A precision medicine approach to management of acute myeloid leukemia in older adults.

PURPOSE OF REVIEW: Therapy selection in older adults with acute myeloid leukemia (AML) can be challenging because of a higher incidence of high-risk cytogenetic and molecular features conferring chemoresistance and poor functional status leading to increased treatment-related toxicities. The purpose of this review is to highlight the recent advances in precision medicine in AML that have shown promise to improve outcomes of older adults. RECENT FINDINGS: The utilization of next generation sequencing to identify and target actionable mutations can influence therapy selection in one-third of patients and can result in higher response rates as well as survival compared with those who do not receive targeted therapy. Oral targeted agents are available for AML with IDH 1, IDH2, or FLT3 mutations. Low-intensity venetoclax-based regimens have shown high rates of responses in AML, particularly among those with NPM1 and IDH2 mutations; responses are often durable and associated with minimal residual disease (MRD) negativity. Multiple studies have demonstrated the prognostic significance of flow cytometric MRD, with potential implications for subsequent therapy. SUMMARY: Novel approaches for AML risk-stratification, MRD assessment, and a precision medicine approach offer significant promise to improve survival and quality of life of older adults.

Venous thromboembolism in patients with hematologic malignancy and thrombocytopenia.

The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Forty-seven patients (36.7%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/µL (range 2,000-45,000/µL) versus 165,000/µL (50,000-429,000/µL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic-dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21-1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. © 2016 Wiley Periodicals, Inc.

Peril in the Pipeline: Unraveling the threads of PFAS contamination in U.S. drinking water systems.

We examined the spatial distribution of Per- and Polyfluoroalkyl Substances (PFAS) in the US drinking water and explored the relationship between PFAS contamination, public water systems (PWS) characteristics, and socioeconomic attributes of the affected communities. Using data from the EPA's third Unregulated Contaminant Rule, the Census Bureau, and the Bureau of Labor Statistics, we identified spatial contamination hot spots and found that PFAS contamination was correlated with PWSs size, non-surface raw water intake sources, population, and housing density. We also found that non-white communities had less PFAS in drinking water. Lastly, we observed that PFAS contamination varied depending on regional industrial composition. The results showed that drinking water PFAS contamination was an externality of not only some industrial activities but also household consumption.

Precision Medicine in Myeloid Malignancies: Hype or Hope?

PURPOSE OF REVIEW: We review how understanding the fitness and comorbidity burden of patients, and molecular landscape of underlying acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) at the time of diagnosis is now integral to treatment. RECENT FINDINGS: The upfront identification of patients' fitness and molecular profile facilitates selection of targeted and novel agents, enables risk stratification, allows consideration of allogeneic hematopoietic cell transplantation in high-risk patients, and provides treatment selection for older (age ≥ 75) or otherwise unfit patients who may not tolerate conventional treatment. The use of measurable residual disease (MRD) assessment improves outcome prediction and can also guide therapeutic strategies such as chemotherapy maintenance and transplant. In recent years, several novel drugs have received FDA approval for treating patients with AML with or without specific mutations. A doublet and triplet combination of molecular targeted and other novel treatments have resulted in high response rates in early trials. Following the initial success in AML, novel drugs are undergoing clinical trials in MDS. Unprecedented advances have been made in precision medicine approaches in AML and MDS. However, lack of durable responses and long-term disease control in many patients still present significant challenges, which can only be met, to some extent, with innovative combination strategies throughout the course of treatment from induction to consolidation and maintenance.

Determinants of ten-year overall survival of acute myeloid leukemia: a large national cancer database analysis.

