disease-free survival (DFS) by age group [5-year LR = 3.9 % (95 % confidence interval (CI) 1.5-6.2) vs. 4.5 % (95 % CI 3.5-5.6) and 5-year DFS = 75.3 % (95 % CI 70.2-80.7) vs. 77.7 % (95 % CI 75.6-79.8), p = 0.94] in patients aged <40 and ≥40 years, respectively. On multivariate analysis, larger tumor size, lymphovascular invasion, and nodal positivity were associated with increased risk of DR. Age and type of surgery were not significantly associated with either outcome. CONCLUSIONS: Young age at diagnosis is not an independent risk factor for LR or DR in patients with TNBC.

Validation of Clinical Tools for Vaginal and Vulvar Symptom Assessment in Cancer Patients and Survivors.

INTRODUCTION: Health care professionals can play a pivotal role in promoting vulvovaginal health through assessment and appropriate intervention. AIM: To develop and validate brief clinical measurements to facilitate the identification of vulvovaginal symptoms in patients with and survivors of cancer. METHODS: One hundred seventy-five women survivors of cancer attending a Female Sexual Medicine and Women's Health Program from September 26, 2012 through October 31, 2014 completed the Vaginal Assessment Scale (VAS) and the Vulvar Assessment Scale (VuAS)-a modified version of the VAS that targets vulvar symptoms. Pelvic examination results were recorded using a clinical examination checklist. MAIN OUTCOME MEASURES: Internal consistency of the two scales was assessed using Cronbach α, and the correlation between scales and other outcomes was reported. RESULTS: The internal consistency measurements of the VAS and VuAS at the first visit were 0.70 and 0.68, which decreased to 0.53 and 0.66 at the last visit. The VAS composite and VuAS composite scores were moderately correlated with each other (0.42 and 0.45 at first and last visits, respectively). A strong correlation was observed between VAS pain with intercourse and Female Sexual Function Index (FSFI) pain with intercourse (-0.63 and -0.71 at the first and last visits, respectively). Worse pain with examination, worse functioning on the FSFI pain, lubrication, and total scores, and worse vulvar irritation were correlated with more severe symptoms on the VAS and VuAS. CONCLUSION: The VAS and VuAS are simple tools that can be used by clinicians to assess health concerns in women diagnosed with and treated for cancer. Validation is needed across diverse settings and groups of women.

Beyond the dose-limiting toxicity period: Dermatologic adverse events of patients on phase 1 trials of the Cancer Therapeutics Evaluation Program.

BACKGROUND: Dermatologic adverse events (AEs) can be key determinants of overall drug tolerability and of the maximum tolerated and recommended phase 2 doses in phase 1 trials. The authors present the largest dedicated analysis of dermatologic AEs on phase 1 trials to date. METHODS: Data from a prospectively maintained database of patients with solid tumors who were enrolled onto Cancer Therapeutics Evaluation Program (CTEP)-sponsored phase 1 trials of cytotoxic or molecularly targeted agents (MTAs) from 2000 to 2010 were analyzed. Cumulative incidence, site, and type of drug-related dermatologic AEs were described and compared. The timing of worst drug-related dermatologic AEs was summarized. RESULTS: In total, 3517 patients with solid tumors and 6165 unique, drug-related dermatologic AEs were analyzed, including 1545 patients on MTA-only trials, 671 on cytotoxic-only trials, and 1392 on combination MTA and cytotoxic trials. Of 1270 patients who had drug-related dermatologic events, the timing of the worst AE was as follows: 743 (cycle 1), 303 (cycle 2), and 224 (cycle 3 or later). Although the cumulative incidence of grade ≥3 drug-related AEs increased to 2.4% by cycle 6, it was only 1.6% at the end of cycle 1. The cumulative incidence of drug-related AEs was highest in patients who received MTA-only therapy (P < .001) and differed by dose level (P < .001). In patients who received MTA-only therapy, drug-related AEs were most common for combination kinase inhibitor-containing therapy (P < .001). CONCLUSIONS: A substantial proportion of drug-related dermatologic AEs occur after the traditional dose-limiting toxicity monitoring period of phase 1 clinical trials. Future designs should account for late toxicities.

Impact of Body Mass Index on Clinical Axillary Nodal Assessment in Breast Cancer Patients.

BACKGROUND: More than one-third of American adults are obese, and an elevated body mass index (BMI) is postulated to reduce the sensitivity of the clinical evaluation of the axilla. Clinical nodal examination is important in allocating breast cancer patients to appropriate axillary management. This study sought to determine whether BMI influences the rate of nodal positivity in women designated clinically as node-negative (cN0) by physical examination. METHODS: Breast cancer patients deemed cN0 who underwent sentinel lymph node biopsy (SLNB) from February 2006 to December 2011 were identified from a prospectively maintained database. Clinicopathologic features including BMI and axillary surgery results were recorded and compared among pathologically node-negative and node-positive patients. RESULTS: Overall, 5142 cN0 patients underwent 5262 SLNB procedures during the study period. Nearly one-third of the patients (28 %) were obese (BMI, >30 kg/m(2)). A positive SLN was identified in 25 % of the patients, and 84 % proceeded to axillary lymph node dissection. Predictors of SLN positivity included younger age, larger tumor size, high nuclear grade, multifocality, and lymphovascular invasion. An increased BMI did not correlate with a higher likelihood of SLN positivity (p = 0.6). The likelihood of cN0 patients having a high burden of axillary metastases (>3 positive nodes) was 4 % overall and, similarly, did not differ according to BMI (p = 0.4). CONCLUSION: Elevated BMI was not associated with a higher likelihood of SLN positivity or heavy nodal disease burden among women staged as cN0 by physical exam. These findings indicate that physical examination is appropriate and sufficient for preoperative axillary evaluation of women undergoing initial surgery regardless of patient BMI.