William Shomali

Pro-adrenomedullin as a novel biomarker for predicting infections and response to antimicrobials in febrile patients with hematologic malignancies

BACKGROUND Health professionals and researchers have become increasingly interested in biomarkers that help them in diagnosis of infections with recent growing attention to procalcitonin (PCT) and pro-adrenomedullin (proADM). METHODS This study compares proADM to PCT as diagnostic and prognostic biomarkers of infection in febrile patients with hematologic malignancies (HMs). From June 2009 to December 2010, 340 febrile HM patients were evaluated for presence of sepsis, systemic inflammatory response syndrome (SIRS), documented infections, and response to antimicrobial therapy. RESULTS ProADM and PCT levels were measured at onset of fever and then on days 4-7 afterward. Of the 340 patients, 103 had definite sepsis, and 159 had SIRS. Only proADM initial levels were significantly higher in patients with localized bacterial infections than in those with no documented infection (P = .019) and in patients with definite sepsis than those with SIRS (P = .023). The initial proADM and PCT levels were significantly higher in neutropenic patients with BSIs than in those without documented infections (P = .010 and P = . 011, respectively). Follow-up, proADM, and PCT levels decreased significantly in response to antimicrobial therapy in patients with bacterial infections (BSIs or localized; P = .007 and P = .002, respectively). CONCLUSIONS ProADM and PCT have promising roles in assisting clinicians in managing febrile HM patients. However, proADM appears to have the advantage of predicting localized bacterial infection and differentiating sepsis from SIRS.

The utility of proadrenomedullin and procalcitonin in comparison to C-reactive protein as predictors of sepsis and bloodstream infections in critically ill patients with cancer*.

Objectives:Infections in critically ill patients continue to impose diagnostic and therapeutic challenges. We seek to investigate the utility of proadrenomedullin and procalcitonin as diagnostic and prognostic biomarkers in febrile critically ill patients with cancer and compare their performance with that of C-reactive protein. Design:Single-center prospective cohort study. Setting:Tertiary care, academic, university hospital. Patients:One hundred fourteen critically ill patients with cancer with fever. Interventions:None. Measurements and Main Results:Blood samples were withdrawn on the day of fever onset and 4 to 7 days thereafter, and the serum proadrenomedullin, procalcitonin, and C-reactive protein levels were measured using the Kryptor technology afterward. Of the 114 adult patients, 27 had bloodstream infections, 36 had localized infections, and the remaining had no infections. The area under the receiver operating characteristic curve for bloodstream infection diagnosis was significantly greater for proadrenomedullin (0.70; 95% CI, 0.59–0.82) and procalcitonin (0.71; 95% CI, 0.60–0.83) compared with C-reactive protein (0.53; 95% CI, 0.39–0.66) (p = 0.021 and p = 0.003, respectively). Receiver operating characteristic analysis also showed that proadrenomedullin (p = 0.005) and procalcitonin (p = 0.009) each had a better performance than C-reactive protein in predicting patients’ mortality within 2 months after their fever onset. Regarding patients’ response to antimicrobial therapy, proadrenomedullin, procalcitonin, and C-reactive protein levels all significantly decreased from baseline to follow-up in responders (p ⩽ 0.002), whereas only proadrenomedullin level significantly increased in nonresponders (p < 0.0001). In patients with documented infections, proadrenomedullin (0.81; 95% CI, 0.71–0.92) and procalcitonin (0.73; 95% CI, 0.60–0.85) each had a greater area under the curve compared with C-reactive protein (0.59; 95% CI, 0.45–0.73) as for as predicting response (p = 0.004 and p = 0.043, respectively). However, for all febrile patients, proadrenomedullin had a significantly greater area under the curve for predicting favorable response than procalcitonin (p < 0.0001). Conclusion:In critically ill patients with cancer, proadrenomedullin and procalcitonin both have a promising role in predicting bloodstream infections in a manner more helpful than C-reactive protein. These two biomarkers were superior to C-reactive protein in the prognostic analysis of response to antimicrobial therapy for those patients with documented infections. However, proadrenomedullin was superior to procalcitonin in predicting response in all febrile patients and was unique in showing increased levels among nonresponders.

