Management of Acquired Factor VIII Inhibitors With NovoSeven and Obizur.

Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the production of autoantibodies against coagulation factor VIII (FVIII). AHA is associated with significant morbidity and mortality primarily as a result of bleeding. Although many disorders are associated with the development of these inhibitors, up to 50% of cases remain idiopathic. The approach to therapy involves an initial strategy often to control acute bleeding episodes followed by definitive treatment to eradicate the inhibitor with immunosuppressive agents. We present the case of a 63-year-old Caucasian male hospitalized for severe Covid-19 who developed bleeding due to an acquired FVIII inhibitor that had never been treated definitively. Our case presentation focuses on in-hospital management of this patient's acute bleeding episodes with by-passing agents and recombinant porcine factor VIII.

Salivary Duct Carcinoma: Case Reports and Brief Review of the Literature.

Salivary duct carcinoma (SDC) is an uncommon and highly aggressive tumor associated with high morbidity and mortality. According to the World Health Organization, it is an extremely rare malignancy with an estimated incidence of 1-1.2 in 1,000,000 patients. Standard treatment for SDC is wide surgical resection along with lymph node dissection followed by adjuvant radiation therapy. The role of adjuvant chemotherapy is not known. In this report, we present three cases of SDC. A 71-year-old female with T1N0M0 disease was treated with total parotidectomy, ipsilateral neck dissection, and adjuvant radiotherapy without evidence of disease recurrence at 5 months. The second is a 59-year-old female with TXN1M0 disease who was treated with total parotidectomy with ipsilateral level I-IV neck dissection and adjuvant radiotherapy without evidence of disease occurrence at 21 months. The third case is a 79-year-old male with widely metastatic disease, including brain metastases, treated with cranial irradiation, leuprolide, and lapatinib who remains under home hospice care.

Infection Masquerading as Recurrence of Pancreatic Ductal Adenocarcinoma: A Cautionary Tale.

We present a case of a 59-year-old male undergoing adjuvant chemotherapy for his pancreatic adenocarcinoma post-surgical resection. He had an acute rise in carbohydrate antigen (CA) 19-9 level, which raised suspicion of metastatic disease. Instead, the patient was diagnosed to have a liver abscess, the treatment of which brought the CA 19-9 level back to normal. Unfortunately, although CA 19-9 is Food and Drug Administration (FDA)-approved tumor marker for pancreatic cancer, it is also elevated in several benign conditions, causing fear of cancer and unnecessary diagnostic workup. Hence, caution is necessary for interpreting the significance of its elevation.

Retrospective Analysis of Inflammatory Markers and Patient Characteristics in Hospitalized Covid-19 Patients: An Early Experience in Louisiana.

Background The community transmission of coronavirus disease 2019 (Covid-19) was detected in Baton Rouge, Louisiana, in March 2020. Several previous studies have reported elevations of inflammatory markers in Covid-19 positive patients and suggested a possible correlation to disease severity. Methods We identified 69 patients from Baton Rouge General (BRG) Hospital who were admitted with acute hypoxic respiratory failure and laboratory confirmed positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) between March 13 and April 5, 2020. Demographic and laboratory data were obtained through a review of medical records. Statistical analysis was performed on several inflammatory markers in association with clinical disease severity. Results We identified 69 patients with confirmed Covid-19 infection. The mean (±SD) age of the patients was 65±14 years, 68% were male and 32% were female. A total of 13 patients (19%) were considered to have mild disease, 25 (36%) had moderate disease, and 31 (45%) were considered to have severe disease. A total of nine patients died (13%), 25 (36%) have been discharged from the hospital, 20 (29%) remain in the ICU, and 15 (22%) remain admitted to the hospital at the time of writing. Lymphopenia was common among hospitalized patients (39%) and was found to be statistically more pronounced in patients with severe disease (p<0.05). Inflammatory marker elevations were also seen in several patients, with statistically significant elevations in C-reactive protein (CRP) and lactate dehydrogenase (LDH) (p <0.05). We found no statistically significant associations between ferritin, D-dimer, troponin I, body mass index (BMI), or creatine kinase (CK) with disease severity. Conclusions During the first three weeks of the Covid-19 outbreak in Baton Rouge, Louisiana, the most common reason for admission amongst Covid-19 positive patients was acute hypoxic respiratory failure. Previously, several studies have suggested a correlation between elevated inflammatory markers and disease severity. The presence of lymphopenia and elevations of CRP and LDH may be helpful in the risk stratification of these patients. In an effort to guide clinical decision making and provide insight into disease severity, further characterization of Covid-19 infection in hospitalized patients is urgently needed.

