Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design.

Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62 microM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P(1), P(2), and P(3) substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S(2)' pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon alpha to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.

Orbital wall approach with preoperative orbital imaging for identification and retrieval of lost or transected extraocular muscles.

PURPOSE: To report the results of an anterior approach along the orbital wall to recover a lost or transected extraocular muscle. METHODS: This is a retrospective review of lost or transected muscles retrieved by an anterior orbitotomy approach to the adjacent orbital wall because they were unable to be recovered by a standard conjunctival approach. Magnetic resonance imaging or computed tomography was performed on all subjects before surgery. RESULTS: Six patients underwent anterior orbitotomy via an orbital wall approach; all had undergone an attempted retrieval from a standard transconjunctival approach that failed. Five muscles had been lost from surgical or traumatic transection, and 1 muscle had been lost during strabismus surgery. The muscle location at retrieval ranged from 20 to 25 mm (mean, 23 mm) posterior to the limbus. The duration that these muscles were disinserted ranged from 7 days to 7.5 years (mean, 24 months). Preoperative deviation in primary gaze ranged from 15 to 50 PD, whereas first day postretrieval deviations all measured less than 8 PD. After a mean follow-up of 162 weeks, the mean deviation in primary gaze was 2 PD (range, orthotropia to 7 PD of esotropia). CONCLUSIONS: Anterior orbitotomy along the orbital wall with preoperative orbital imaging of extraocular muscle anatomy and function combine to create a valuable approach for retrieval of a lost or transected muscle. This technique may successfully retrieve lost or transected muscles that previously were irretrievable when using a standard transconjunctival approach.

Chondrocyte culture and assay.

Chondrocytes constitute the sole cell type found within cartilage, and control the formation and composition of cartilage. Cellular, biochemical and pharmacological studies of arthritis and other cartilage disorders have increasingly focused on chondrocyte function. Three methods are presented in this unit for culturing chondrocytes, and two assays are described that characterize proteoglycan synthesis, a key measure of chondrocyte function.Chondrocytes constitute the sole cell type found within cartilage, and control the formation and composition of cartilage.

Serum calcitonin precursors in sepsis and systemic inflammation.

High serum levels of the calcitonin (CT) prohormone, procalcitonin (pro-CT), and its component peptides occur in systemic inflammation and sepsis. Using two different assays, we undertook a prospective study to determine the utility of serum precalcitonin peptides (pre-CT) as markers in this condition. Twenty-nine patients meeting criteria for the systemic inflammatory response syndrome were studied daily in two intensive care units. Sera were collected, and APACHE II scores were determined until recovery or death. All patients had markedly elevated serum pre-CT. Prognostically, peak values were the most important. The highest values portended mortality, and a lower level could be ascertained below which all patients survived. Peak pre-CT levels were significantly higher in patients with infection documented by blood cultures than in those patients with no documented infection from any source (P < 0.05). Mature CT remained normal or only moderately elevated. Compared with the serum pre-CT levels, receiver operating characteristic curve analysis revealed that the APACHE II scores, although more cumbersome, were better overall predictors of mortality. Thus, pre-CT is an important serum marker for systemic inflammatory response syndrome and is predictive of outcome. It also provides data concerning the presence of severe infection and may prove to be clinically useful for proactive patient care.

Changes in cochlear mechanics during vocalization: evidence for a phasic medial efferent effect.

The mustached bat, Pteronotus p. parnellii, has a finely tuned cochlea that rings at its resonant frequency in response to an acoustic tone pip. The decay time (DT) and frequency of these damped oscillations can be measured from the cochlear microphonic potential (CM) to study changes in cochlear mechanics. In this report, we describe phasic changes that occur in synchrony with communication sound vocalizations of the bat. Three animals with chronically implanted electrodes were studied. During the experiments, 1-2 ms tone pips were emitted from a speaker every 200 ms. This triggered a computer analysis of the resulting CM to determine the DT and cochlear resonance frequency (CRF) of the ringing. The time relative to vocalizations was determined by monitoring the output of a microphone placed near a bat's mouth. Similar results were obtained from all three bats tested. In a representative case, the average DT was 2.33 +/- 0.25 ms while the bat was quiet, but it decreased by 46% to 1.26 +/- 0.75 during vocalizations, which indicates a greater damping of the cochlear partition. Sometimes, DT started decreasing immediately before the bat vocalized. After the end of a vocalization, the return to baseline values varied from rapid (milliseconds) to gradual (1-2 seconds). The CRF also changed from baseline values during vocalization, although the amount and direction of change were not predictable. When gentamicin was administered to block the action of medial olivocochlear (MOC) efferents, DT reduction was still evident during vocalization but less pronounced. We conclude that phasic changes in damping occur in synchrony with vocalization, and that the MOC system plays a role in causing suppression. Since suppression can begin prior to vocalization, this may be a synkinetic effect, mediated by neural outflow to the ear in synchrony with neural outflow to the middle ear muscles and the muscles used for vocalization.

Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits.

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

Hybrid multi/single layer array transducers for increased signal-to-noise ratio.

