Poor Prognostic Sign Research Articles

Zoster? I Think Not: A Rare Site of Metastatic Colon Cancer

Skin metastasis of solid tumors accounts for only 2% of all skin tumors, most commonly occurring in primary breast and lung cancer. Cutaneous metastatic disease of colorectal cancer (CRC) is a rare phenomenon only occurring in about 5% of cases. A 49 year old man with microsatellite unstable, KRAS mutated, BRAF wild-type stage IV colon adenocarcinoma complicated by a malignant pleural effusion and pulmonary embolism on apixaban presented with shortness of breath and pruritic rash for one month. He had nausea, vomiting, and abdominal pain. Physical exam showed tachycardia to 115bpm, bulky bilateral anterior cervical lymphadenopathy, and a non-tender abdomen. His skin exam revealed multiple erythematous grouped papules scattered over a dusky erythematous large patch involving the left trunk. Chest x-ray showed new left pleural effusion with improvement of prior right pleural effusion. Labs showed hyponatremia 130mmol/L, hemoglobin 12.9g/dL, and WBC 14.4K/UL. The patient underwent thoracentesis with catheter placement for management of recurrent pleural effusion. He was started on empiric valacyclovir for suspected zoster without improvement in lesions. Biopsy of skin lesions was performed showing cutaneous metastases of colon adenocarcinoma. Valacylovir was discontinued, and the patient was discharged home with oncology follow up to start treatment with pembrolizumab given the microsatellite instability status of his malignancy. The most common site of cutaneous metastasis in CRC is the abdomen, affecting prior incision sites. Cutaneous metastatic cancer can have a variety of appearances. Color may range from flesh-like to violaceous and lesions may be single or multiple, firm, painless, mobile, and nodular. Appearance may mimic lipomas or epidermal cysts. Less frequently lesions may mimic an infectious process with a presentation that appears as a more erythematous indurated lesion but may in fact be inflammatory metastatic carcinoma. Histologic and genetic features may resemble the primary tumor. Awareness of cutaneous metastatic disease is important as it generally indicates widespread disease and is considered a poor prognostic sign. Treatment options may include wide local excision for isolated lesions, however extensive cases may require palliative systemic therapy. As skin lesions may mimic other benign processes, biopsy should be performed on suspicious skin lesions in patients with known cancer as it could signify cutaneous disease spread.Figure: Left trunk skin with multiple grouped papules scattered over a large erythematous skin patch. Biopsy was consistent with colon adenocarcinoma.

Microbiome Analysis for Assessments of Treatment Response and Salvage Prognosis in Infected Diabetic Foot Ulcers

Category: Basic Sciences/Biologics, Diabetes Introduction/Purpose: Diabetic foot ulcers (DFUs) contribute to 80% of non-traumatic lower-extremity amputations. Surgeons are often forced to make surgical decision without adequate prognostic information. DFU infections are often polymicrobial, representing complex microbial communities. A microbiota is the ecological community of various microorganisms that share body space. Currently, the methods of detecting an active infection, identifying the pathogenic bacteria within the microbiome, measuring the response to therapy, and assessing prognosis are limited. Using a molecular genomic technique of 16 S rRNA sequencing, our goals are to assess the pathogenic bioburden of DFUs and to monitor the bacterial community changes in response to antibiotic treatment. Our hypothesis is that the microbiome in DFUs responding to debridement and antibiotics treatment is distinct from those that fail to respond. Methods: Patients with type I or II diabetes who presented with an infected DFU were enrolled. Infections were identified using clinical signs. The DFU size was measured and classified using the Wagner classification. Enrolled patients were initially managed with foot salvaging therapy (FST): irrigation and debridement followed by wet-to-dry dressings and 6 weeks of intravenous antibiotic treatment. Superficial and deep DFU samples were obtained and evaluated by 16 S rRNA microbiome analysis and qPCR for bacterial abundance. This was repeated at 4, 8, and 12 weeks following the initiation of FST. At 12 weeks, patients were divided into two groups, healed and non-healed, based on the change in the size of the wound and absence or presence of 12 secondary signs of infection. Alpha- and beta-diversity were measured by the Shannon index and Bray-Curtis dissimilarity index to evaluate changes in the microbiome between the healed and non-healed groups. Results: From July 2015 to August 2016, 21 patients were enrolled and 3 deceased due to medical comorbidities. Of the 18 patients available for follow-up, 10 failed FST and 8 healed. The qPCR and microbiome analysis revealed that the bacterial abundance and diversity of the bacterial community were substantially reduced following debridement and intravenous antibiotic treatment. At the initial enrollment, those group that healed versus non-healed showed significant differences in microbiome composition, with the healed group enriched with Actinomycetales and Staphylococcus, and the non-healed group enriched with Bacteroidales and Streptococcus. At week 4, such differences disappeared and bacterial abundance significantly decreased. New differences were evident at week 8: the healed group was enriched with Actinomycetales and non-healed group with Bacilli. Conclusion: Abundant presence of Bacteroidales and Streptococcus at the initial presentation of infected DFU maybe a poor prognostic sign for healing with FST. Through molecular analysis of the wound microbiome, we can identify pathogens of prognostic value at the initial cultures and assess response to therapy with significant differences at 8 weeks after. Our study provides useful information for counseling patients of treatment prognosis and determining to pursuit further foot salvage versus amputation.

