Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification

We have previously reported that the key apoptosis related gene caspase 8 (CASP8) is frequently silenced in small cell lung cancer (SCLC) tumors and cell lines usually, but not always, by aberrant promoter methylation. Because CASP8 is a key component of the death-inducing signaling complex (DISC) when specific death receptors (including DR4, DR5, FAS) are activated by their specific ligands (TRAIL/FASL), we examined expression of the components of the DISC complex in lung cancer cell lines. MYC family members are frequently amplified (MYC+ve) in SCLC, and MYC is a potent inducer of apoptosis. We examined 34 SCLC lines (12 of which were MYC+ve) and 22 NSCLC lines. CASP8 gene expression was frequently lost (79%) at message and protein levels in SCLC but not in non-SCLC (NSCLC). MYC amplification was present in 45% of SCLC cell lines, which had lost CASP8 expression, but not in any of the CASP8 positive lines. The frequency of CASP8 loss was significantly higher in MYC+ve SCLC compared to MYC-ve SCLC or in NSCLC. Analyses of other DISC components showed significantly higher rates of loss of expression of CASP10, DR5, FAS and FASL in SCLC compared to NSCLC. The loss of expression of proapoptotic DISC components was significantly higher in MYC+ve SCLC cell lines and these lines were completely resistant to TRAIL. Expression of CASP10 (a caspase closely related to CASP8) was frequently absent at the protein level in both SCLC and NSCLC lines. Expression of c-FLIP (proteolytically inactive homolog of CASP8) was inversely related to expression of CASP8. Our major conclusions are: (a) The death receptor pathway is differently inactivated at multiple levels in lung cancer cell lines; and (b) MYC amplification in SCLC is associated with inactivation of most components of the DISC complex, with resistance to TRAIL and with expression of c-FLIP. These findings may have considerable clinical and therapeutic implications.     

Anesthesia for oncogenic osteomalacia—A rare paraneoplastic syndrome

Two patients with a diagnosis of oncogenic osteomalacia are described. This rare disease, characterized by secretion of fibroblast growth factor-23 by the tumor cells, causes myopathy, extreme debilitation and severe osteopathy because of severe hypophosphatemia. Both patients presented with severe bone pain, pathological fractures and proximal muscle weakness. Multiple diagnostic tools had to be utilized to settle the diagnosis of this rare disease. Although supplemental therapy for hypophosphatemia is usually started preoperatively, surgical excision of the causative tumor is the only definite treatment. Surgery is almost always curative; however, there is a lack of discourse in the literature regarding the anesthetic implications for the disease. The complete pathophysiology of the disease, clinical picture, its diagnostic intricacies as well as the salient points in its anesthetic management are discussed in this report.     

Propofol and non-propofol based sedation for outpatient colonoscopy-prospective comparison of depth of sedation using an EEG based SEDLine monitor

Propofol is a popular anesthetic sedative employed in colonoscopy. It is known to increase the patient satisfaction and improve throughput. However, there are concerns among the clinicians with regard to the depth of sedation, as a deeper degree of sedation is known to increase the incidence of aspiration and other adverse events. So we planned to compare the depth of sedation between propofol and non-propofol based sedation in patients undergoing outpatient colonoscopy, as measured by an electroencephalogram (EEG) based monitor SEDLine monitor (SedlineInc., San Diego, CA). The non-randomized prospective observational study was performed in the outpatient gastroenterology suite of the Hospital of the University of Pennsylvania, Philadelphia. Patients included ASA class I–III aged more than 18 years scheduled for colonoscopy under Propofol or non-propofol based sedation. After an institutional review board approval, a written consent was obtained from prospective patients. Sedation (propofol or non-propofol based) was administered by either a certified nurse anesthetist under the supervision of an anesthesiologist (propofol) or a registered endoscopy nurse under the guidance of the endoscopist performing the procedure (non-propofol sedation). Depth of sedation was measured with an EEG based SEDLine monitor. The sedation providers were blinded to the patient state index—the indicator of depth of sedation. PSI (patient state index—SEDLine reading) was documented at colonoscope insertion, removal and at the return of verbal responsiveness after colonoscope withdrawal. Sedation spectrum was retrieved from the data stored on the SEDLine monitor. Patients sedated with propofol experience significantly deeper degrees of sedation at all times during the procedure. Additionally, during significant part of the procedure, they are at PSI levels associated with deep general anesthesia. The group that received propofol was more deeply sedated and had lower PSI values. Lighter propofol titration protocols may lead to improved patient care such as lowering risk of aspiration and hypotension. The role of processed EEG monitors such as the SEDLine monitor to improve sedation protocols remains to be determined. Trial registration We obtained an ethical clearance from the Institute. No trial registration was mandated, as no interventional drug or investigational device were used during the study.     