Ibrutinib-Associated Cardiac Tamponade with Concurrent Antiplatelet Therapy.

Ibrutinib is approved for the first-line treatment of chronic lymphocytic leukemia (CLL). A well-known side effect of ibrutinib therapy is increased bleeding risk, which ranges from mild mucocutaneous bleeding to rarely life-threatening hemorrhage. The increased bleeding tendency associated with ibrutinib is thought to be related to its effect on several platelet signaling pathways, which can be exacerbated in the setting of concurrent antiplatelet or anticoagulant therapy. We present an 82-year-old male with CLL on ibrutinib and concurrent antiplatelet therapy who developed cardiac tamponade due to a hemorrhagic pericardial effusion requiring emergent placement of a pericardial window. This case further highlights the risk of major bleeding in patients treated with ibrutinib and concurrent antiplatelet therapy.

Microdrilling Surgery Augmented With Intra-articular Bone Marrow Aspirate Concentrate, Platelet-Rich Plasma, and Hyaluronic Acid: A Technique for Cartilage Repair in the Knee.

The ideal treatment of large full-thickness chondral lesions in the knee, especially "kissing lesions" and osteoarthritis, has not been determined. Microdrilling surgery augmented with injections of peripheral blood stem cells and hyaluronic acid has been used to treat patients with a wide range of articular cartilage disease including patients with bipolar lesions and joint space narrowing. Excellent results in this difficult patient population have been reported, and second-look biopsy has shown repair tissue very similar to native hyaline cartilage. Because of Food and Drug Administration regulations, this technique is not currently allowed in the United States. We describe a Food and Drug Administration-compliant modification of this technique using microdrilling augmented with intra-articular bone marrow aspirate concentrate, platelet-rich plasma, and hyaluronic acid.

Quantitative electron phase imaging with high sensitivity and an unlimited field of view.

As it passes through a sample, an electron beam scatters, producing an exit wavefront rich in information. A range of material properties, from electric and magnetic field strengths to specimen thickness, strain maps and mean inner potentials, can be extrapolated from its phase and mapped at the nanoscale. Unfortunately, the phase signal is not straightforward to obtain. It is most commonly measured using off-axis electron holography, but this is experimentally challenging, places constraints on the sample and has a limited field of view. Here we report an alternative method that avoids these limitations and is easily implemented on an unmodified transmission electron microscope (TEM) operating in the familiar selected area diffraction mode. We use ptychography, an imaging technique popular amongst the X-ray microscopy community; recent advances in reconstruction algorithms now reveal its potential as a tool for highly sensitive, quantitative electron phase imaging.

Synthesis, physicochemical characterization, and self-assembly of linear, dibranched, and miktoarm semifluorinated triphilic polymers.

Linear, dibranched and miktoarm amphiphiles containing both hydrophobic and fluorophilic moieties were synthesized and characterized in an attempt to elucidate the relationship between semi-fluorinated amphiphile structure and aggregate behaviour in aqueous solution. For the linear and dibranched amphiphiles, there was an exponential decrease in critical aggregation concentration (CMC) and a logarithmic increase in core microviscosity with increasing length of the fluorocarbon segments; while the miktoarm architecture produced no notable trend in microviscosity or CMC. Furthermore, the linear and dibranched surfactants showed enhanced kinetic stability, dissociating more slowly in the presence of human serum than did either the dibranched or miktoarm amphiphiles. Finally, encapsulation studies with the hydrophobic drug paclitaxel (PTX) showed that the ability to solubilize and retain PTX increased with the presence and with the increasing size of the fluorocarbon moiety for both the linear and dibranched amphiphiles, while no such trend was observed for the miktoarm amphiphiles.