ADAM-17 expression is enhanced by FoxM1 and is a poor prognostic sign in gastric carcinoma

BackgroundThe ADAMs proteases are a multifunctional family of proteins, many of which participate in the pathogenesis of cancers. The expression and regulation of ADAMs has not yet been fully examined in gastric cancer. Materials and methodsUsing reverse transcription-PCR, messenger RNA expression of ADAM-9, ADAM-10, ADAM-11, ADAM-12, ADAM-15, ADAM-17, ADAM-28, and ADAM-33 was detected in gastric cancer. ADAM-10, ADAM-17, ADAM-28, and FoxM1 expression in gastric cancer was detected by Western blot and immunohistochemistry. The correlation between ADAM-17 and FoxM1 was analyzed in vivo and in vitro. ResultsThe messenger RNA levels of ADAM-9, ADAM-10, ADAM-15, ADAM-17, ADAM-28, and ADAM-33 were increased in tumor tissues compared with adjacent normal tissue, especially ADAM-10, ADAM-17, and ADAM-28. FoxM1 expression correlated significantly with ADAM-17 expression. FoxM1 regulates ADAM-17 expression in vivo and in vitro, which in turn influences proliferation and tumor growth of gastric cancer cells. Furthermore, Cox regression analysis revealed that FoxM1 and ADAM-17 are independent prognostic factors for patients with gastric cancer. ConclusionsThese results indicate that overexpression of ADAMs may contribute to gastric cancer progression and that ADAM-17 is a downstream target of FoxM1. Overall, the present study highlights the potential for FoxM1 and ADAMs as potential therapeutic targets for patients with gastric carcinoma.

Abstract 1815: Extracellular vesicles derived from lung cancer cell may contribute to the formation of malignant pleural effusion via activating Stat3/Tissue factor/VEGF

Abstract Malignant pleural effusion (MPE) is a poor prognostic sign for patients with non-small-cell lung cancer (NSCLC) and is noted around 15% at the time of initial diagnosis and 50% in their later courses. Previously, we have shown that IL-6/Stat3/tissue factor (TF)/VEGF pathway enhances lung cancer angiogenesis, metastasis and the generation of MPE. In the current study, we demonstrated that EVs derived from lung cancer cells may also contribute MPE formation. We first used ultra-filtration (UF) method as well as the classical ultra-centrifugation (UC) method to isolate EV from lung cancer cell line and demonstrated that the EVs isolated by UF method were characteristic with exosome marker in Western Blotting (Alix, CD63, and Tsg101), morphology at Transmission electron microscopy (TEM) and size in Nanosight system (30 to 150 nm). After labeling these EVs with the green fluorescent dye Cellvue, EVs uptake in AS2 cell can be imaged by the fluorescent microscopy. After the EV uptake of recipient cell, the oncogenic signal such as Stat3 and AKT were activated with increasing phosphorylation at Western blotting comparing to those adding serum free medium. Using the ELISA method, we found the cargos in these EV were enriched in IL6. We also found these cargo derived from EVs, containing high VEGF and TF, induced more prominent extravasation than serum free medium did in Miles assays. In clinical sample, we also isolated cancer cell from MPE and the purity of the cells was confirmed by immunofluorescent staining with specific TTF-1expression of lung adenocarcinoma. After short-term culture, EV from MPE cancer cell have the characteristic of exosome marker and induced more prominent extravasation than serum free medium as EV from AS2 cell did. And we also isolated EV direct from MPE and pleural effusion from congestive heart failure (CHF) patients. And we found EV derived from MPE induced more prominent extravasation than those derived from CHF in Miles assays. In conclusion, we demonstrated the UF is clinical assessable method for isolating EV from body fluid and EV derived from lung cancer cell and MPE may contribute oncogenic and angiogenic signal transmission accelerating the formation of MPE. Citation Format: Chien-Chung Lin, Wei-Lun Huang, Wu-Chou Su. Extracellular vesicles derived from lung cancer cell may contribute to the formation of malignant pleural effusion via activating Stat3/Tissue factor/VEGF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1815. doi:10.1158/1538-7445.AM2017-1815

