Bernard Tawfik

The neutrophil to albumin ratio as a predictor of pathological complete response in rectal cancer patients following neoadjuvant chemoradiation.

Pathological complete response (pCR) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), in patients with locally advanced rectal cancer, occurs in 15–27% of patients. Because blood cell counts and albumin are a direct indicator of the host environment, a response to nCRT might be predicted by these markers. This study was carried out to determine whether the neutrophil to albumin ratio (NAR) was predictive of pCR in veteran patients. Ninety-eight patients with rectal cancer who underwent standard nCRT, followed by TME were analyzed. Pre-nCRT and post-nCRT hematologic data were collected. Univariate and multivariate analyses were carried out. Kaplan–Meier curves were constructed with our primary endpoint of pCR. Male patients (99%), age 62.4±9.1 years, BMI=27.4±5.9 kg/m2, rectal cancer distance from anal verge=7.1±4.5 cm (SD), interval between nCRT and TME=8 weeks, 55% patients=low anterior resection, 95% received 5-fluorouracil, and all patients received radiation, with 15% achieving a pCR. Univariate analysis showed that pre-nCRT carcinoembryonic antigen (15.8±45.1 vs. 3.5±5.3 ng/dl; P=0.002) and the pre-nCRT NAR (16.4±4.8 vs. 14.2±1.6; P=0.002) were associated with pCR. On multivariate analysis, pre-nCRT carcinoembryonic antigen (odds ratio=0.41, 95% confidence interval 0.22–0.77) and pre-nCRT NAR (odds ratio=0.76, 95% confidence interval 0.60–0.97) remained independent predictors of pCR. Overall survival between nonresponders and pCR patients at 1, 5, and 10 years was 96, 62, and 44% versus 93, 85, and 61%, P=0.13, and disease-free survival was 95, 60, and 47% versus 93, 85, and 61%, P=0.17; respectively. Our study shows that the pre-nCRT NAR is an independent predictor of pCR. These findings should be applied to other cohorts to determine its validity and reliability for use as a potential predictor of pCR.

Ischemic stroke in a patient with moderate to severe inherited factor VII deficiency

Thrombosis is known to occur in patients with rare inherited bleeding disorders, usually in the presence of a thrombotic risk factor such as surgery and/or factor replacement therapy, but sometimes spontaneously. We present the case of a 72-year-old African American male diagnosed with congenital factor VII (FVII) deficiency after presenting with ischemic stroke, presumably embolic, in the setting of atherosclerotic carotid artery stenosis. The patient had an international normalized ratio (INR) of 2.0 at presentation, with FVII activity of 6% and normal Extem clotting time in rotational thromboelastometry. He was treated with aspirin (325 mg daily) and clopidogrel (75 mg daily) with no additional bleeding or thrombotic complications throughout his admission. This case provides further evidence that moderate to severe FVII deficiency does not protect against thrombosis.

The Novel Protease-Activated Receptor 1 Antagonist Vorapaxar as a Treatment for Thrombosis in Afibrinogenemia

Afibrinogenemia is a rare disorder characterized by the absence of detectable fibrinogen due to genetic mutations.1 The common presentation is spontaneous or unusual bleedingwithminor trauma. But the recent case report and review by Santoro et al highlights that many patients present with thrombosis with or without bleeding, representing challenging clinical situations.2 Here, we add insight into management of these patients with a case of a patient with afibrinogenemia who developed recurrent arterial stenosis refractory to dual antiplatelet therapy and fibrinogen replacement treated with the novel protease-activated receptor 1 (PAR-1) antagonist vorapaxar. Fibrinogen is a glycoprotein that is produced in the liver and stored in platelet α granules after uptake from plasma.1 Fibrinogen functions in fibrin clot formation, thrombin regulation, platelet aggregation, and fibrinolysis. Afibrinogenemia is an autosomal recessive disorder associatedwith a quantitative deficiency of fibrinogen and a prevalence of 1 in 1,000,000.3 The clinical manifestations of afibrinogenemia include umbilical cord hemorrhage and bleeding in the gastrointestinal (GI) tract, genitourinary tract, mucosa, skin, and the central nervous system.4 Approximately 30% of patients with afibrinogenemia may also have thrombotic complications due to the antithrombin function of fibrinogen. Rarely patients may have both bleeding and thrombotic complications related to the disease.5,6 Treatment for hemorrhage includes antifibrinolytics and/or fibrinogen replacement therapy with fresh frozen plasma, cryoprecipitate, and plasma-derived fibrinogen concentrate.7 In the setting of a thrombotic phenotype, there is no clear consensus, but treatment with low molecular weight heparin, antiplatelet agents, vasodilators, lepirudin, and direct thrombin inhibitors with fibrinogen replacement therapy has been used.8 We present a case of a patient with bleeding and thrombotic complications associated with congenital afibrinogenemia treated with the novel PAR-1 antagonist vorapaxar (Zontivity, Aralez Pharmaceuticals Inc.) and fibrinogen replacement therapy (►Fig. 1). The patient is a 34-year-old Hispanic woman with a past medical history of sensorineural hearing loss, type 1 renal tubular acidosis, GI bleed, and congenital afibrinogenemia. The patient’s history of afibrinogenemiawas associatedwith episodes of gingival bleeding, hemarthrosis, menorrhagia, and hematemesis. She was treated with on-demand infusions of cryoprecipitate for many years with control of symptoms. In April 2010, she began having recurrent painful edema in her right great toe that progressed to her other digits and foot and was relieved with cryoprecipitate infusions. Over the next year, the pain became more persistent. Evaluation for ischemia with an angiogram demonstrated stenosis of the infrarenal aorta and narrowing of the dorsalis pedis artery. In June 2011, she was started on fibrinogen concentrate infusion to reduce the risk of bleeding intraoperatively and underwent endovascular aortic repair with endoprosthetic stents placed to dilate the distal aortic stenosis. She was treated with clopidogrel 75 mg orally (PO) once daily (QD), aspirin 81 mg PO QD, and prophylactic fibrinogen concentrate infusions 2000 mg IV (intravenous) once weekly due to the history of GI bleeding. She developed recurrent microembolic phenomena after cessation of clopidogrel, which was restarted. In July 2016, she presented with complaints of cramping lower extremity pain on exertion that had progressed to pain at rest and was admitted for critical limb ischemia. Angiogram of the infrarenal abdominal aorta revealed multifocal hypodense plaques in the proximal third of the stents bilaterally consistent with mild-to-moderate in-stent stenosis (►Figs. 2 and 3). She then underwent bilateral common femoral artery exploration with kissing balloon angioplasty with resolution of the stenosis and patent bilateral lower extremities postprocedure. After discharge from the hospital, there was grave concern that she had developed in-stent stenosis while on