Clinical trials do not routinely capture long-term overall survival (OS) in acute myeloid leukemia (AML). We utilized a large National Cancer Database (NCDB) to determine different factors affecting 10-year OS in AML. For patients, 18-59 years who were treated with chemotherapy only without upfront hematopoietic cell transplant (HCT), younger age, female, CBF AML, higher income, and private insurance conferred higher 10-year OS. Among patients, 18-59 years treated with chemotherapy and upfront HCT, younger age and private insurance conferred higher 10-year OS. In a Cox proportional hazard model, the likelihood of death decreased with younger age, fewer comorbidities, treatment at an academic center, private insurance, and use of multiagent chemotherapy. Our results demonstrate poor long-term OS even among younger patients and highlights disparities in leukemia care based on insurance type.

Clinical conundrum: managing iron overload after renal transplantation.

Iatrogenic iron overload, which is not uncommon in patients undergoing long-term haemodialysis, arises from a combination of multiple red cell transfusions and parenteral iron infusions that are administered to maintain a haemoglobin concentration of approximately 10 g/dL. Although iron overload due to genetic haemochromatosis is conventionally managed by phlebotomy, patients with haemoglobinopathies and chronic transfusion-induced iron overload are treated with iron-chelation therapy. However, the management of iron overload in our patient who presented with hepatic dysfunction and immunosuppressive drug-induced mild anaemia in the post-renal transplant setting posed unique challenges. We report on the decision-making process used in such a case that led to a successful clinical resolution of hepatic iron overload through the combined use of phlebotomy and erythropoiesis stimulating agents, while avoiding use of iron-chelating agents that could potentially compromise both hepatic and renal function.

Novel Treatment Paradigms in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease marked by the presence of several driver mutations and molecular subgroups even in a single patient. The genetic and molecular heterogeneity is also reflected by a progressive shift from a morphologic classification to one informed by causative genomic changes. Cytogenetic results and somatic mutations are increasingly being utilized to guide use of intensive chemotherapy and low-intensity chemotherapy, particularly among older adults. Utilization of next-generation sequencing in AML has led to increasing use of targeted treatments for actionable mutations. Quantitative real-time polymerase chain reaction-based mutational analysis and multicolor flow cytometry offer sensitive assays that can detect minimal residual disease (MRD). Several studies have shown that MRD negativity, as defined by specified cutoff values, is highly prognostic with potential therapeutic implications. The last 3 years mark an unprecedented history in the drug development in AML with approval of 8 new drugs and large portfolio of ongoing early and late-phase trials of several promising drugs. Multiple combinatorial trials of approved agents and approval of newer agents in the future will continue to change the therapeutic landscape of AML.

Preoperative Pulmonary Function Tests (PFTs) and Outcomes from Resected Early Stage Non-small Cell Lung Cancer (NSCLC).

BACKGROUND: Preoperative pulmonary function tests (PFTs) predict operative morbidity and mortality after resection in lung cancer. However, the impact of preoperative PFTs on overall outcomes in surgically-resected stage I and II non-small cell lung cancer (NSCLC) has not been well studied. PATIENTS AND METHODS: This is a retrospective study of 149 patients who underwent surgical resection as first-line treatment for stage I and II NSCLC at a single center between 2003 and 2014. PFTs [forced expiratory volume in 1 sec (FEV1), Diffusing Capacity (DLCO)], both absolute values and percent predicted values were categorized into quartiles. The Kaplan-Meier method and Cox regression analysis were used to determine whether PFTs predicted for overall survival (OS). Logistic regression was used to estimate the risk of postoperative complications and length of stay (LOS) greater than 10 days based on the results of PFTs. RESULTS: The median age of the cohort was 68 years. The cohort was predominantly males (98.6%), current or ex-smokers (98%), with stage I NSCLC (82.76%). The majority of patients underwent a lobectomy (n=121, 81.21%). The predominant tumor histology was adenocarcinoma (n=70, 47%) followed by squamous cell carcinoma (n=61, 41%). The median follow-up of surviving patients was 53.2 months. DLCO was found to be a significant predictor of OS (HR=0.93, 95% CI=0.87-0.99; p=0.03) on univariate analysis. Although PFTs did not predict for postoperative complications, worse PFTs were significant predictors of length of stay >10 days. CONCLUSION: Preoperative PFTs did not predict for survival from resected early-stage NSCLC, but did predict for prolonged hospital stay following surgery.