Surgical treatment of detrusor underactivity: a short term proof of concept study

ABSTRACTObjectives To compare the surgical outcomes of men with bladder outlet obstruction (BOO) due to benign prostatic obstruction (BPO) to those with detrusor underactivity (DU) or acontractile detrusor (DA).Materials and Methods This retrospective, IRB approved study included men who underwent BPO surgery for refractory LUTS or urinary retention. Patients were grouped based on videourodynamic (VUDS) findings: 1) men with BOO, 2) men with DU and 3) men with DA. The primary outcome measure was the Patient Global Impression of Improvement (PGII). Secondary outcome measures included uroflow (Qmax), post-void residual volume (PVR) and the need for clean intermittent catheterization (CIC).Results One hundred and nineteen patients were evaluated: 1) 34 with BOO, 2) 62 with DU and 3) 23 with DA. Subjective success rate (PGII) was highest in the BOO group (97%) and those with DU (98%), while DA patients had a PGII success of 26%, (p<0.0001). After surgery, patients with BOO had the lowest PVR (68.5mL). Fifty-six patients (47%) performed CIC pre-operatively (47% of BOO, 32% of DU and 87% of DA patients). None of the patients in the BOO and DU groups required CIC post operatively compared to16/23 (69%) of patients in the DA group (p<0.0001).Conclusions BPO surgery is a viable treatment option in men with presumed BOO and DU while DA is a poor prognostic sign in men who do not void spontaneously pre-operatively.

Prolonged epileptiform EEG runs are associated with persistent seizures in juvenile myoclonic epilepsy

ObjectiveIn juvenile myoclonic epilepsy (JME), various EEG characteristics have been suggested as poor prognostic signs, but their significance is unclear. The aim of this study was to assess the influence of EEG variables on seizure and psychosocial outcome after a follow-up exceeding 20 years. Methods396 EEG recordings were available for assessment in 40 patients (42 complete digital, 330 paper segments and 24 written reports only). Mean follow-up was 31 years (range 20–68). The number of EEGs per patient ranged from 2 to 23 (mean 9). Twenty-one patients were in remission for >5 years, whereas 19 had persistent seizures. Favorable psychosocial outcome was found in 14 of 37. EEGs were retrospectively categorized into four main groups; normal, slowing, epileptiform discharges or both slowing and epileptiform discharges, with further sub-classification. Hyperventilation and photoparoxysmal responses were also evaluated. Scoring of EEG findings was blinded to seizure and psychosocial outcome. ResultsSignificant associations were found between poor seizure control and prolonged ≥3s epileptiform runs, p=0.03 (8/19 vs 2/21), long ≥3s photoparoxysmal runs, p=0.04 (6/19 vs 1/21) and long ≥3s hyperventilation-induced epileptiform runs, p=0.02 (5/19 vs 0/21). The strongest association between persistent seizures and EEG was found when all epileptiform runs ≥3s were combined (p=0.007), with a positive predictive value equal to 79% and a negative predictive value equal to 69%. Fast (4-5c/s) spike-wave runs were also more frequent in patients with persistent seizures compared to the remission group, p=0.04 (9/19 vs 3/21). Other epileptiform elements occurred equally in the two prognostic groups. Psychosocial outcome was not influenced by EEG findings. Prolonged runs within 6 months from first recording did also predict clinical outcome, p=0.03; (8/19 vs 2/21), with a positive predictive value equal to 80% and a negative predictive value equal to 63%. SignificanceFast spike-wave runs and prolonged (≥3s) epileptiform runs, including photoparoxysmal and hyperventilation-induced runs were associated with persistent seizures in JME. Focal EEG abnormalities were not associated with clinical outcome. Conceivably, the duration of epileptiform bursts reflects the degree of deficient intracortical inhibition. Prolonged runs may represent an essential predictive feature for poor seizure control in JME.