Can procalcitonin distinguish infectious fever from tumor-related fever in non-neutropenic cancer patients?†

Procalcitonin (PCT) has been proposed as a marker of infection and was studied in neutropenic patients. This study investigated its role in non‐neutropenic febrile cancer patients (NNCPs).

Granulocyte transfusions in hematologic malignancy patients with invasive pulmonary aspergillosis: outcomes and complications

BACKGROUND Granulocyte transfusions (GTXs) have been used successfully as an adjunctive treatment option for invasive infections in some neutropenic patients with underlying hematologic malignancy (HM). PATIENTS AND METHODS We sought to determine the impact of GTX as an adjunct to antifungal therapy in 128 patients with HM and prolonged neutropenia (≥14 days) with a proven or probable invasive aspergillosis (IA) infection by retrospectively reviewing our institutional database. RESULTS Fifty-three patients received GTX and 75 did not. By univariate analysis, patients with invasive pulmonary aspergillosis who received GTX were less likely to respond to antifungal therapy (P = 0.03), and more likely to die of IA (P = 0.009) when compared with the non-GTX group. Among patients who received GTX, 53% developed a pulmonary reaction. Furthermore, IA-related death was associated with the number of GTX given (P = 0.018) and the early initiation of GTX within 7 days after starting antifungal therapy (P = 0.001). By multivariate competing risk analysis, patients who received GTX were more likely to die of IA than patients who did not receive GTX (P = 0.011). CONCLUSIONS Our study suggests that GTX does not improve response to antifungal therapy and is associated with worse outcomes of IA infection in HM patients, particularly those with pulmonary involvement.BACKGROUND Granulocyte transfusions (GTXs) have been used successfully as an adjunctive treatment option for invasive infections in some neutropenic patients with underlying hematologic malignancy (HM). PATIENTS AND METHODS We sought to determine the impact of GTX as an adjunct to antifungal therapy in 128 patients with HM and prolonged neutropenia (≥14 days) with a proven or probable invasive aspergillosis (IA) infection by retrospectively reviewing our institutional database. RESULTS Fifty-three patients received GTX and 75 did not. By univariate analysis, patients with invasive pulmonary aspergillosis who received GTX were less likely to respond to antifungal therapy (P = 0.03), and more likely to die of IA (P = 0.009) when compared with the non-GTX group. Among patients who received GTX, 53% developed a pulmonary reaction. Furthermore, IA-related death was associated with the number of GTX given (P = 0.018) and the early initiation of GTX within 7 days after starting antifungal therapy (P = 0.001). By multivariate competing risk analysis, patients who received GTX were more likely to die of IA than patients who did not receive GTX (P = 0.011). CONCLUSIONS Our study suggests that GTX does not improve response to antifungal therapy and is associated with worse outcomes of IA infection in HM patients, particularly those with pulmonary involvement.

Nephrostomy Tube Related Pyelonephritis in Patients with Cancer: Epidemiology, Infection Rate and Risk Factors