Thrombocytopenia in Patients with Chronic Hepatitis C Virus Infection.

Thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection is a major problem. The pathophysiology is multifactorial, with auto-immunogenicity, direct bone marrow suppression, hypersplenism, decreased production of thrombopoietin and therapeutic adverse effect all contributing to thrombocytopenia in different measures. The greatest challenge in the care of chronic HCV patients with thrombocytopenia is the difficulty in initiating or maintaining IFN containing anti-viral therapy. Although at present, it is possible to avoid this challenge with the use of the sole Direct Antiviral Agents (DAAs) as the primary treatment modality, thrombocytopenia remains of particular interest, especially in cases of advanced liver disease. The increased risk of bleeding with thrombocytopenia may also impede the initiation and maintenance of different invasive diagnostic and therapeutic procedures. While eradication of HCV infection itself is the most practical strategy for the remission of thrombocytopenia, various pharmacological and non-pharmacological therapeutic options, which vary in their effectiveness and adverse effect profiles, are available. Sustained increase in platelet count is seen with splenectomy and splenic artery embolization, in contrast to only transient rise with platelet transfusion. However, their routine use is limited by complications. Different thrombopoietin analogues have been tried. The use of synthetic thrombopoietins, such as recombinant human TPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMDGF), has been hampered by the development of neutralizing antibodies. Thrombopoietin-mimetic agents, in particular, eltrombopag and romiplostim, have been shown to be safe and effective for HCV-related thrombocytopenia in various studies, and they increase platelet count without eliciting any immunogenicity Other treatment modalities including newer TPO analogues-AMG-51, PEG-TPOmp and AKR-501, recombinant human IL-11 (rhIL-11, Oprelvekin), recombinant human erythropoietin (rhEPO), danazol and L-carnitine have shown promising early result with improving thrombocytopenia. Thrombocytopenia in chronic HCV infection remain a major problem, however the recent change in DAAs without IFN, as the frontline therapy for HCV, permit to avoid the dilemmas associated with initiating or maintaining IFN based anti-viral therapy.

Emerging targeted therapies in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths in United States, accounting for more than one-fourth of the deaths annually. Although comparatively rare and relatively less studied, genetic abnormalities other than epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and Kirsten rat sarcoma (KRAS) mutations account for significant proportion of the driver mutations identified thus far. The targeted agents against B-rapidly accelerated fibrosarcoma (BRAF) V600E mutation, MNNG-HOS transforming gene (MET) pathway, ROS1 rearrangement, rearranged during transfection (RET) rearrangement, and HER2 pathways offer promising therapeutic options. Recruiting patients with these rarer mutations to well-designed, large multicenter trials to further validate the use of targeted agents remains a challenge. The clinical data and ongoing trials with these agents are reviewed in this article.

Risk of second primary malignancies and survival of adult patients with polycythemia vera: A United States population-based retrospective study.

Although the median survival in polycythemia vera (PV) is 14 years, mortality is higher than in an age- and sex-matched population. This study included 3941 PV patients diagnosed between 2000-2012 from Surveillance, Epidemiology and End Results (SEER) 13 registry to determine 5-year survival and the incidence of second primary malignancies (SPM). The actuarial 5 year survival in the overall cohort was 79.5%. The cumulative incidence of SPM was 13.1% at 10 years. SPMs occurred at a standardized incidence ratio (SIR) of 1.29 (95% CI = 1.16-1.43; p < 0.001) with an absolute excess risk (AER) of 42.49 per 10 000 population. A significantly higher risk was noted for acute myeloid leukemia (SIR = 12.24; 95% CI = 8.17-17.8; p-value < 0.001) and chronic myeloid leukemia (SIR = 10.66; 95% CI = 3.75-19.6; p-value < 0.001). Patients with PV are at a high risk of SPM and leukemic transformation, which may compromise long-term survival.

