Potential Overtreatment Research Articles

Geographic Variation in the Treatment of US Heart Transplant Candidates

The current priority ranking system for US heart transplant candidates is based on treatment intensity which may encourage the overtreatment of relatively stable candidates. This paper aims to describe national variation in the intensity of treatment of adult heart transplant candidates and identify center-level predictors of potential overtreatment.

Multiplex Immunohistochemistry Provides Insight Into Cross‐Talk Between Myoepithelial And Immune Cells In Ductal Carcinoma In Situ (DCIS) Progression

Every year in the U.S. ~50,000 women are diagnosed with Ductal Carcinoma in Situ (DCIS). Long term studies of untreated DCIS show ~30% of women progressed to invasive breast cancer (IBC), providing strong rational for treating DCIS similar to early stage IBC. Disease management entails breast‐conserving surgery (BCS) in ~70% of women with or without adjuvant radiation therapy (RT), or unilateral and/or bilateral mastectomy in about 30% of women. While RT and mastectomy reduce risk of IBC or DCIS ipsilateral recurrence, support of potential overtreatment is suggested by long term outcome studies demonstrating low mortality from DCIS (1–2% at 10 years) regardless of treatment received. Thus, prognostic markers that can distinguish DCIS at high versus low risk of progression are needed to personalize treatment decisions. The tumor microenvironment, including myoepithelial and immune cells, has been shown by us and others to play a pivotal role in tumor progression, and we have advanced murine models to study human DCIS progression. In an immune compromised model, the loss of myoepithelial cell calponin, a regulatory component of smooth muscle contraction, specifically corresponded with a ~130‐fold increased probability of adjacent human tumor cells expressing the poor prognostic tumor biomarker p63; implicating calponin as a tumor suppressor protein that acts on adjacent tumor cells. Using immune competent murine models, we find faster progression to invasive tumors, suggesting a supportive role for the immune system in DCIS to IBC progression. We hypothesized that pro‐tumorigenic immune cells will be found near DCIS lesions that have lost myoepithelial differentiation markers and/or tumor cells that have a poor‐prognostic basal phenotype. To test this hypothesis, we have developed novel computer‐assisted computational methods to characterize the integrity of the myoepithelial cell layer in DCIS lesions and to provide near‐neighbor analysis to identify proximity to immune cells. This method involves image segmentation to identify the myoepithelial cell layer using the combined IHC images of SMA, calponin, and CK18, followed by geometric quantification to determine relative expression as well as physical proximity between distinct biomarker (Figure 1). We validated the ability of this computational method to determine loss of myoepithelial cell‐differentiation markers by comparing results to a pathologist's visual annotation, and found a Pearson's‐correlation coefficient of R = 0.959. Utilizing FFPE breast tissues from a cohort of women diagnosed with DCIS (OHSU IRB #15514), we performed multiplex sequential immunohistochemical (IHC) staining for markers of myoepithelial differentiation state (p63, SMA, calponin), immune cells (lymphoid: CD45, CD8, CD3, Foxp3, Granzyme B, PD‐1) and prognostic biomarkers (cyclooxygenase‐2, p16, ki67, ER, PR, Her‐2, tenascin‐c, cytokeratin 5). Our results show that loss of the myoepithelial differentiation marker calponin is associated with a relative decrease in CD4+Foxp3+ T regulatory cells and a concurrent increase in CD8+PD‐1+ T cells. These data suggest that 1) during DCIS progression there may be activation of cytotoxic effectors and concomitant decrease in Tregs to support tumor suppression, and 2) myoepithelial cell integrity may facilitate the activation state of local immune cells. Future studies include assessment for the role of myeloid lineages in myoepithelial cell integrity and DCIS progression.Support or Funding InformationThis research work is supported by OHSU Knight Cancer Institute – Borchard Early Investigator Award to SJ, OHSU OCTRI ‐ NW Kaiser specimen retrieval opportunity to PS and SJ, Susan G. Komen Post‐Doctoral fellowship to EM (PDF17480342).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract 190: Use of Intensive Glycemic Management in Older Adults With Diabetes. An Analysis From the Diabetes Collaborative Registry