PURPOSE Nephrostomy tube placement is often necessary to avert acute renal failure in patients with cancer with obstructive uropathy or in patients with ureteral leak. However, there have been limited published studies on the rate and risk of nephrostomy tube related pyelonephritis in patients with cancer. Therefore, in this study we determined rates of nephrostomy tube related pyelonephritis and predisposing risk factors in patients with cancer. MATERIALS AND METHODS We retrospectively reviewed patients who underwent nephrostomy tube placement between September 1, 2009 and September 16, 2010 at MD Anderson Cancer Center. Patients were followed for 90 days. The primary outcome assessed was the development of nephrostomy tube related pyelonephritis and the secondary outcome was the development of asymptomatic bacteriuria. We also determined risk factors associated with pyelonephritis. RESULTS Of the 200 patients analyzed 38 (19%) had pyelonephritis and 15 (7.5%) had asymptomatic bacteriuria. Of the nephrostomy tube related infections 34 cases (89%) were with the primary nephrostomy tube. Subsequently 4 of the patients who underwent nephrostomy tube exchange had an episode of pyelonephritis. Pyelonephritis developed within the first month in 19 (10%) patients. Prior urinary tract infection and neutropenia were found to be significant risk factors for pyelonephritis (p = 0.047 and 0.03, respectively). CONCLUSIONS The placement of nephrostomy tubes in patients with cancer is associated with a significant rate of pyelonephritis. Neutropenia and history of urinary tract infection were significant risk factors for pyelonephritis. This finding warrants further investigation into preventive strategies to reduce the infection rate.

Can procalcitonin differentiate Staphylococcus aureus from coagulase-negative staphylococci in clustered gram-positive bacteremia?

Procalcitonin (PCT) and pro-adrenomedullin (ProADM) have been proposed as diagnostic and prognostic biomarkers of infection. Between July 2009 and January 2012, we studied the role of these biomarkers in 163 patients with clustered gram-positive and gram-negative bacteremia. PCT levels were significantly higher in patients with Staphylococcus aureus and gram-negative bacteremia than those with coagulase-negative staphylococci (CoNS) isolated from blood cultures (P = 0.29 and <0.001, respectively). ProADM levels were only significantly higher in patients with gram-negative bacteremia (median 1.46 nmol/L) than those with CoNS (median 1.01 nmol/L) (P = 0.04). Among patients with CoNS, PCT, and ProADM, levels failed to differentiate blood contamination (medians 0.24 ng/mL and 0.97 nmol/L) from true bacteremia (medians 0.26 ng/mL and 1.14 nmol/L) (P = 0.51 and 0.57, respectively). In cancer patients, PCT (and to a lesser extent, ProADM) was useful in differentiating CoNS from S. aureus and gram-negative bacteremia.

Safe and effective use of ponatinib in a patient with chronic myeloid leukemia and acute venous thromboembolism on therapeutic anti-coagulation