Reducing Wait Time Between Admission and Chemotherapy Initiation

PURPOSE Reducing the length of stay is a high-priority objective for all health care institutions. Delays in chemotherapy initiation for planned preadmissions lead to patient dissatisfaction and prolonged length of stay. PATIENTS AND METHODS A multidisciplinary team was formed as part of the ASCO Quality Training Program. We aimed to reduce the time to initiation of chemotherapy from patient arrival at Parkland Hospital from a median of 6.2 hours at baseline to 4 hours over a 6-month period (35% reduction). The team identified inconsistency in blood work requirements, poor communication, and nonstandard patient arrival times as key causes of delay in the process. Plan-Do-Study-Act (PDSA) cycles were implemented based on identified improvement opportunities. The outcome measure was time from arrival to chemotherapy start. Data were obtained from time stamps in the electronic health record. RESULTS The first PDSA cycle included patient reminders to arrive at specific times, improved communication using a smartphone secure messaging application, and preadmission notes by oncology fellows detailing whether fresh blood work were needed on admission. Baseline data from 36 patients and postimplementation data from 28 patients were analyzed. Median time from admission to chemotherapy initiation preprocess change was 6.2 hours; it was 3.2 hours postchange. A sustained shift in the process was apparent on a control chart. CONCLUSION Delays in initiation of chemotherapy can be prevented using classic quality improvement methodology and a multidisciplinary team. We aim to further refine our PDSA cycles and ensure sustainability of change.

Utility and proposed algorithm of CSF flow cytometry in hematologic malignancies

In patients with hematologic malignancies, multiparameter flow cytometry (FCM) offers greater sensitivity than cytology in detecting malignant cells in the initial cerebrospinal fluid (CSF) specimen. However, the role of FCM in assessment of subsequent specimens is unclear. We developed an algorithm to reduce the number of low-yield FCM tests without significant impact on clinically meaningful results. Patients with hematologic malignancies were studied in a derivation cohort, and the following algorithm was developed: (1) cytology and FCM on all initial samples, (2) cytology on all subsequent samples, and (3) FCM on subsequent samples only if previous FCM was positive. A separate population served as the validation cohort. The derivation cohort included 197 patients representing 1157 cytology and 543 FCM samples. Common malignancies were B-Cell ALL (25.3%), diffuse large B cell lymphoma (29.4%), and Burkitt lymphoma (7.7%). In the derivation cohort, the algorithm yielded a sensitivity of 90.0% (95% CI, 81.2–95.6%) and a specificity of 100% (95% CI, 98.9–100.0%). The validation cohort included 132 patients with 563 cytology and 602 FCM samples. In the validation cohort, the testing algorithm yielded a sensitivity of 87.5% (95% CI, 75.9–94.8%) and a specificity of 100% (95% CI, 99.1–100.0%). Of the 15 samples that were missed by the algorithm, FCM findings did not impact patients’ management because of known CNS disease (seven patients) or they were responding to treatment (eight patients). CSF testing in hematologic malignancies using the proposed algorithm presents an evidence-based approach to reduce the number of unnecessary FCM tests of CSF without compromising patient care.