Prognostic Value of Blood Urea Nitrogen in Acute Upper GI Bleeding

Elevation of the blood urea nitrogen (BUN) is a poor prognostic sign in acute pancreatitis. To determine if it also predicts poor outcomes in acute

Early Lance–Adams syndrome after cardiac arrest: Prevalence, time to return to awareness, and outcome in a large cohort

IntroductionEarly myoclonus after cardiac arrest (CA) is traditionally viewed as a poor prognostic sign (status myoclonus). However, some patients may present early Lance–Adams syndrome (LAS): under appropriate treatment, they can reach a satisfactory functional outcome. Our aim was to describe their profile, focusing on pharmacologic management in the ICU, time to return of awareness, and long-term prognosis. MethodsAdults with early LAS (defined as generalized myoclonus within 96h, with epileptiform EEG within 48h after CA) were retrospectively identified in our CA registry between 2006 and 2016. Functional outcome was assessed through cerebral performance categories (CPC) at 3 months, CPC 1–2 defined good outcome. ResultsAmong 458 consecutive patients, 7 (1.5%) developed early LAS (4 women, median age 59 years). Within 72h after CA, in normothemia and off sedation, all showed preserved brainstem reflexes and localized pain. All patients were initially treated with valproate, levetiracetam and clonazepam; additional agents, including propofol and midazolam, were prescribed in the majority. First signs of awareness occurred after 3–23 days (median 11.8); 3/7 reached a good outcome at 3 months. ConclusionEarly after CA, myoclonus together with a reactive, epileptiform EEG, preserved evoked potentials and brainstem reflexes suggests LAS. This condition was managed with a combination of highly dosed, large spectrum antiepileptic agents including propofol and midazolam. Even if awakening was at times delayed, good outcome occurred in a substantial proportion of patients.

High-Dose Filgrastim Treatment of Nonregenerative Pancytopenia Associated With Chronic Canine Ehrlichiosis

To report the management and outcome of a dog with canine monocytic ehrlichiosis and nonregenerative pancytopenia, with high doses of filgrastim. An 8-year-old male, mixed-breed dog, weighing 5.6kg, presented with a 1-month history of hyporexia, adynamia, and a weight loss of approximately 1kg. The general condition of the dog was observed to be poor as follows: lethargy, tachycardia, marked pallor of the mucous membranes, petechiae on the abdomen, hepatosplenomegaly, and cervical lymphadenopathy. A complete blood count analysis revealed severe leukopenia, thrombocytopenia, and anemia. A direct immunofluorescence assay using anti-Ehrlichia canis-immunoglobin G (1:400) yielded positive result. The dog was diagnosed with nonregenerative pancytopenia associated with canine monocytic ehrlichiosis. The dog presented poor prognostic signs (neutropenia, thrombocytopenia, and severe anemia). The dog was treated with antibiotics and a short course of high-dose filgrastim (50µg/kg, SC, q 48h for 4 days) to stimulate bone marrow response, prednisone to decrease peripheral platelet destruction, and an iron supplement to compensate for the iron deficiency in the bone deposits. Although temporary side effects associated with filgrastim use, such as bone pain, bleeding, and the worsening of thrombocytopenia, were observed, the treatment improved the clinical course and the cell counts in less than a month. The treatment protocol used in this case might be an alternative for treating cases of severe myelosuppression. This treatment plan can substantially change the clinical course of the disease for the better, compared to conventional treatment.

Early presentation of cerebral fat embolism

Cerebral fat embolism syndrome has been identified in patients with long bone trauma, and usually occurs after a symptom free interval of 12 h. Treatment includes supportive care, and outcome is variable. We describe a case with earlier than expected presentation with good outcome despite poor initial prognostic signs.

Orbital MALT Lymphoma after Autologous Stem Cell Transplantation for Follicular Lymphoma as Relapse of Diffuse Large B-Cell Lymphoma

We report a patient who developed orbital MALT lymphoma after autologous peripheral blood stem cell transplantation for follicular lymphoma as relapse of diffuse large B-cell lymphoma. A 54-year-old woman with systemic lymphadenopathy was diagnosed with diffuse large B-cell lymphoma by left supraclavicular lymph node biopsy, and underwent 6 courses of R-CHOP chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, leading to complete response. Five years later in the follow-up, an abdominal mass with abnormal uptake was found by whole-body 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography, and computed tomography-guided biopsy demonstrated follicular lymphoma. She underwent 4 courses of R-IDEA chemotherapy with rituximab, ifosfamide, dexamethasone, etoposide, and cytarabine, resulting in partial response, and then, underwent autologous peripheral blood stem cell transplantation with myeloablative conditioning with R-MCEC chemotherapy (rituximab, ranimustine, cyclophosphamide, etoposide, and carboplatin). She was well for the following 3 years with no treatment until the development of a right orbital mass. The excisional biopsy this time revealed MALT lymphoma. She underwent 3 courses with rituximab monotherapy and local orbital radiation at the total dose of 30 Gy. She had no relapse for the following three years. Relapse as MALT lymphoma after hematopoietic stem cell transplantation for relapsed and refractory lymphoma may not be a poor prognostic sign.