Background: Older adults with diabetes are less likely to benefit and more likely to be harmed by intensive glucose control. Prior research has shown that many older adults continue to be intensively managed despite guidelines that recommend that treatment targets should be relaxed in these patients. As many new agents have been introduced with minimal risk of hypoglycemia, we examined contemporary data to understand to what extent older patients with diabetes are still intensively managed with agents that can cause hypoglycemia. Methods: We examined A1c and treatment data in adults ≥75 years with type 2 diabetes from 151 US outpatient sites in DCR. Patients were categorized as poor control (A1c >9%), moderate control (A1c >8-9%), conservative control (A1c 7-8%), tight control/low-risk agents (A1c <7% on meds with low risk for hypoglycemia), and tight control/high-risk agents (A1c <7% on insulin, sulfonylureas, or meglitinides). Adults with A1c <7% on no glucose-lowering medications were excluded. We used hierarchical logistic regression to examine patient and site factors associated with tight control/high-risk agents vs. conservative control or tight control/low-risk agents. Results: Among 30,696 older adults with diabetes, 5,596 (18%) had moderate or poor control, 9,227 (30%) conservative control, 7,893 (26%) tight control/low-risk agents, and 7,980 (26%) tight control/high-risk agents (Fig. A). Older age, male sex, heart failure, chronic kidney disease, and coronary artery disease were each independently associated with a greater odds of tight control/high-risk agents (Fig. B). After adjusting for patient factors, there were no differences among practice specialties (endocrinology, primary care, cardiology) in how aggressively patients were managed. Conclusion: Despite greater availability of agents that do not cause hypoglycemia, a quarter of older adults with type 2 diabetes are tightly controlled with high-risk medications. These results suggest potential overtreatment of a substantial proportion of patients. Efforts are needed to provide more specific guidance on how to safely treat older adults with diabetes (both through targeting treatment with low-risk agents and through de-escalation of glucose control) and then to efficiently translate that guidance into busy clinical practice.

Patients\u2019 experiences of diagnosis and management of papillary thyroid microcarcinoma: a qualitative study

BackgroundIn recent years management practices in relation to low-risk papillary microcarcinoma (PMC) have been evolving with increased awareness of the potential overdiagnosis and overtreatment of PMCs, and guidelines recommendations for non-surgical management options such as active surveillance. This study aimed to develop an in-depth understanding of patients’ experiences of the communication of their PMC diagnosis, their treatment preferences and decision making.MethodsSemi-structured qualitative interviews with 25 patients diagnosed pre-operatively with PMC < 1 year since their diagnosis and treatment. Interviews were conducted between September 2015 and July 2016 and were audio-recorded and transcribed verbatim. Framework analysis method was used to analyse the data.ResultsThe diagnosis and treatment experience of PMC patients varied widely. The majority of patients were asymptomatic, and their PMC was initially detected via an imaging test requested for a reason unrelated to a thyroid disorder or symptom. Clinicians generally described PMC to patients as being a “small” or “slow-growing” cancer, and there was little evidence that clinicians had discussions about the possibility of overdiagnosis or overtreatment. Overall, surgery was the only option discussed and offered to patients. Patients preference for treatment was largely based on eliminating the possibility of the cancer spreading (thyroidectomy) or not wanting to be on thyroid replacement medication for the rest of their life (hemi-thyroidectomy). Many patients reported emotional and physical side-effects associated with their diagnosis and treatment, however patients generally indicated that active surveillance is not something they would have been interested in if it was offered to them.ConclusionsEvidence continues to emerge that many patients with PMCs may be overdiagnosed, and management guidelines are recommending more conservative management options for these patients. As a result, shared decision making around treatment options is vital so that patients are fully aware of the meaning of their diagnosis and their management options including active surveillance. Importantly, interventions to reduce unnecessary diagnoses of PMC are critically needed.