Effects of clenbuterol on contractility and Ca2+ homeostasis of isolated rat ventricular myocytes.

Clenbuterol, a compound classified as a beta2-adrenoceptor (AR) agonist, has been employed in combination with left ventricular assist devices (LVADs) to treat patients with severe heart failure. Previous studies have shown that chronic administration of clenbuterol affects cardiac excitation-contraction coupling. However, the acute effects of clenbuterol and the signaling pathway involved remain undefined. We investigated the acute effects of clenbuterol on isolated ventricular myocyte sarcomere shortening, Ca2+ transients, and L-type Ca2+ current and compared these effects to two other clinically used beta2-AR agonists: fenoterol and salbutamol. Clenbuterol (30 microM) produced a negative inotropic response, whereas fenoterol showed a positive inotropic response. Salbutamol had no significant effects. Clenbuterol reduced Ca2+ transient amplitude and L-type Ca2+ current. Selective beta1-AR blockade did not affect the action of clenbuterol on sarcomere shortening but significantly reduced contractility in the presence of fenoterol and salbutamol (P < 0.05). Incubation with 2 microg/ml pertussis toxin significantly reduced the negative inotropic effects of 30 microM clenbuterol. In addition, overexpression of inhibitory G protein (Gi) by adenoviral transfection induced a stronger clenbuterol-mediated negative inotropic effect, suggesting the involvement of the Gi protein. We conclude that clenbuterol does not increase and, at high concentrations, significantly depresses contractility of isolated ventricular myocytes, an effect not seen with fenoterol or salbutamol. In its negative inotropism, clenbuterol predominantly acts through Gi, and the consequent downstream signaling pathways activation may explain the beneficial effects observed during chronic administration of clenbuterol in patients treated with LVADs.

A repeat audit of spinal board usage in the emergency department.

An audit of spinal board usage in 2002 was repeated [Malik MHA, Lovell ME. Current spinal board usage in emergency departments across the UK. Int J Care Injured 2003;34:327-9]. It is acknowledged that this device should be used for extrication and transport, with usual removal after the primary survey. This repeat audit was carried out to try and discover whether there have been changes regarding the use of spinal boards since its publication. We found improvements have been made in some areas including the removal of patients from boards with 21% now removing patients immediately (5% previously) and 58% removing patients following clearance on the lumbar and thoracic spine by a senior clinician after log roll (52% previously). In 2006, 21% (43% previously) are still leaving patients on spinal boards routinely until radiological evidence provides clearance, 45% will place patients on boards after their arrival even if they were not on one in pre-hospital management (48% previously) and the number of boards the department owns, remained similar. In house audits of usage remained largely unchanged at 22%. We recommend ongoing departmental review of practice.

Combination treatment with weekly docetaxel and gemcitabine for advanced non-small-cell lung cancer in elderly patients and patients with poor performance status: results of a Minnie Pearl Cancer Research Network phase II trial.