The IGF1-PI3K-Akt Signaling Pathway in Mediating Exercise-Induced Cardiac Hypertrophy and Protection.

Regular physical activity or exercise training can lead to heart enlargement known as cardiac hypertrophy. Cardiac hypertrophy is broadly defined as an increase in heart mass. In adults, cardiac hypertrophy is often considered a poor prognostic sign because it often progresses to heart failure. Heart enlargement in a setting of cardiac disease is referred to as pathological cardiac hypertrophy and is typically characterized by cell death and depressed cardiac function. By contrast, physiological cardiac hypertrophy, as occurs in response to chronic exercise training (i.e. the 'athlete's heart'), is associated with normal or enhanced cardiac function. The following chapter describes the morphologically distinct types of heart growth, and the key role of the insulin-like growth factor 1 (IGF1)- phosphoinositide 3-kinase (PI3K)-Akt signaling pathway in regulating exercise-induced physiological cardiac hypertrophy and cardiac protection. Finally we summarize therapeutic approaches that target the IGF1-PI3K-Akt signaling pathway which are showing promise in preclinical models of heart disease.

Neurofilaments as a biomarker of axonal loss in multiple sclerosis

Background Neurofilaments (NF-H) might be a potential biomarker of CNS tissue damage in MS, but their potential predictive value for the future disease course, disability, disease progression, and treatment response needs to be investigated. Aim of the work The aim of this study is to evaluate the role of serum phosphorylated neurofilament H as a marker in multiple sclerosis and correlate it's level with clinical expanded disability status scale (EDSS) and magnetic resonance imaging findings. Subjects and methods Study included 40 patients and 20 healthy control, 20 patients with relapsing remitting multiple sclerosis (RRMS) and 20 patients with secondary progressive multiple sclerosis (SPMS). All patients in this study were subjected to full history taking and clinical examination and scoring according to the EDSS scores, routine laboratory investigations, measuring of serum phosphorylated neurofilament-H (PNF-H) levels and neuroradiological assessment. Results Patients with secondary progressive multiple sclerosis were more likely to have a high serum (PNF-H) titer compared to patients with relapsing remitting multiple sclerosis, and these levels were significantly correlated with EDSS scores in both patients groups. Conclusion The increase in (PNF-H) titer during the progressive phase of the disease together with the correlation of (PNF-H) levels with all clinical scales and radiological lesions (e.g. gadolinium-enhanced lesions and black holes) suggests that cumulative axonal loss is responsible for sustained disability and that high (PNF-H) level is a poor prognostic sign.

Prognostic significance of repeat biopsy in lupus nephritis: Histopathologic worsening and a short time between biopsies is associated with significantly increased risk for end stage renal disease and death

Background/purposeApproximately half of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), a major cause of morbidity and early mortality in that disease. Prolonged renal inflammation is associated with irreversible kidney damage which confers a 30% risk of end stage renal disease (ESRD), making early, aggressive treatment mandatory. Failure to achieve therapeutic response or recurrence of renal flare often prompts repeat biopsy. However, the role of repeat biopsy in determining long-term renal prognosis remains controversial. For this reason repeat biopsies are usually not utilized unless clinical evidence of refractory or recurrent disease is already present, despite known mismatches between clinical and biopsy findings. The current study quantifies the degree to which histopathologic worsening between first and second biopsies and duration between them predicts ESRD and death. MethodsMedical records of 141 LN patients with more than one biopsy were obtained from a single large urban medical center. Cases were attained using billing codes for diagnosis and procedures from 1/1999–1/2015. Biopsy worsening was defined as unfavorable histopathologic classification transitions and/or increased chronicity; if neither were present, the patient was defined as non-worsening. We used Cox proportional hazard models to study the relationship between ESRD and survival adjusting for covariates which included age at first biopsy, gender, race, initial biopsy class, and initial induction therapy. ResultsOf 630 patients screened, 141 had more than one biopsy. Advancing chronicity was detected in 48 (34.0%) and a renal class switch to worse grade of pathology was found in 54 (38.3%). At least one of these adverse second biopsy features was reported in 79 (56.0%) patients. Five years following initial biopsy, 28 (35.4%) of those with worsening histopathology on second biopsy developed ESRD, compared to 6 (9.7%) of non-worsening patients and 10 (12.7%) of patients with worsening histopathology had died compared to 2 (3.2%) of non-worsening patients. Biopsy worsening was associated with a significantly greater 15-year risk of ESRD (Hazard Ratio 4.2, p=0.0001) and death (Hazard Ratio 4.3, p=0.022), adjusting for age, gender, race, biopsy class, and treatment. Time between first and second biopsies was <1year in 32 patients, 1–5years in 81, and >5years in 28. Over a 15-year period, those with <1year between first and second biopsies (presumably enriched for patients with early clinical signs of progression) had a significantly greater risk of ESRD (Hazard Ratio 13.7, p<0.0001) and death (Hazard Ratio 16.9, p=0.0022) after adjusting for age, gender, race, biopsy class, and treatment. ConclusionA repeat renal biopsy demonstrating worsening pathology increases the risk of ESRD and death more than four-fold compared to non-worsening patients. Given known potential mismatch between biopsy and clinical data, repeat biopsies may add important information and justify changes in treatment not considered on clinical grounds. Earlier detection of poor prognostic signs in those without early clinical deterioration might improve outcomes in enough patients to reconsider cost effectiveness of routine repeat biopsy.