Colorectal Carcinoma and Emerging Targeted Therapies.

Targeted therapies for specific mutations in colorectal cancer have led to an increase in patient overall survival.

Case of acquired or pseudo-Pelger-Huët anomaly.

Pelger-Huët anomaly (PHA) is a rare benign autosomal-dominant anomaly with an incidence of ∼1 in 6000. It does not cause neutrophilia, but it can cause a false increase in band forms. It should be differentiated from acquired or pseudo-Pelger-Huët anomaly (PPHA), which has similar morphology, however; it is associated with different pathological states like Myelodysplastic syndrome, as well as with certain infections and drugs. We report a case of a 67-year-old Caucasian gentleman with past medical history of rheumatoid arthritis, type II diabetes mellitus and hypothyroidism, who presented with 1 day history of fever (101°F) and night sweats. Medications include ibuprofen, methotrexate, hydroxychloroquine and levothyroxine. Patient denied any other symptoms. His work-up showed normal WBC count (8.6) and increase in bands (24%). The patient was admitted for further evaluation. During the next 2 days, the patient did not have any fever or any new symptoms. Peripheral blood smear was done as part of his work-up for bandemia, showed findings suggestive of PHA. Ibuprofen was discontinued. Follow-up few weeks later showed normal blood smear. Diagnosis of PPHA was made. The presented case showed that we should think of PHA\PPHA in any case with normal total WBC count and significant shift to the lift with no apparent explanation. Looking at smears directly under the microscopes is crucial to make diagnosis.

Fondaparinux for Management of Heparin-induced Thrombocytopenia after Cardiovascular Intervention: A Systematic Review.

OBJECTIVES: The efficacy and safety of fondaparinux, an emerging therapeutic option for heparin-induced thrombocytopenia (HIT), remain unclear in cardiac surgery patients with HIT. METHODS: Using several search criteria, we reviewed all cases of fondaparinux use in patients who developed HIT after any cardiovascular intervention and were indexed in MEDLINE by August 2014. Based on pre-specified criteria, cases were divided into confirmed HIT, probable HIT and possible HIT. The outcome of fondaparinux use in each group was compared using Chi-square test. RESULTS: Of 43 total cases, 22 had confirmed HIT and 21 had possible HIT. Valve replacement or repair (39%) and heart transplant or ventricular assist device placement (21%) were the most common preceding cardiovascular interventions. Creatinine clearance <30 ml was present in 27% and 52% of confirmed and possible HIT respectively. Overall the risk of new thrombosis and bleeding with fondaparinux were 4.6% and 7% respectively, without any differences in the two subgroups. The majority (86%) of cases improved clinically; of the remainder patients, similar percentage of cases with possible HIT and confirmed HIT died (24% vs. 5%; p= 0.102). None of the deaths were attributed to HIT or complications of bleeding. CONCLUSION: Within the limitations of this study, the risk of thrombosis and bleeding with fondaparinux use in cardiac surgery patients with HIT are low and largely comparable to outcomes reported in literature with other agents.

Chemotherapy use in stage III colon cancer: a National Cancer Database analysis.

BACKGROUND: Although adjuvant chemotherapy in stage III colon cancer improves overall survival, prior studies have shown that it is underused. We analyzed different factors that may influence its use. METHODS: This is a retrospective study of stage III colon cancer patients (n = 207,718) diagnosed between 2000 and 2011 in the National Cancer Data Base (NCDB). The NCDB contains ~70% of new cancer diagnosis from >1500 American College of Surgeons accredited cancer programs in the United States and Puerto Rico. The chi-squared test was used to determine any difference in characteristics of patients who did or did not receive chemotherapy. RESULTS: A total of 35% of all stage III colon cancer patients, and 38% of stage III cases undergoing surgery, did not receive adjuvant chemotherapy. The use of chemotherapy had increased in recent years (64% in 2007-2011 versus 59% in 2000-2002; p < 0.0001). Its use was lower in whites (61%), females (60%), patients ⩾60 years (55%), patients with one or more comorbidities (55%), nonacademic centers (62%), those with medicare insurance (52%), lower education (61%) and income levels (59%, all p < 0.0001). The nonwhite and uninsured were more likely to be <60 years old. CONCLUSION: More than one-third did not receive adjuvant chemotherapy, although its use has increased in more recent years. Age was one of the most important determinants of chemotherapy use, which may explain higher rates in nonwhite and uninsured. In addition to patient characteristics, race, gender and socioeconomic factors influence chemotherapy use. These findings have important implications for healthcare reform.