Abstract P2-11-24: Disparities in the application of post-mastectomy radiotherapy in Switzerland: A pooled analysis of 7 cancer registries over the 2003-2005 period

Abstract Background: The aim of this study was to identify factors that influence the delivery of post-mastectomy radiotherapy (PMRT) in Switzerland, and to analyze the adherence to consensus guidelines. Methods: Based on 7 regional cancer registries covering 45% of the Swiss population, we identified 1408 women which underwent mastectomy for stage I-III breast cancer between January 1, 2003 and December 31, 2005. We categorized patients according to ASCO grouping in similar fashion to other comparable studies: low-risk group (T1/T2 N0): PMRT not routinely recommended; intermediate-risk group (T1/T2 N1): PMRT controversial; high risk group (T3-T4 and/or N2-N3): PMRT recommended. We further investigated factors leading to potential overtreatment (PMRT in low-risk group) or undertreatment (absence of PMRT in high-risk group). Data analysis was performed for the entire cohort, and separately for patients &amp;lt;70 years and ≥ 70 years of age. Probability of receiving PMRT was assessed using multivariable logistic regression. Results: A total of 421 patients (29.9%) received adjuvant RT after mastectomy. The rate of PMRT delivery was 67% in the high-risk group, compared to 6% and 18% in the low-risk and intermediate-risk groups, respectively. For patients at high-risk of chest wall recurrence after mastectomy (T3-T4 or N2-N3 disease), the risk of PMRT omission wassignificantly associated to older age (OR 4.25 [95% CI: 2.27-7.95] for patients ≥ 70 years) and to the absence of chemotherapy (OR 4.30 [95% CI: 1.97-9.36]). In patients with T3-T4 disease, PMRT was delivered in 77% of patients &amp;lt; 70 years and in 42% of patients ≥ 70 years (p&amp;lt;0.001). In patients with N2-N3 disease, PMRT was delivered in 82% of patients &amp;lt; 70 years and in 51% of patients ≥70 years (p&amp;lt;0.001). PMRT was delivered to 28 patients (7%) at low-risk of recurrence after mastectomy (T1-T2 N0, negative margins). It was more frequently offered to patients &amp;lt;40 years of age (OR 3.86 [95% CI: 1.01-14.76]), with T2 tumors (OR 3.43 [95% CI: 1.45-8.11]) and negative hormone receptor status (OR 2.60 [95% CI: 1.04-6.50]). Positive or close surgical margins (&amp;lt; 1mm) were a strong indicator for PMRT (p=0.001) and chest wall boost (p&amp;lt;0.03). Conclusions: After mastectomy, one third of patients (33.26%) with high-risk disease did not receive PMRT. Even if we consider only patients &amp;lt; 70 years, a non-trivial proportion of patients with clear indication for treatment delivery did not receive PMRT (T3-T4 disease: 23%; N2-N3 disease: 18%). Further analyses are planned to explain the apparent failure of evidence-based guidelines to impact the adoption of PMRT in women with high-risk breast cancer. Citation Format: Zwahlen DR, Ess S, Zimmermann M, Bordoni A, Bouchardy C, Frick H, Konzelmann I, Mousavi M, Rohrmann S, Oehler C. Disparities in the application of post-mastectomy radiotherapy in Switzerland: A pooled analysis of 7 cancer registries over the 2003-2005 period [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-24.

Missed diagnosis and overtreatment of COPD among smoking primary care population in Central Greece: old problems persist.

BackgroundThe diagnosis of COPD is not always consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy in daily clinical practice, especially in primary care. This study aimed to estimate the overall COPD prevalence and severity, to identify differences between newly and previously diagnosed patients, and to evaluate the potential COPD overtreatment in a smoking population attending a primary care spirometry surveillance program.MethodsA study was conducted in 10 primary health care centers of Central Greece during a 7-month period. Eligible participants were aged ≥40 years and were either current smokers or exsmokers.ResultsA total of 186 subjects were included (68% males, mean age 62.3±12.6 years, mean life-time tobacco exposure 50 pack-years). COPD prevalence was 17.8%, identified to be higher in elderly males. Forty-two percent of the COPD group were newly diagnosed patients, who were of younger age, current smokers, presented with less dyspnea and better health status, and mainly appeared with mild-to-moderate disease. Interestingly, 61.4% of non-COPD and 85.7% of newly diagnosed COPD individuals had been using inhaled medication under primary care provider’s prescription without ever undergoing spirometry or further evaluation by a pulmonologist; thus, the phenomena of COPD overdiagnosis and missed diagnosis came into the spotlight. Moreover, only 26.3% of known COPD patients were properly medicated according to GOLD guidelines, while half of them were inappropriately treated with triple inhaled therapy.ConclusionWe reported a significant prevalence of COPD in smoking population attending this spirometry program. A remarkable proportion of COPD patients were undiagnosed and made case finding worthwhile. Underutilization of spirometry in the diagnosis and management of COPD as well as general practitioners’ nonadherence to the GOLD treatment guidelines was confirmed by our data. These findings highlight the need for a major overhaul and culture change in primary care settings of Central Greece.