Prognosis of Patients with Standard- or Intermediate-Risk Acute Myeloid Leukemia Presenting with Residual Disease after One Induction Cycle Is Improved If Remission Is Achieved Following Re-Induction Given By Day 14 Compared to Second-Line Therapy Given 24-40 Days after Induction

Introduction: Failure to achieve remission following standard induction is a poor prognostic sign in patients with acute myeloid leukemia (AML). However, as there is no consensus on the optimal number of induction cycles and/or the best indication and timing for re-induction, the definition of refractory AML is still debatable. A clinically relevant definition of refractoriness should be associated with poor long-term prognosis. This is of particular importance for patients who eventually achieve remission (CR1) and in whom referral for allogeneic stem cell transplantation (alloSCT) in CR1 may be controversial. It was previously reported that AML patients who achieved CR1 following re-induction given on day 14 of therapy, had a long-term survival identical to that of patients who achieved CR1 after one induction cycle. To the best of our knowledge, no data are available regarding the prognosis of patients who achieved CR1 after a second cycle of intensive chemotherapy, administered at the end of neutropenic period.The current study compared the prognosis of AML patients who achieved CR1 after one induction cycle to that of patients who achieved CR1 following a second cycle of chemotherapy given either as re-induction by day 14 or as a second-line therapy administered on days 24-40 of the first induction.Patients and Methods: Data of all leukemia patients admitted to the Rambam Medical Center between the years 1993 and 2015 were retrospectively collected. Adults diagnosed with de-novo AML who achieved CR1 following one or two cycles of therapy were included in the study. Patients diagnosed with APL or high-risk AML, as defined based on a poor-risk karyotype or presence of FLT3-ITD mutation, were excluded from the analysis. It is common practice at our center to assign patients for re-induction according to day 14 bone marrow (BM) results. Yet, for various reasons, this paradigm is not followed in some patients. Overall survival (OS), leukemia-free-survival (LFS), and death rates were compared in the study participants. Multivariate analysis for prediction of death, including the use and timing of second-line therapy, was performed.Results: Six hundred and forty three de novo AML patients were treated at Rambam during the study period. After exclusion of patients with high-risk AML, 492 individuals were left. Of them, 242 patients achieved CR1 after one cycle of induction (control group), 53 after induction + re-induction administered by day 14 (re-induction group) and 38 achieved CR1 after induction followed by second-line therapy prescribed on days 24-40 (second-line group).Median OS was 25.9, 23.5 and 15.1 months for patients in control, re-induction and second-line groups, respectively. Median LFS was 14.7, 10 and 8.16 months for the corresponding groups, respectively. Differences in OS and LFS were statistically significant between the control and second-line groups (p<0.0001 for both comparisons), and between the re-induction and second-line groups (p=0.007 for OS; p=0.001 for LFS). Differences in OS and LFS between the control and re-induction groups were insignificant (p=0.46, p=0.49). In multivariate analysis including all patients, age and cytogenetics were the only significant factors to predict survival. When the 40 patients presenting with standard-risk (favorable) cytogenetics were excluded, age and treatment were the only significant factors to predict survival in multivariate analysis.Conclusions: Despite previous reports showing similar outcomes in patients who achieved CR1 post re-induction and those achieving CR1 with one induction cycle, some physicians are reluctant to start re-induction as early as day 14. We herein report a significantly better prognosis in patients achieving CR1 after re-induction given by day 14 compared to those achieving CR1 after a second cycle of therapy prescribed on days 24-40. These data may have 2 practical implications. First, in AML patients with residual disease, an effort should be made to start re-induction as early as day 14. Second, for intermediate-risk patients, a failure to achieve CR1 after one induction cycle should not alter post-remission decisions, if CR1 was achieved with re-induction by day 14. This may not be true for patients who achieved CR1 with second-line therapy prescribed on days 24-40. Our study was not powered to examine whether alloSCT could improve the outcome of these refractory AML patients. DisclosuresNo relevant conflicts of interest to declare.