The purpose of this study was to evaluate the feasibility, toxicity, and efficacy of the combination of weekly docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer (NSCLC) who are either elderly or have poor performance status (PS). Patients with stage IIIB or IV NSCLC who had received no previous chemotherapy and were = 70 years of age were eligible for this clinical trial. Patients < 70 years of age were also eligible if they had poor PS or were considered poor candidates for standard platinum-based combination chemotherapy regimens. All patients received chemotherapy with gemcitabine 800 mg/m2 and docetaxel 30 mg/m2, both drugs administered by 30-minute intravenous infusions on days 1, 8, and 15. Treatment courses were repeated every 28 days. Patients were reevaluated after completion of 2 treatment courses; responding patients continued treatment until disease progression or for a maximum of 6 courses. Between August 1999 and June 2000, 64 patients (73% with stage IV disease) were treated at 17 participating sites in the Minnie Pearl Cancer Research Network. Eighteen of 64 patients enrolled (28%) had objective response to treatment; an additional 25 patients (39%) had stable disease. Median survival was 7 months, with 1- and 2-year survival rates of 30% and 17%, respectively. Treatment was well tolerated by most patients. Grade 3/4 leukopenia occurred in 7 patients (11%), but no patient required hospitalization for neutropenia/fever. One patient developed fatal bilateral pneumonitis, which was possibly treatment-related. The combination of weekly docetaxel/gemcitabine is active and relatively well tolerated in most patients with advanced age or poor PS with advanced NSCLC. A randomized comparison of this regimen versus single-agent weekly docetaxel is in progress.

Phase I trial of gemcitabine, administered as a standard and constant dose-rate infusion, in combination with paclitaxel in patients with advanced solid tumors (LOA-2).

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine and paclitaxel combination therapy when administered to patients with advanced solid tumors, using two infusion schedules of each agent. Paclitaxel was administered on day 1, followed by gemcitabine, and gemcitabine alone was administered on day 8, of each 21-day treatment course. In the initial phase of the trial, paclitaxel was administered during 3 hours and gemcitabine during 30 minutes (schedule A). After the MTD was determined on this schedule, patients were then treated with paclitaxel during 1 hour and gemcitabine at a fixed dose-rate of 10 mg/m(2)/min (schedule B). Forty-six patients were treated with 176 courses at 7 dose levels. The MTD for schedule A was 1,300 mg/m(2) and 200 mg/m(2) and for schedule B was 1,000 mg/m(2) and 200 mg/m(2) for gemcitabine and paclitaxel, respectively. The DLT for schedule A was neutropenia and for schedule B was neutropenia and thrombocytopenia. Nonhematologic toxicity was relatively mild. Gemcitabine and paclitaxel, using both schedules of administration in the current trial, is a promising chemotherapeutic regimen.

A phase I trial of gemcitabine and infusional 5-fluorouracil (5-FU) in patients with refractory solid tumors: Louisiana Oncology Associates protocol no. 1 (LOA-1).

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine (GEM) (Gemzar) and 5-fluorouracil (5-FU) combination therapy when administered to patients with advanced solid tumors. GEM was administered intravenously over 30 minutes on days 1, 8, and 15, and 5-FU was administered as a continuous intravenous infusion from day 1 through day 15 of each 28-day treatment course. Seventeen patients (13 men and 4 women, median age 57, all previously treated with chemotherapy) were treated with 68 courses at 3 dose levels: 800/200, 1,000/200, and 1,000/300 [GEM (mg/m2/week)/ 5-FU (mg/m2/day)]. Two further patients were not fully evaluable for toxicity; one died from a probable pulmonary embolism, and one refused further treatment after developing grade II mucositis and dermatitis after her day 1 to 7 treatment. At the third dose level, 2 of 4 patients developed grade III mucositis; one also developed grade IV neutropenia with fever and grade III thrombocytopenia. Patient accrual then resumed at the second dose level. At this level, 10 patients were treated, with two developing grade III mucositis. One of these patients also developed grade IV dermatitis. No other patient developed grade III or IV side effects. Prophylactic dexamethasone was initiated after 4 of the first 7 patients (including 1 of the not fully evaluable patients) developed dermatitis-grade IV in 1 patient and grade II in the remaining 3 patients. After the steroids were initiated, 4 of the last 11 patients treated developed dermatitis, but grade 1 in all cases. One patient with metastatic gastric cancer achieved a near-complete response of his gastric mass and adrenal metastasis. Minor responses were achieved in a patient with colon carcinoma and a patient with an ethmoid sinus adenoid cystic carcinoma. The MTD and recommended dose for phase II clinical trials of GEM and 5-FU on the above schedule is 1,000 mg/m2 and 200 mg/m2 respectively, with mucositis as the DLT.