Can Interrogation of Tumour Characteristics Lead us to Safely Omit Adjuvant Radiotherapy in Patients with Early Breast Cancer?

Adjuvant radiotherapy after breast-conserving surgery has been an important component of the standard of care for early breast cancer. Improvements in breast cancer care have resulted in a substantial reduction in local relapse rates over recent decades. Although the proportional benefits of adjuvant radiotherapy are similar for different prognostic risk groups of patients, the absolute benefits depend on the risk of relapse and therefore vary considerably between prognostic groups. Radiotherapy is not without risk and for some patients at very low risk of relapse the risks of radiotherapy may outweigh the benefit, leading to potential overtreatment.Randomised controlled trial (RCT) evidence shows that omission of radiotherapy in low risk early breast cancer does not reduce overall survival or increase breast cancer mortality and local recurrences are salvageable. Despite this there has not been a change in practice regarding omission of radiotherapy. The reasons for this may include challenges in patient selection. Recent advances in immunohistochemistry and genomic profiling may improve risk stratification and the development of biomarkers to directed therapies. Several RCTs have quantified the benefit of radiotherapy in reducing local relapse. Where a treatment benefit is known but is considered to be so small not to be clinically relevant then alternatives to RCTs may be considered to answer the question of need. This is because we can assess risk against a fixed ‘absolute’ boundary rather than needing a randomised comparator. The prospective cohort study is an alternative to the RCT design to answer the question of need for radiotherapy. The feasibility of recruitment into biomarker-directed de-escalation studies will become apparent as more studies open. The challenge is to determine if we are able to accurately risk stratify patients and avoid unnecessary toxicity, thereby tailoring the need for adjuvant breast radiotherapy on an individual patient basis.

Potential of Hematopoietic Stem Cells and Mitotic Activity in Peripheral Lymphocytes to Predict Life Expectancy of Patients with Metastatic Non-Small Cell Lung Cancer after Conventional Therapy

To prevent potential overtreatment of metastatic non-small cell lung cancer, the individual parameters of circulating hematopoietic stem cells (HSCs) (percentage of CD133+ HSCs, CD34+ HSCs, and mitotic activity in the circulating lymphocyte fraction) were measured before conventional cytotoxic therapy in 35 patients by flow cytometry and then compared retrospectively with their individual survival periods. The plot of dependence of the CD133+ HSC × mitotic activity product versus CD34+ HSC revealed the prognostic properties during the survival period (range 0.3 - 124 months). Discrimination of patients with an expected survival shorter than 12 months was possible based on the positions of individual points on the plot, with a sensitivity and specificity of ∼100 each and a diagnostic odds ratio of 1250. The evaluation of individual lymphoproliferative resources before cytotoxic treatment may be useful for the optimal therapeutic compromise between the desired inhibition of malignant target cells and the life-threatening depression of lymphocytopoiesis.

Gene Expression Analyses in Early Breast Carcinoma — Quo Vadis?

AbstractIn order to establish whether adjuvant therapy should be administered in patients with breast carcinoma, it is decisive to have as precise as possible an assessment of the risk of recurrence. In this context, gene expression — and thus gene expression signatures as well — have become a focus of attention as prognostic factors. For practical application, it is important to be able to analyze gene expression signatures in formalin-fixed, paraffin-embedded tumor tissue. Careful analytic and clinical validations and a high level of evidence (LoE) are required in order to avoid imprecise risk classification and thus potential overtreatment or undertreatment of the patients. Among the commercially available gene expression signatures, the Working Group on Gynecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie, AGO) currently grades MammaPrint® and Oncotype DX® as having LoE IA, with prospective study results; and Endopredict® and Prosigna® as having LoE IB. The panel members at this year’s St. Gallen consensus conference also voted by a majority in favor of the possible usage of Oncotype DX®, MammaPrint®, Prosigna®, EndoPredict®, and Breast Cancer Index®. These multigene tests can be used in selected patients with hormone receptor–positive and HER2-negative findings if none of the other criteria allow a treatment decision to be made.