Management and Outcome of Heparin-Induced Thrombocytopenia in Pregnancy: A Systematic Review.

OBJECTIVE: Safety and efficacy of therapeutic agents used for heparin-induced thrombocytopenia are not established in pregnancy. METHODS: MEDLINE database was searched in November 2014 to identify all patients who received therapy for HIT during pregnancy. RESULTS: A total of 12 patients with the median age of 28 years (range 21-39) were diagnosed with HIT at the median gestational age of 20 weeks (range 5-34). Clinical probability (4T) score for HIT was high (50%) or intermediate (50%) and associated with thrombosis in 50%. Patients were initially managed with lepirudin (33%), argatroban (25%), danaparoid (25%) or fondaparinux (17%) and ultimately bridged to vitamin K antagonist or maintained on lepirudin. All patients had resolution of HIT. Complications included therapeutic abortion prior to valve replacement for valve thrombosis (8%), preterm delivery (18%) and preeclampsia (8%). Except for one instance of hypoplastic lung related to preterm delivery, none of the other newborns had any complications during delivery. CONCLUSION: Confirmed cases of HIT in pregnant patients appear to be rare. Within the limits of retrospective analysis, the use of argatroban, danaparoid, fondaparinux and lepirudin may be effective in preventing the thrombotic complications of HIT in pregnancy. The effect of HIT or its therapy on obstetrical complications cannot be determined based on this study since many of the obstetrical complications are common in otherwise healthy pregnancies. Although this study did not identify any fetal teratogenicity except hypoplastic lung related to preterm delivery, small number of cases treated with various therapies precludes any definite conclusion.

Systemic therapy in stage IV pancreatic cancer: a population-based analysis using the National Cancer Data Base.

BACKGROUND: Pancreatic cancer accounts for approximately 7% of all cancer deaths. More than half of all pancreatic cancers are stage IV at diagnosis, where systemic chemotherapy is used with the goal of life prolongation as well as palliation. The patient characteristics and health system factors that drive the use of systemic therapy are unknown. METHOD: This is a retrospective study of stage IV pancreatic cancer patients (n = 140,210) diagnosed between 2000 and 2011 in the NCDB. NCDB contains approximately 70% of new cancer diagnosis from more than 1500 accredited cancer programs in the United States and Puerto Rico. Chi-squared test was used to determine any differences in characteristics of patients who did or did not receive systemic therapy. RESULTS: Our study demonstrated that only 49.1% of stage IV pancreatic cancer patients received systemic therapy. The use of systemic therapy is significantly lower in female, African American/Hispanic, patients older than 40 years, those without insurance or with Medicare and Medicaid, higher Charlson Comorbidity Score, poor economic and educational status and in nonacademic centers. CONCLUSIONS: This is the largest study to evaluate the determinants of systemic therapy use in stage IV pancreatic cancer. The use of systemic therapy was significantly lower in patients older than 40 years, lower educational status, nonprivate insurance and with higher Charlson Comorbidity Scores. In addition, the use of systemic therapy was lower with female sex, African Americans/Hispanic, and lower socio-economic status. Understanding the barriers in the use of systemic therapy as well as appropriate utilization of systemic therapy can both optimize cancer care.

Differentiating malignant hypertension-induced thrombotic microangiopathy from thrombotic thrombocytopenic purpura.