A Rare Case of Salmonella Bacteremia in a Patient with Cryptogenic Liver Cirrhosis

Introduction: Nontyphoid salmonella infections are most often associated with contaminated food products. Most cases of salmonella bacteremia in liver cirrhosis have been associated with an advanced stage of liver cirrhosis and hepatocellular carcinoma. Case: A 54 year old female with past medical history significant for cryptogenic liver cirrhosis, gastroesophageal reflux disease and hypertension presented with complaint of fever for the last 3 days. She had associated diffuse abdominal pain and 10-15 episodes of non-bloody, non-mucus diarrhea. Her temperature was 39.1 C, BP 134/79 mmHg, pulse 96/min and oxygen saturation 100% on room air. Physical exam was pertinent for soft, moderately distended abdomen with tenderness to deep palpation in all quadrants and 2+ edema in bilateral lower extremities. Lab work revealed a white blood cell count of 7000/μL, platelets 74,000/ μL, creatinine 0.8 mg/dL, albumin 2.2 g/dL, AST 78 IU, ALT 29 IU and total bilirubin 2 mg/dL. Ultrasound abdomen was concerning for hepatic cirrhosis, large amount of ascites and thickened gall bladder wall without stones or sludge. Bedside diagnostic paracentesis was done to evaluate for spontaneous bacterial peritonitis, which revealed only 378 white blood cells (10% polynuclear and 90% mononuclear) but no organisms. However, the blood and the stool cultures drawn at admission were finalized as growing Salmonella species. The patient was then treated with IV ciprofloxacin and responded appropriately. Discussion: Bacteremia is a poor prognostic sign in patients with liver cirrhosis because of its occurrence late in the course of cirrhosis. Escherichia coli and Klebsiella pneumoniae are the most commonly isolated organisms. Only seldom cases of Salmonella bacteremia have been reported. Nontyphoid salmonellosis is associated with immunocompromised conditions, including extremes of age, alteration of the endogenous bowel flora, malignancy, autoimmune disorders and reticuloendothelial blockade. Patients with liver cirrhosis have defects in both humoral and cell-mediated immunity. The rediculoendothelial cells represent a potent filtering mechanism for portal bloodborne pathogens which is impaired in patients with liver cirrhosis. The occurrence of nontyphoid Salmonella bacteremia has been reported patients with an advanced stage of liver cirrhosis and hepatocellular carcinoma. The Model for end stage liver disease score was calculated as 17 in above case.Figure 1

Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment

Transplant-associated thrombotic microangiopathy (TA-TMA) is a multifactorial disorder caused by systemic vascular endothelial injury that can be triggered by several mechanisms during the transplant process. Thrombotic microangiopathy may affect multiple systems and occurs in ~30% of patients undergoing hematopoietic stem cell transplantation. A subgroup of patients with thrombotic microangiopathy develop TA-TMA, and the other may develop other thrombotic microangiopathic disorders such as thrombotic thrombocytopenic purpura, a condition with similar finding but different pathophysiology involving ADAMTS-13. The mortality rates in patients who develop severe TA-TMA are in excess of 80%. Recent investigations show that complement system activation in patients with TA-TMA is a very poor prognostic sign and implicates complement dysregulation as a key pathway in the pathogenesis of TA-TMA and its disease phenotype. The original diagnostic criteria for TA-TMA included hematologic and renal injury markers, which are limited in their ability to detect only advanced disease, and therefore may result in delayed TA-TMA diagnosis in transplant patients. A recent set of diagnostic criteria added markers of complement activation, proteinuria, and hypertension, with predicted improved detection of early TA-TMA. Supportive care that includes elimination of potentially toxic agents such as calcineurin inhibitors and sirolimus, adequate antimicrobial treatment, and maintaining adequate renal functions using renal replacement therapy may be sufficient for treatment of mild-to-moderate TA-TMA. Plasma exchange, which is a potentially curative therapy in thrombotic thrombocytopenic purpura, has no proven efficacy in TA-TMA. Blocking the complement system with eculizumab is currently the most effective treatment to circumvent the poor outcome in patients with severe TA-TMA.