Ruling out clinically significant prostate cancer with negative multi-parametric MRI.

To evaluate the negative predictive value (NPV) of a negative prostate multi-parametric magnetic resonance imaging (mpMRI) in ruling out clinically significant prostate upon 12-core systematic biopsy. We retrospectively reviewed 114 men evaluated at our institution who underwent systematic 12-core biopsy within 1year of a negative prostate mpMRI. Clinicopathologic features were evaluated and NPV was calculated for detection of clinically significant (Gleason≥7) cancer. Regression analysis was performed to identify clinical predictors of biopsy outcome. Overall, 88 (77.2%) patients in our cohort had no cancer detected upon biopsy. The highest pathologic grade was Gleason 6 (3+3) in 22 (19.3%) patients, and Gleason≥7 in 4 (3.6%) patients. NPV for detecting Gleason≥7 cancer was 96.5% (95% CI 93.1-99.9%) in the entire negative MRI cohort, 100% in those who were prostate biopsy naïve (n=20), 100% in those with a prior negative biopsy (n=53), and 90% in those who have had a previous positive biopsy and on active surveillance (n=41). Regression analysis identified no predictors of significant cancer in our cohort. In our cohort of men with no lesions detected on prostate mpMRI, we found very low rates of clinically significant cancer on systematic 12-core biopsy. In the few patients who diagnosed with prostate cancer, the majority had low-risk disease and could remain on active surveillance. Although validation studies and greater sample size is needed before clinical recommendations can be made, our data suggest patients with negative mpMRI evaluated by experienced radiologists may avoid unnecessary prostate biopsy and potential overtreatment.

Identifying and treating subclinical thyroid dysfunction in pregnancy: emerging controversies.

Thyroid hormones are essential for an adequate growth and development of the fetus. In addition to the classical association between maternal hypothyroidism and neurological impairment in the progeny, other adverse reproductive events have been associated with maternal thyroid dysfunction including infertility, miscarriage and preterm delivery. Although all scientific societies endorse the treatment of overt hypothyroidism; the management and/or treatment of subclinical hypothyroidism, hypothyroxinemia or antithyroid antibody-positive women should be considered with caution. Important trials have found no clear benefit of treatment of subclinical hypothyroidism in terms of cognitive outcomes; however, other interventional studies appear to reduce some of the obstetric and perinatal complications. As a result, the dilemma between universal screening or selective screening of women at high risk of thyroid dysfunction during pregnancy remains unresolved. Despite this, levothyroxine is also now regularly prescribed by gynaecologists and centres for reproductive medicine. In this context, there is increasing concern regarding the risk of over diagnosis and subsequent potential overtreatment. Taken together, we need to reconsider how thyroid dysfunction should be identified in pregnant women and highlight the arguments for and against the use of levothyroxine in obstetric practices. Our main findings: the mismatch between the guidelines recommendations and the use of LT4 in clinical settings as well as the disparity of criteria between scientific societies from different medical specialties. In conclusion, it is essential to reach agreements between both endocrinologists and obstetricians.

Early effect of Medicare Shared Savings Program accountable care organization participation on prostate cancer care.