OBJECTIVES: Malignant hypertension can cause thrombotic microangiopathy (TMA) and the overall presentation may mimic thrombotic thrombocytopenic purpura (TTP). This presents a dilemma of whether or not to initiate plasma exchange. The objective of the study was to determine the clinical and laboratory manifestations of malignant hypertension-induced TMA, and its outcomes. METHODS: Using several search terms, we reviewed English language articles on malignant hypertension-induced TMA, indexed in MEDLINE by 31 December 2013. We also report a new case. All these cases were analyzed using descriptive statistics. RESULTS: A total of 19 patients, with 10 males, had a median age of 38 years at diagnosis; 58% had a history of hypertension. Mean arterial pressure at presentation was 159 mmHg (range 123-190 mmHg). All had prominent renal dysfunction (mean creatinine of 5.2 mg/dl, range 1.7-13 mg/dl) but relatively modest thrombocytopenia (mean platelet count of 60 × 103/µl, range 12-131 × 10(3)/µl). Reported cases (n = 9) mostly had preserved ADAMTS-13 activity (mean 64%, range 18-96%). Following blood pressure control, the majority had improvement in presenting symptoms (100%) and platelet counts (84%); however, only 58% had significant improvement in creatinine. More than half (53%) needed hemodialysis. One patient died of cardiac arrest during pacemaker insertion. CONCLUSION: Prior history of hypertension, high mean arterial pressure, significant renal impairment but relatively modest thrombocytopenia and lack of severe ADAMTS-13 deficiency (activity <10%) at diagnosis are clues to diagnose malignant hypertension-induced TMA. Patients with malignant hypertension respond well to antihypertensive agents and have favorable nonrenal outcomes.

Emerging therapy options in heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening thrombotic complication of heparin, which is the result of platelet activation by anti-PF4/heparin antibodies. With lepirudin and danaparoid no longer available in the US, treatment options are limited to argatroban, fondaparinux (off-label use) and bivalirudin (for patients undergoing percutaneous coronary intervention). Both argatroban and bivalirudin are parenteral drugs and require close monitoring and hospitalization. Fondaparinux is contraindicated in patients with significant renal impairment and is associated with a small risk of HIT. Anticoagulants approved for thromboprophylaxis and management of thromboembolic conditions such as rivaroxaban, dabigatran, and apixaban have fixed oral dose, rapid onset of action and does not require monitoring. These novel agents do not interact with anti-PF4/heparin antibody and offer attractive therapy options for HIT. Their utility in HIT has been supported by a few clinical reports, however, larger studies are needed before they can be utilized in clinical practice. Therapeutic plasma exchange has been utilized with some success in patients with HIT, who need heparin reexposure for cardiac surgery but their safety and efficacy needs further exploration. 2-O, 3-O desulfated heparin, which lacks any anticoagulant effect, has been shown to reduce the development of HIT in murine models. Finally, novel targets based on the molecular pathogenesis of HIT are being studied for therapeutic drug development. We hope that the availability of novel therapies in the future will expand the options available for the management of HIT.

Exertional Chest Pain and Dyspnea From Hyperviscosity Syndrome Related to Marginal Zone Lymphoma.

Hyperviscosity syndrome is usually seen in Waldenstrom macroglobulinemia with the serum viscosity > 4 cP. It commonly manifests as skin or mucosal bleeding, visual abnormalities and neurological symptoms. We describe a case of a 65-year-old man, who presented with chronic exertional chest pain and dyspnea without other manifestation and had hyperviscosity syndrome related to marginal zone lymphoma (MZL) even with a marginally elevated plasma viscosity. The symptoms resolved after initiation of chemotherapy. This case illustrates that MZL can cause hyperviscosity syndrome, which can manifest with cardiopulmonary symptoms without other clinical features even at a marginally elevated plasma viscosity. Atypical cases of hyperviscosity syndrome can, thus, present diagnostic challenges and require a high index of suspicion.