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Michael J. Hall

Inherited mutations in 1 of 4 known mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are associated with various cancer risks collectively referred to as Lynch syndrome. Roughly 3 of every 100 new colorectal cancers (CRCs) have an underlying Lynch mutation. Tumor-based screening for Lynch among all patients with newly diagnosed CRC could theoretically improve the ability to identify Lynch and prevent cancer among at-risk family members, but the patient-level and social implications of this approach must be carefully considered before adopting this strategy. Poorly addressed issues include the role/timing of informed consent for testing, access and cost barriers associated with genetic counseling and DNA testing, psychosocial burdens to the thousands of middle-aged and elderly patients with CRC coping with surgical and chemotherapy treatments and poor prognosis, the need for providers to warn third-party relatives of risk for Lynch syndrome, limited effectiveness of screening, and the cost burden to society when poor DNA testing uptake, test limitations, and modest screening compliance are considered. Diverse barriers to the success of a population-based Lynch screening program in the United States remain (e.g., clinical resource needs, financial limitations, clinical expertise gaps, educational deficits). Data supporting clinical efficacy (feasibility) and effectiveness (real-life performance) are critical before important policy changes are adopted, especially where issues of hereditary cancer risk and genetic privacy are involved.

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Peter L. Greenberg

Chronic red blood cell transfusion support in patients with myelodysplastic syndromes (MDS) is often necessary but may cause hemosiderosis and its consequences. The pathophysiologic effects of iron overload relate to increased non-transferrin bound iron generating toxic oxygen free radicals. Studies in patients with MDS and thalassemia major have shown adverse clinical effects of chronic iron overload on cardiac function in patients who underwent polytransfusion. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. A small group of patients with MDS who had undergone effective subcutaneous desferrioxamine (DFO) chelation for 1 to 4 years showed substantial hematologic improvements, including transfusion independence. However, because chronic lengthy subcutaneous infusions of DFO in elderly patients have logistic difficulties, this chelation therapy is generally instituted late in the clinical course. Two oral iron chelators, deferiprone (L1) and deferasirox (ICL670), provide potentially useful treatment for iron overload. This article reviews data indicating that both agents are relatively well tolerated, were at least as effective as DFO for decreasing iron burdens in comparative thalassemia trials, and (for deferiprone) were associated with improved cardiac outcomes. These outcomes could potentially alter the tissue siderosis-associated morbidity of patients with MDS, particularly those with pre-existing cardiac disease.

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Nivedita Arora, Arjun Gupta, Hong Zhu, Alana Christie, Jeffrey J. Meyer, Saad A. Khan and Muhammad S. Beg

Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2–T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17–1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47–1.73, men vs women), race (HR, 1.51; 95% CI, 1.34–1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82–0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.

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Rodger J. Winn

Clinical practice guidelines must be outcome driven. Indeed, the validity of a guideline rests on showing that following recommendations will lead to projected health and cost outcomes.1 The primary outcomes proposed for guideline use include survival, toxicity, heath-related quality of life (QOL), and cost effectiveness.2 Patient preferences have also been recognized as factor that must be considered in making guideline recommendations.3 This prescription seems fairly straightforward, and in many instances, determining which outcomes to apply is as well. Recommendations for adjuvant regimens typically use overall or disease-free survival, acceptable toxicity profiles, and costs falling into the accepted range as a constellation of outcomes used to judge whether a regimen should be included. For many guideline users, treatment effectiveness––its impact on a major clinical outcome such as survival––is assumed to trump all other outcomes. In guidelines development, however, this is only true if that treatment's impact on other outcomes is believed to be minimal or inconsequential. In situations in which evaluating multiple outcomes points to opposing views of patient benefit, creating and following guideline recommendations can be problematic. From a purely clinical perspective, balancing effectiveness with toxicity can present difficult value judgments. For example, should adjuvant chemotherapy be recommended to elderly node-negative breast cancer patients; should allogeneic bone marrow procedures be recommended as first-line treatment in several diseases? The NCCN Myeloid Growth Factor Guidelines present a vivid example of the difficulties of attempting to assess “competing” outcomes. The first question that arises for this supportive care algorithm is what is the...
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scientific peer-review process and are overseen by the ORP. An NCCN study funded through the grant mechanism is highlighted below. Phase II Study of Ofatumumab as Front-line Treatment in Elderly, Unfit Patients With Chronic Lymphocytic Leukemia

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Adam J. Kole, John M. Stahl, Henry S. Park, Sajid A. Khan and Kimberly L. Johung

Background: Definitive chemoradiotherapy (CRT) is recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Anal Carcinoma for all patients with stage I anal canal cancer. Because these patients were not well represented in clinical trials establishing CRT as standard therapy, it is unclear whether NCCN recommendations are being closely followed for stage I disease. This study identified factors that predict for NCCN Guideline–concordant versus NCCN Guideline–discordant care. Methods: Using the National Cancer Data Base, we identified patients diagnosed with anal canal carcinoma from 2004 to 2012 who received concurrent CRT (radiotherapy [RT] 45.0–59.4 Gy with multiagent chemotherapy), RT alone (45.0–59.4 Gy), or surgical procedure alone (local tumor destruction, tumor excision, or abdominoperineal resection). Demographic and clinicopathologic factors were analyzed using the chi-square test and logistic regression modeling. Results: A total of 1,082 patients with histologically confirmed stage I anal cancer were identified, among whom 665 (61.5%) received CRT, 52 (4.8%) received RT alone, and 365 (33.7%) received only a surgical procedure. Primary analyses were restricted to patients receiving CRT or excision alone, as these were most common. Multivariable analysis identified factors independently associated with reduced odds of CRT receipt: low versus intermediate/high tumor grade (adjusted odds ratio [AOR], 0.21; 95% CI, 0.14–0.29; P<.001), tumor size <1 cm vs 1 to 2 cm (AOR, 0.24; 95% CI, 0.17–0.35; P<.001), age ≥70 versus 50 to 69 years (AOR, 0.36; 95% CI, 0.24–0.54; P<.001), male sex (AOR, 0.63; 95% CI, 0.45–0.90; P=.009), and treatment at an academic versus a non-academic facility (AOR, 0.58; 95% CI, 0.41–0.81; P=.002). Conclusions: Despite the NCCN recommendation of CRT for stage I anal cancer, at least one-third of patients appear to be receiving guideline-discordant management. Excision alone is more common for patients who are elderly, are male, have small or low-grade tumors, or were evaluated at academic facilities.

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Clifford Ko, Janak Parikh, Irina Yermilov and James Tomlinson

elderly patients undergoing abdominal operations . J Am Coll Surg 2005 ; 201 : 870 – 883 . 6. Lawrence VA Hazuda HP Cornell JE . Functional independence after major abdominal surgery in the elderly . J Am Coll Surg 2004 ; 199 : 762 – 772

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Heidi Klepin, Supriya Mohile and Arti Hurria

hospitalized patients . JAMA 1998 ; 279 : 1187 – 1193 . 5 Freyer G Geay JF Touzet S . Comprehensive geriatric assessment predicts tolerance to chemotherapy and survival in elderly patients with advanced ovarian carcinoma: a GINECO study . Ann

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scientific peer-review process and are overseen by the ORP. NCCN-sponsored studies funded through the grant mechanism are highlighted below. Phase II Study of Ofatumumab as Front-Line Treatment in Elderly, Unfit Patients With Chronic Lymphocytic

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Margaret Tempero

I learn a lot from my patients. I remember a very elderly man who often asked me rather unusual questions. Should he buy a new suit? Should he get his teeth fixed? It didn’t take me long to understand that he was trying to assess whether, given