Accountable care organizations (ACOs) can improve prostate cancer care by decreasing treatment variations (ie, avoidance of treatment in low-value settings). Herein, the authors performed a study to understand the effect of Medicare Shared Savings Program ACOs on prostate cancer care. Using a 20% Medicare sample, the authors identified men with newly diagnosed prostate cancer from 2010 through 2013. Rates of treatment, potential overtreatment (ie, treatment in men with a ≥75% chance of 10-year mortality from competing risks), and Medicare payments were measured using regression models. The impact of ACO participation was assessed using difference-in-differences analyses. Before implementation of ACOs, the treatment rate was 71.8% (95% confidence interval [95% CI], 70.2%-73.3%) for ACO-aligned beneficiaries and 72.3% (95% CI, 71.7%-73.0% [P = .51]) for non-ACO-aligned beneficiaries. After implementation, this rate declined to 68.4% (95% CI, 66.1%-70.7% [P = .017]) for ACO-aligned beneficiaries and 69.3% (95% CI, 68.5%-70.1% [P<.001]) for non-ACO-aligned beneficiaries. There was no differential effect noted for ACO participation. The rate of potential overtreatment decreased from 48.2% (95% CI, 43.1%-53.3%) to 40.2% (95% CI, 32.4%-48.0% [P = .087]) for ACO-aligned beneficiaries and increased from 44.3% (95% CI, 42.1%-46.5%) to 47.0% (95% CI, 44.5%-49.5% [P = .11]) for non-ACO-aligned beneficiaries. These changes resulted in a significant relative decrease in overtreatment of 17% for ACO-aligned beneficiaries (difference-in-differences, 10.8%; P = .031). Payments were not found to be differentially affected by ACO alignment. The treatment of prostate cancer and annual payments decreased significantly between 2010 and 2013, but ACO participation did not appear to impact these trends. Among men least likely to benefit, Medicare Shared Savings Program ACO alignment was associated with a significant decline in prostate cancer treatment. Cancer 2018;124:563-70. © 2017 American Cancer Society.

Potential overtreatment among men aged 80 years and older with localized prostate cancer in Japan.

Despite treatment guidelines recommending observation for men with low‐risk prostate cancer with life expectancy <10 years, a majority of elderly patients choose active treatment, which may result in overtreatment. Given the growing burden of prostate cancer among men aged ≥80 years (super‐elderly men), accumulation of survival data for evaluation of overtreatment among super‐elderly patients is imperative. Here, we report results of a population‐based cohort study to clarify potential overtreatment of super‐elderly men with localized prostate cancer. We used cancer registry data from the Monitoring of Cancer Incidence in Japan project, which covers 47% of the Japanese population. The subjects were men diagnosed with prostate cancer between 2006 and 2008. Follow‐up period was 5 years. We calculated 5‐year relative survival rates among the active treatment and observation groups after imputation for missing values. Of the 48 782 patients with prostate cancer included in the analysis, 15.1% were super‐elderly men. The 5‐year relative survival rates of super‐elderly men with localized cancer were 105.9% and 104.1% among the active treatment and observation groups, respectively. This excellent relative survival rate in the observation group remained consistent even after stratification by tumor grade. Of the 2963 super‐elderly men with localized cancer, 252 (8.5%) with curative treatment and 1476 (49.8%) with hormone therapy were assumed to have been overtreated. The proportion of overtreatment was estimated to reach 80% after imputation. These specific survival data in super‐elderly men in the observation group can be useful in shared decision‐making for these patients and may lead to a reduction in overtreatment.

De-escalating and escalating surgery in the management of early breast cancer

In the setting of increased awareness regarding the need to address potential overtreatment in the management of breast cancer patients with favorable-prognosis disease, this article reviews three relevant instances in which the extent of surgery has been safely decreased: margin width in patients with ductal carcinoma in situ; axillary management in clinically node-negative women undergoing primary breast-conserving surgery; and the use of neoadjuvant chemotherapy followed by sentinel node biopsy for patients presenting with node-positive breast cancer.The management of the axillary nodes over the past decade highlights the potential to de-escalate surgery in the era of multimodality therapy. Similar opportunities exist for the use of radiotherapy. To fully realize the potential of de-escalating surgery, new communication strategies must be developed to convince patients that bigger is not necessarily better.

Overinterpretation is common in pathological diagnosis of appendix cancer during patient referral for oncologic care.