Entropy correlates with Richmond Agitation Sedation Scale in mechanically ventilated critically ill patients

Sedation is routinely used in intensive care units. However due to absence of objective scoring systems like Bispectral Index and entropy our ability to regulate the degree of sedation is limited. This deficiency is further highlighted by the fact that agitation scores used in intensive care units (ICU) have no role in paralyzed patients. The present study compares entropy as a sedation scoring modality with Richmond Agitation Sedation Scale (RASS) in mechanically ventilated, critically ill patients in an ICU. Twenty-seven, mechanically ventilated, critically ill patients of either sex, 16–65 years of age, were studied over a period of 24 h. They received a standard sedation regimen consisting of a bolus dose of propofol 0.5 mg/kg and fentanyl 1 μg/kg followed by infusions of propofol and fentanyl ranging from 1.5 to 5 mg/kg/h and 0.5 to 2.0 μg/kg/h, respectively. Clinically relevant values of RASS for optimal ICU sedation (between 0 and ?3) in non-paralyzed patients were compared to corresponding entropy values, to find if any significant correlation exists between the two. These entropy measurements were obtained using the Datex-Ohmeda-M-Entropy? module. This module is presently not approved by Food and Drug Administration (FDA) for monitoring sedation in ICU. A total of 527 readings were obtained. There was a statistically significant correlation between the state entropy (SE) and RASS [Spearman’s rho/r_s = 0.334, p < 0.0001]; response entropy (RE) and RASS [Spearman’s rho/r_s = 0.341, p < 0.0001]). For adequate sedation as judged by a RASS value of 0 to ?3, the mean SE was 57.86 ± 16.50 and RE was 67.75 ± 15.65. The present study illustrates that entropy correlates with RASS (between scores 0 and ?3) when assessing the level of sedation in mechanically ventilated critically ill patients.     

Quantitative neuromuscular ultrasound in the intensive care unit

Introduction: Intensive care unit acquired weakness (ICU‐AW) results from a complex mixture of nerve and muscle pathology, and early identification is challenging. This pilot study was designed to examine the ultrasonographic changes that occur in muscles during ICU hospitalization. Methods: Patients admitted to the ICU for acute respiratory failure were enrolled prospectively and underwent serial muscle ultrasound for thickness and gray‐scale assessment of the tibialis anterior, rectus femoris, abductor digiti minimi, biceps, and diaphragm muscles over 14 days. Results: Sixteen participants were enrolled. The tibialis anterior (P = 0.001) and rectus femoris (P = 0.041) had significant decreases in gray‐scale standard deviation when analyzed over 14 days. No muscles showed significant changes in thickness. Conclusions: Ultrasound is an informative technique for assessing muscles of patients in the ICU, and lower extremity muscles demonstrated increased homogeneity during ICU stays. This technique should be examined further for diagnosing and tracking those with ICU‐AW. Muscle Nerve, 2013     

Scrotal leiomyosarcoma associated with bilateral epididymo-orchitis

Leiomyosarcoma of the scrotum is a rare tumor. We report the case of a 60-year-old man who presented with bilateral testicular enlargement that was clinically misdiagnosed as a testicular tumor. The tumor was excised by bilateral inguinal orchiectomy. Histopathologic examination revealed a scrotal wall leiomyosarcoma with bilateral epididymo-orchitis.