In medical ultrasound imaging, two-dimensional (2-D) array transducers are necessary to implement dynamic focusing in two dimensions, phase correction in two dimensions and high speed volumetric imaging. However, the small size of a 2-D array element results in a small clamped capacitance and a large electrical impedance, which decreases the transducer signal-to-noise ratio (SNR). We have previously shown that SNR is improved using transducers made from multi-layer PZT, due to their lower electrical impedance. In this work, we hypothesize that SNR is further increased using a hybrid array configuration: in the transmit mode, a 10 Omega electronic transmitter excites a 10 Omega multi-layer array element; in the receive mode, a single layer element drives a high impedance preamplifier located in the transducer handle. The preamplifier drives the coaxial cable connected to the ultrasound scanner. For comparison, the following control configuration was used: in the transmit mode, a 50 Omega source excites a single layer element, and in the receive mode, a single layer element drives a coaxial cable load. For a 5x102 hybrid array operating at 7.5 MHz, maximum transmit output power was obtained with 9 PZT layers according to the KLM transmission line model. In this case, the simulated pulse-echo SNR was improved by 23.7 dB for the hybrid configuration compared to the control. With such dramatic improvement in pulse-echo SNR, low voltage transmitters can be used. These can be fabricated on integrated circuits and incorporated into the transducer handle.

Autogenous fascia augmentation of a partially extirpated muscle with a subperiosteal medial orbitotomy approach.

INTRODUCTION: Endoscopic sinus surgery can result in serious extraocular muscle dysfunction. The medial rectus muscle is more frequently affected than other extraocular muscles. METHODS: A transconjunctival subperiosteal medial orbitotomy was successful in retrieving a partially extirpated medial rectus muscle after endoscopic sinus surgery. RESULTS: A previous attempt to localize this muscle by conventional surgery with extensive exploration was unsuccessful. A Hummelsheim procedure was also abandoned after a rupture of the nasal aspect of the inferior rectus muscle occurred. CONCLUSION: The approach we describe allowed adequate visualization of the posterior orbital content, as well as adequate space for suture placement.

Practice patterns in the diagnosis and treatment of anxiety and depression in the medically ill. A survey of psychiatrists.

By use of a survey that assessed practice patterns and responses to case vignettes of anxiety and depression in the medically ill, 38 psychiatrists were compared with 10 national leaders in consultation-liaison psychiatry. On the case vignettes, percentage agreement with the experts varied significantly by case and by question. Fifty-eight percent of the time the psychiatrists agreed with the experts on whether to order laboratory tests as compared with an 81% agreement level on whether to use psychotherapy. Multiple regression analysis revealed that the best model to predict lower agreement with the experts was years in practice plus percentage of time spent in solo (vs. group) practice (r2 = 0.40). This study extended previous data-based pharmacoepidemiology by assessing multiple aspects of psychiatrists' practice patterns. Psychiatrists who are more distant from training years and more isolated from the current stimulation of colleagues may be particularly appropriate targets for continuing education.

Optimization of signal-to-noise ratio for multilayer PZT transducers.

In medical ultrasound imaging, two-dimensional (2-D) array transducers are desirable to implement dynamic focusing and phase aberration correction in two dimensions as well as volumetric imaging. Unfortunately, the small size of a 2-D array element results in a small clamped capacitance and a large electrical impedance near the resonance frequency. This results in poor signal-to-noise ratio (SNR) of the array elements. It has previously been demonstrated that transducers made from multilayer PZT ceramics have lower electrical impedance and greater SNR than comparable single layer elements. A simplified circuit model has been developed to optimize the SNR for multilayer ceramic (MLC) transducers. In this model, an electronic transmitter excites the array element and in the receive mode, the element drives a coaxial cable load terminated by a high impedance preamplifier. The transducer impedance is Zt/N2, where N is the number of piezoelectric layers. Maximum transmit signal is obtained when N = Ntx such that the transducer impedance, Zt/Ntx2, is matched to the source impedance. Maximum receive signal is obtained when N = Nrx such that the transducer impedance, Zt/Nrx2, is matched to the coaxial cable reactance. For maximum pulse-echo signal, the transducer should be designed with N = square root of Ntx Nrx, the geometric mean of Ntx and Nrx. Using this optimization technique, a 1.5-D array was designed with 3 layers for maximum pulse-echo SNR. Results of simulations from the simplified circuit analysis were consistent with those of the KLM model. The 3 layer array was fabricated as well as a single layer control array. The measured transmit signal and receive signal agreed with the simulation results.

Psychiatric aspects of the eosinophilia-myalgia syndrome.

The eosinophilia-myalgia syndrome (EMS) is a rare systemic disease caused by presumably contaminated L-tryptophan. Thirteen outpatients with EMS were found to have a high degree of depression, anxiety, and difficulty adjusting to illness. Pre-EMS history of major depression but not EMS severity predicted poor adjustment to illness.

Escalation of a fetish: coprophagia in a nonpsychotic adult of normal intelligence.

A 47-year-old man is described whose fetish of fecal smearing, coprophilia, escalated to coprophagia in a setting of depression and alcohol abuse. The case is the first described in a nonpsychotic adult of normal intelligence. Treatment focused upon the depression and substance abuse as well as on the psychodynamic issues that fostered his despair and allowed the fetish to evolve into coprophagia.

A program to develop residents as teachers.

Residents are recognized as important and influential teachers of medical students. Although they are expected to teach and evaluate students, few residents have been taught how, and most would like to receive training to develop and improve their skills as teachers. We developed a "Residents as Teachers" retreat based on our faculty development program for clinical preceptors. We focused on clinical precepting skills, including evaluation/feedback, and the ability to prepare and deliver a brief presentation. The program increased knowledge and skills and improved attitudes about teaching, as reflected in self-reports, observed performance, and medical student ratings. The retreat also provided a valuable social experience for residents. The program has been considered beneficial by residents, program faculty members, medical students, the student clerkship director, and the residents' primary care preceptors. The retreats form the centerpiece of our curriculum for residents as teachers and have become an annual tradition in the residency program.