ContextLow-grade appendiceal mucinous neoplasm (LAMN) and appendiceal adenocarcinoma are known to cause the majority of pseudomyxoma peritonei (PMP, i.e. mucinous ascites); however, recognition and proper classification of these neoplasms can be difficult despite established diagnostic criteria.ObjectiveTo determine the pathological diagnostic concordance for appendix neoplasia and related lesions during patient referral to an academic medical center specialized in treating patients with PMP.DesignThe anatomic pathology laboratory information system was searched to identify cases over a two-year period containing appendix specimens with mucinous neoplasia evaluated by an outside pathology group and by in-house slide review at a single large academic medical center during patient referral.Results161 cases containing appendix specimens were identified over this period. Forty-six of 161 cases (28.6%) contained appendiceal primary neoplasia or lesions. Of these, the originating pathologist diagnosed 23 cases (50%) as adenocarcinoma and 23 cases (50%) as LAMN; however, the reference pathologist diagnosed 29 cases (63.0%) as LAMN, 13 cases (28.3%) as adenocarcinoma, and 4 cases (8.7%) as ruptured simple mucocele. Importantly, for cases in which the originating pathologist rendered a diagnosis of adenocarcinoma, the reference pathologist rendered a diagnosis of adenocarcinoma (56.5%, 13 of 23), LAMN (39.1%, 9 of 23), or simple mucocele (4.3%, 1 of 23). The overall diagnostic concordance rate for these major classifications was 71.7% (33 of 46) with an unweighted observed kappa value of 0.48 (95% CI, 0.27–0.69), consistent with moderate interobserver agreement. All of the observed discordance (28.3%) for major classifications could be attributed to over-interpretation. In addition, the majority of LAMN cases (65.5%) had potential diagnostic deficiencies including over-interpretation as adenocarcinoma and lacking or discordant risk stratification (i.e. documentation of extra-appendiceal neoplastic epithelium).ConclusionsAppendiceal mucinous lesions remain a difficult area for appropriate pathological classification with substantial discordance due to over-interpretation in this study. The findings highlight the critical need for recognition and application of diagnostic criteria regarding these tumors. Recently published consensus guidelines and a checklist provided herein may help facilitate improvement of diagnostic concordance and thereby reduce over-interpretation and potential overtreatment. Further studies are needed to determine the extent of this phenomenon and its potential clinical impact.

Trends in Reoperation After Initial Lumpectomy for Breast Cancer

Surgery after initial lumpectomy to obtain more widely clear margins is common and may lead to mastectomy. To describe surgeons' approach to surgical margins for invasive breast cancer, and changes in postlumpectomy surgery rates, and final surgical treatment following a 2014 consensus statement endorsing a margin of "no ink on tumor." This was a population-based cohort survey study of 7303 eligible women ages 20 to 79 years with stage I and II breast cancer diagnosed in 2013 to 2015 and identified from the Georgia and Los Angeles County, California, Surveillance, Epidemiology, and End Results registries. A total of 5080 (70%) returned a survey. Those with bilateral disease, missing stage or treatment data, and with ductal carcinoma in situ were excluded, leaving 3729 patients in the analytic sample; 98% of these identified their attending surgeon. Between April 2015 and May 2016, 488 surgeons were surveyed regarding lumpectomy margins; 342 (70%) responded completely. Pathology reports of all patients having a second surgery and a 30% sample of those with 1 surgery were reviewed. Time trends were analyzed with multinomial regression models. Rates of final surgical procedure (lumpectomy, unilateral mastectomy, bilateral mastectomy) and rates of additional surgery after initial lumpectomy over time, and surgeon attitudes toward an adequate lumpectomy margin. The 67% rate of initial lumpectomy in the 3729 patient analytic sample was unchanged during the study. The rate of final lumpectomy increased by 13% from 2013 to 2015, accompanied by a decrease in unilateral and bilateral mastectomy (P = .002). Surgery after initial lumpectomy declined by 16% (P < .001). Pathology review documented no significant association between date of treatment and positive margins. Of 342 responding surgeons, 69% endorsed a margin of no ink on tumor to avoid reexcision in estrogen receptor-positive progesterone receptor-positive cancer and 63% for estrogen receptor-negative progesterone- receptor-negative cancer. Surgeons treating more than 50 breast cancers annually were significantly more likely to report this margin as adequate (85%; n = 105) compared with those treating 20 cases or fewer (55%; n = 131) (P < .001). Additional surgery after initial lumpectomy decreased markedly from 2013 to 2015 concomitant with dissemination of clinical guidelines endorsing a minimal negative margin. These findings suggest that surgeon-led initiatives to address potential overtreatment can reduce the burden of surgical management in patients with cancer.