One-hour paclitaxel plus carboplatin in the treatment of advanced non-small cell lung cancer: results of a multicentre, phase II trial.

The aim of this phase II study was to determine the activity and toxicity of paclitaxel (administered by 1-h infusion) and carboplatin in advanced non-small cell lung cancer when used in a multicentre, community-based treatment setting. 100 chemotherapy-naive patients with stage IIIB or IV non-small cell lung cancer were treated between March 1995 and February 1996. All patients had Karnofsky performance status 70-100, measurable disease and adequate bone marrow, kidney and liver function. All patients received intravenous (i.v.) paclitaxel 225 mg/m2 by 1-h infusion followed immediately by carboplatin at a targeted area under the concentration time curve (AUC) of 6.0 using the Calvert formula. Courses were repeated every 21 days. Colony stimulating factors were not used routinely. 38 of 94 evaluable patients (40%) had objective responses to treatment (3 complete responses, 35 partial responses). An additional 32 patients had stable disease at initial re-evaluation. Weight gain during treatment was experienced by 47% of patients with objective response or stable disease. The median survival in this group of 100 patients was 8 months, with an actuarial 1-year survival of 42%. Leucopenia was common, but hospitalisation for treatment of neutropenia and fever occurred in only 3% of courses. Cumulative peripheral neuropathy was common, but usually appeared after the third or fourth course and was severe (grade 3) in only 15% of patients. Other grade 3 and 4 toxicity was uncommon. There was one treatment-related death due to sepsis. This large multicentre community-based phase II trial demonstrated the efficacy of paclitaxel and carboplatin combination chemotherapy in advanced non-small cell lung cancer. When paclitaxel is given by 1-h infusion, this regimen is easily administered in the outpatient setting.

Long-term follow-up of a randomized post-induction therapy trial in acute myelogenous leukemia (a Southeastern Cancer Study Group trial).

A phase III clinical trial was designed to determine if more intensive induction and consolidation therapy for acute myeloblastic leukemia increases the remission rate and prolongs survival. A minor objective was to determine if the use of non-cross resistant drugs was more effective than the same drugs used for induction. Patients with untreated leukemia between the ages of 15 and 50 were given daunorubicin 45 mg/m2 for the first 3 days of a 10-day continuous infusion of cytosine arabinoside, initially at a dose of 2000 mg/m2 but reduced to 100 mg/m2 because of toxicity. Those under 36 achieving a complete remission and with an histocompatible donor were assigned to a transplant arm. The rest were randomized to receive one of three consolidation arms: A, cytosine arabinoside, 200 mg/m2 daily for 7 days and daunorubicin 45 mg/m2 daily for 3 days for three courses; B, one course as in Arm A followed by amsacrine, 120 mg/m2 daily for 5 days followed by a 5-day continuous infusion of azacytidine, 150 mg/m2/day; C, thioguanine and cytosine arabinoside, 100 mg/m2 every 12 h and daunorubicin 10 mg/m2 daily for 5 days for three courses followed by four maintenance courses of cytosine arabinoside, 100 mg/m2 daily for 5 days and daunorubicin, 45 mg/m2 for 2 days every 13 weeks. From 1981 to 1986, 398 eligible patients were enrolled and 219 achieved a complete remission. The initial induction dose of cytosine arabinoside was reduced after five of 29 patients exhibited fatal gastrointestinal toxicity. Only 11 patients were assigned to the transplant arm. There were no significant differences in the consolidation arms. The 5 year disease-free survivals were 38, 31 and 27% in arms A, B, and C respectively. Intensive consolidation therapy with the same or different drugs used in induction was as effective as lower dose consolidation followed by maintenance therapy.