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the clonal proliferation of a hematopoietic stem cell carrying the reciprocal translocation between the long arms of chromosomes 9 and 22 [1]. This translocation results in the fusion of the Breakpoint Cluster Region (BCR) gene on chromosome 22 with the Abelson leukemia (ABL1) gene on chromosome 9. This leads to a constitutively active tyrosine kinase preventing apoptosis and promoting uncontrolled cellular proliferation [2]. Ponatinib, a 3rd generation oral TKI, is more potent than imatinib in inhibiting the BCR-ABL tyrosine kinase. It is effective in patients with CML of various stages of the disease, including those that harbor the T315I mutation [3]. Ponatinib was first approved by the US Food and Drug Administration for CML patients who are resistant or intolerant to prior TKI therapy. Ponatinib’s most common adverse events include hypertension, rash, dry skin and abdominal pain [4]. Its marketing was suspended after the emergence of data indicating higher rates of arterial and venous thrombosis than previously reported. Vascular events were reported in 48% of participants in the phase 1 study and 24% in the phase 2 study [4–6]. Venous thromboembolic (VTE) disease was recently reported in 5% of patients on longer-term follow-up of the abovementioned studies [7,8]. Vascular events have also been reported in patients treated with nilotinib and dasatinib (especially peripheral arterial occlusive disease). Nevertheless, the risk of vascular events appears to be higher with Ponatinib compared to other TKIs [9,10]. Ponatinib was later reintroduced to the US market, but its indication was narrowed to patients with the T315I mutation or those in whom no other TKI is indicated. Here we report a patient with CML intolerant/resistant to all other available TKIs, who progressed to accelerated phase disease and developed pulmonary embolism (PE) a week prior to starting ponatinib. He is currently tolerating treatment, has reverted back to chronic phase disease and has a complete cytogenetic response with no recurrence of VTE while on therapeutic enoxaparin therapy. A 35 year-old gentleman was found to have an elevated white blood cell (WBC) count of 167 k/ml on complete blood count (CBC) done after initially presenting with excessive bleeding after a tooth extraction. Physical examination was remarkable only for palpable splenomegaly of 10 cm below the left subcostal margin. He had a bone marrow biopsy procedure which showed morphologic findings suggestive of CML. Cytogenetic analysis showed 46,XY t(9;22)(q34;q11.2) which confirmed the diagnosis. He was initially started on hydroxyurea and immediately switched to imatinib 400 mg daily after disease confirmation. He was continued on imatinib for ∼ 20 months then switched to dasatinib 70 mg twice daily after his disease progressed due to poor compliance with imatinib. He achieved complete cytogenetic response (CCyR) and continued taking dasatinib for ∼28 months, but stopped taking it due to financial difficulties. He was subsequently referred to our institution. A repeat bone marrow biopsy showed CCyR. BCR-ABL normalized copy number by quantitative reverse transcriptase-polymerase chain reaction (RTPCR) was 37.52 (log reduction of 0.49, International scale was not reported) on the bone marrow and dasatinib was restarted. Dasatinib was then switched to nilotinib 400 mg twice daily after 7 months, as the patient had significant diarrhea refractory to multiple supportive measures. RT-PCR on peripheral blood before starting nilotinib showed a BCRABL level according to the international scale (BCR-ABLIS %) of 20.92. Bone marrow biopsy after 1 month of starting nilotinib showed continued CCyR, while quantitative RT-PCR on peripheral blood showed a BCR-ABLIS % of 24.28. The patient continued on nilotinib for ∼ 4 months and then switched to bosutinib 500 mg daily due to uncontrolled diarrhea and abdominal pain. The patient continued having diarrhea

Vascular Catheter-Related Infections

Vascular catheters are essential for the care of critically ill patients, those with cancer, and patients undergoing hemodialysis. However, catheter use carries the risk of infection either locally at the site of insertion or systemically as bloodstream infections. Catheter colonization with various organisms, with altered growth rate, building a biofilm matrix resistant to penetration by antimicrobials, plays a major role in the pathogenesis of such infections. Recent advances in diagnostic methods can help salvage the catheter and prevent its unnecessary removal. Management of catheter-related infections depends on the type of catheter, the organism identified, and the complexity of the infection. Novel preventive strategies have been developed and can help eliminate the risk of these serious infections.

Myelophthisic marrow involved by breast cancer and acute myeloid leukemia

![Figure][1] A 53-year-old woman was admitted with right thigh pain. She was diagnosed with estrogen receptor (ER)- and progesterone receptor (PR)-positive stage III adenocarcinoma of the left breast 3 years before. She was treated with lumpectomy and adjuvant doxorubicin and cyclophosphamide

Evaluation of response to enzalutamide (E) consecutively after disease progression on abiraterone/prednisone (AP) and potential predictors of response.

294 Background: Efficacy data of E immediately after AP failure in castrate resistant prostate cancer (CRPC) is limited. Although clinical cross-resistant has been observed, the optimal sequence of these agents is not defined. Specific patient pt) characteristics on AP could be useful in selecting appropriate pts for subsequent therapy with E. Methods: We retrospectively reviewed records of 40 pts with CRPC treated at the Cleveland Clinic with E immediately after disease progression on AP. We evaluated clinical / pathological features that could predict subsequent response or lack thereof to E. For this exploratory analysis, best % change in PSA (%Ch-PSA) was used as indicator of treatment response. Results: Median age at E initiation was 69 (58-81), median time from diagnosis to AP initiation was 6.1 years (0.9-16.3). Median PSA was 30.9ng/mL (1.5-1680) at the time of AP initiation and 66.9ng/mL (2.52-3130) at E initiation. 30/40 and 35/40 pts had bone metastasis at AP and E initiation, respectively. Pri...