Older people with Type 2 diabetes, including those with chronic kidney disease or dementia, are commonly overtreated with sulfonylurea or insulin therapies

To evaluate potential overtreatment with sulfonylurea and insulin therapies amongst older people with Type 2 diabetes, including those with chronic kidney disease or dementia. Using the ECLIPSE Live software tool, we developed a search to examine data on older people (age ≥ 70 years) with Type 2 diabetes, who were prescribed sulfonylurea or insulin therapies over the previous 90 days. Sixteen Norfolk general practices participated, representing a population of 24 661 older people, including 3862 (15.7%) with Type 2 diabetes. Of these, 1379 (35.7%) people were prescribed sulfonylurea or insulin therapies. Data extracted included age, sex, last recorded HbA1c value, renal function and dementia codes. The median age of the study cohort was 78 years. A total of 644 people (47.8%) had chronic kidney disease (estimated GFR < 60 mL/min/1.73m2 ) and 60 people (4.35%) had dementia. The median (interquartile range) HbA1c concentration for the entire cohort was 58 (51-69) mmol/mol [7.5 (6.8-8.5)%], with no difference in median HbA1c between those with or without either chronic kidney disease or dementia. In total, 400 older people (29.9%) had an HbA1c concentration < 53 mmol/mol (7%), of whom 162 (12.1%) had HbA1c < 48 mmol/mol (6.5%). Stratified by prescription for sulfonylurea, insulin or combined insulin and sulfonylurea therapies, 282 (35.2%), 93 (24.2%) and 25 people (16.3%), respectively, had HbA1c < 53 mmol/mol (7.0%). Treatment to an HbA1c target of < 53 mmol/mol (7.0%) was as prevalent in those with chronic kidney disease or dementia as in those without. In the present cohort of older people with Type 2 diabetes prescribed sulfonylurea or insulin therapies, overtreatment was common, even in the presence of comorbidities known to increase hypoglycaemia risk.

Multivariate model to identify women at low risk of cancer upgrade after a core needle biopsy diagnosis of atypical ductal hyperplasia.

Atypical ductal hyperplasia (ADH) identified on percutaneous breast biopsy represents a high-risk lesion, upgrading to cancer with surgical excision in~7-45.8% of cases. Routine excision is questioned due to potential overtreatment and cost. This study evaluates clinical, imaging, and histologic features to predict the risk of upgrade. With IRB approval, a single-institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from June 2005 to June 2013. We reviewed electronic medical records, breast imaging, and biopsy slides. Multiple imputation was used for missing data. Association of various features with cancer upgrade was assessed using logistic regression. Among 399 cases, the upgrade rate to cancer was 16.0%, (95% CI: 12.8-20.0%), with nine invasive cancers and 55 ductal carcinoma in situ (DCIS) only. Via a logistic regression approach, we defined a subgroup with low risk for upgrade: women whose biopsies showed no individual cell necrosis, and either a) 1 focus of ADH with ≥50% removal, or b) 2-3 foci with ≥90% removal. Cases meeting these criteria had an upgrade rate of 4.9% (95% CI: 1.0-8.9%), compared to 21.4% (16.4-26.3%) in cases that did not meet this low-risk definition. ADH on core biopsy with low risk of upgrade to cancer is defined by lack of individual cell necrosis, number of foci of ADH, and percent of imaging lesion removed. If these findings are validated, women whose biopsies meet low-risk criteria might be considered for prevention therapy and surveillance without surgical excision.

PD72-05 NATURAL HISTORY OF PATIENTS TREATED WITH SALVAGE RADIATION THERAPY FOR RISING PSA AFTER RADICAL PROSTATECTOMY: A LONG-TERM SURVIVAL ANALYSIS

PD72-05 NATURAL HISTORY OF PATIENTS TREATED WITH SALVAGE RADIATION THERAPY FOR RISING PSA AFTER RADICAL PROSTATECTOMY: A LONG-TERM SURVIVAL ANALYSIS

PD72-06 ADJUVANT VERSUS EARLY SALVAGE RADIATION THERAPY IN NODE POSITIVE PROSTATE CANCER PATIENTS: A LONG-TERM SURVIVAL ANALYSIS

PD72-06 ADJUVANT VERSUS EARLY SALVAGE RADIATION THERAPY IN NODE POSITIVE PROSTATE CANCER PATIENTS: A LONG-TERM SURVIVAL ANALYSIS