A phase III trial of high-dose cytosine arabinoside with or without etoposide in relapsed and refractory acute myelogenous leukemia. A Southeastern Cancer Study Group trial.

A phase III clinical trial was developed to test whether the addition of etoposide to a high-dose cytosine arabinoside regimen would improve the remission rate, duration of remission, and survival in relapsed and refractory patients with acute myelogenous leukemia. One hundred and thirty-one patients stratified by age, performance status, percentage of marrow blasts, platelet count, bilirubin and presence or absence of clinical infection, refractory or relapsed (+/- 9 months) were randomized to receive high-dose cytosine arabinoside, 3 g/m2 every 12 h for 6 days with or without three doses of etoposide, 100 mg/m2 days 7-9. Of 67 patients randomized to cytosine arabinoside alone, 31% obtained a complete remission with a median remission duration of 11.9 months. Of 66 patients randomized to the combination regimen, 38% obtained a complete remission with a median duration of 25 months. None of these differences were statistically significant. Significantly (p = 0.036) longer survival was seen in patients on the combination regimen under the age of 50. There was no difference in overall survival. Six and 8%, respectively, of patients were free of disease at 5 years. The addition of etoposide to a high-dose cytosine arabinoside regimen had at best a marginal effect at the expense of some increase in toxicity.

The prognostic significance of immunohistochemically detected lymph node micrometastases in colorectal carcinoma.

Micrometastases have been detected by immunocytochemical means in the lymph nodes of patients with otherwise node-negative cancer of the colon and rectum. This study examines the incidence and prognostic significance of nodal micrometastases in Dukes' B carcinoma. Five hundred and fifty-nine lymph nodes from 77 cases of Dukes' B carcinoma were examined for lymph node micrometastases by immunocytochemical staining for cytokeratin AE1:AE3. Micrometastases were detected in 19 cases (25 per cent). Cell clusters were present in ten cases, the remaining nine cases displaying only single cells. The presence of micrometastases was unrelated to age (P = 0.06), sex (P = 0.32), tumour site (P = 0.37), tumour size (P = 0.67), or tumour differentiation (P = 0.66). Ten-year survival estimates by the Kaplan-Meier lifetable method was 47 per cent in patients with and without micrometastases (chi 2 = 0.35 and 1 df, P = ns). The presence of nodal micrometastases detectable only by immunocytochemistry in patients with Dukes' B colorectal cancer does not justify reassignment to a more advanced disease stage.

Clinical pharmacokinetics of 3'-azido-3'-deoxythymidine (zidovudine) and catabolites with formation of a toxic catabolite, 3'-amino-3'-deoxythymidine.

This study investigated pharmacokinetics and metabolism of 3'-azido-3'-deoxythymidine (zidovudine) in patients after a 1-hour intravenous infusion of 2.5 mg/kg zidovudine with a radiolabeled tracer amount of [5-3H]-zidovudine. In addition to unchanged drug and its 5'-O-glucuronide (zidovudine glucuronide), two novel catabolites of zidovudine were detected as 3'-amino-3'-deoxythymidine (AMT), and its 5'-O-glucuronide (GAMT). The AMT apparent plasma elimination half-life (2.70 +/- 0.7 hours) was longer than that of zidovudine (1.20 +/- 0.30 hours) and zidovudine glucuronide (1.60 +/- 0.5 hours). The zidovudine/AMT plasma peak concentration and area under the concentration-time curve ratios were approximately 8 and 5, respectively. Urinary recovery of radioactivity was essentially complete within 24 hours. AMT glucuronide was not detected in urine or plasma, and only low levels of this catabolite were detected in bile. In contrast, AMT was not detected in bile. The substantial levels of AMT in the plasma of patients after zidovudine administration suggests that this catabolite may affect the pharmacodynamic properties of zidovudine in relation to its activity against human immunodeficiency virus replication and cytotoxicity to host cells.