Interleukin-2 reverses CD8(+) T cell exhaustion in clinical malignant pleural effusion of lung cancer.

Malignant pleural effusion (MPE) is a poor prognostic sign for cancer patients, whereas the functional condition of MPE CD8(+) T cells is unknown. Intracavitary immunotherapy with interleukin (IL)-2 has been proven effective in controlling MPE. To elucidate the underlying mechanism, 35 lung cancer (LC) patients with MPE and 12 healthy donors were included in this study. For the IL-2 therapy experiments, after draining partial MPE, we treated 14 patients by administrating IL-2 (3 or 5 × 10(6) U in 50 ml saline) into the thoracic cavity. Before and after IL-2 treatment (40-48 h), the MPE and peripheral blood (PB) were obtained from the subjects. PB from healthy volunteers was collected as control. The expression of programmed cell death 1 (PD-1), granzyme B (GzmB), interferon (IFN)-γ and the proliferation were analysed in CD8(+) T cells from MPE and PB. The CD8(+) T cells in the MPE of LC patients showed lowest GzmB, IFN-γ and proliferation but highest PD-1 expression, compared with that in PB of LC patients and healthy donors. IL-2 treatment reduced the expression of PD-1, increased the expression of GzmB and IFN-γ and enhanced the proliferation of CD8(+) T cells in MPE. In addition, IL-2 treatment reduced carcino-embryonic antigen (CEA) level in MPE. These results indicate that MPE CD8(+) T cells exhibit exhaustion phenotype which can be reversed by IL-2 therapy.

Early neurological deterioration after thrombolysis: Clinical and imaging predictors.

National Institutes of Health Stroke Scale is the most common scale used in stroke patients. An increase of four points or more within 24 h signifies early neurological deterioration. We aimed to establish how often early neurological deterioration occurs in a cohort selected by magnetic resonance imaging and which factors predicted early neurological deterioration. In this single-center study, we collected epidemiological, imaging and outcome data on 569 consecutive patients undergoing reperfusion therapy after magnetic resonance imaging selection. Of these, 33 (5.8%) experienced early neurological deterioration. Seven were due to a symptomatic intracerebral hemorrhage, 23 were caused by extension of ischemia on follow-up imaging and three were due to progression on the basis of small vessel disease. Early neurological deterioration was predicted by a larger perfusion lesion, higher blood glucose and presence of large vessel disease. Penumbra occurred in 34% of patients but only 9% of patients with penumbra experienced early neurological deterioration, thus eroding the value of penumbra as an imaging marker. Early neurological deterioration was a poor prognostic sign. Odds ratio for disability or death was 14.9 (95% confidence interval: 6.5-34.0). Early neurological deterioration is rare. It originates mainly from ischemic infarct growth rather than from hemorrhage. Concern should be highest in patients with elevated blood glucose, larger perfusion lesions and large vessel disease. Prior aspirin use increases risk of symptomatic intracerebral hemorrhage.

Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial

BackgroundWorsening renal function (WRF) is a common endpoint in decompensated heart failure clinical trials because of associations between WRF and adverse outcomes. However, WRF has not universally been identified as a poor prognostic sign, challenging the validity of WRF as a surrogate endpoint. Our aim was to describe the associations between changes in creatinine and adverse outcomes in a clinical trial of decongestive therapies. Methods and ResultsWe investigated the association between changes in creatinine and the composite endpoint of death, rehospitalization or emergency room visit within 60 days in 301 patients in the Diuretic Optimization Strategies Evaluation (DOSE) trial. WRF was defined as an increase in creatinine >0.3 mg/dL and improvement in renal function (IRF) as a decrease >0.3 mg/dL. When examining linear changes in creatinine from baseline to 72 hours (the coprimary endpoint of DOSE), increasing creatinine was associated with lower risk for the composite outcome (HR = 0.81 per 0.3 mg/dL increase, 95% CI 0.67–0.98, P = .026). Compared with patients with stable renal function (n = 219), WRF (n = 54) was not associated with the composite endpoint (HR = 1.17, 95% CI = 0.77–1.78, P = .47). However, compared with stable renal function, there was a strong relationship between IRF (n = 28) and the composite endpoint (HR = 2.52, 95% CI = 1.57–4.03, P < .001). ConclusionThe coprimary endpoint of the DOSE trial, a linear increase in creatinine, was paradoxically associated with improved outcomes. This was driven by absence of risk attributable to WRF and a strong risk associated with IRF. These results argue against using changes in serum creatinine as a surrogate endpoint in trials of decongestive strategies.