A phase I study of cabazitaxel in combination with platinum and 5-fluorouracil (PF) in locally advanced squamous cell carcinoma of head and neck (LA-SCCHN).

BACKGROUND: There is a clinical need to improve outcomes for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), especially in Human Papilloma Virus (HPV) negative and HPV positive subtypes with a significant history of tobacco use. In animal models bearing SCCHN, Cabazitaxel showed an excellent response rate compared to docetaxel and might prove useful in treatment of patients. The primary objective of this study was to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of cabazitaxel when combined with cisplatin and 5-fluorouracil (PF) in induction chemotherapy (IC) for patients with SCCHN. Cabazitaxel-PF IC administered in 3 cycles (each 21 days) followed by concurrent chemoradiation (CRT) or surgery has been evaluated to assess overall response rate (ORR) and progression-free survival (PFS) in this population. METHODS: This phase I study employed a standard 3+3 design. DLT was defined as grade 4 or 5 toxicity or grade 3 toxicity lasting >7days. Out of 40 consented patients with stage IV, curable, previously untreated, LA-SCHHN and poor prognosis, 35 (32M, 3F) were enrolled and evaluated for toxicity: 19 oropharynx, 10 larynx, 2 oral cancer, 1 nasopharynx and 3 hypopharynx. Five dose levels of cabazitaxel (10, 12.5, 15, 17.5 and 20mg/m2) were tested in combination with cisplatin 100mg/m2 and 5-fluorouracil (5-FU) 800mg/m2/d×4days. Dose escalation for cabazitaxel was terminated upon the occurrences of 2 DLTs and the establishment of MTD. Cabazitaxel was then further escalated with cisplatin 75mg/m2 and 5-FU 800mg/m2/d×4days in the subsequent 3 dose levels (17.5, 20 and 22.5mg/m2). In the expansion cohort, 9 patients were enrolled at the 22.5mg/m2 dose level. Following 3 cycles of IC, patients were evaluated for clinical, radiographic, and pathologic response to cabazitaxel-PF before beginning CRT or surgery. RESULTS: There were two DLTs (grade 4 hyperuricemia; neutropenic fever, sepsis, and grade 4 thrombocytopenia) among 2 patients in cohort 5 at the dose of 20mg/m2 of cabazitaxel. There were no DLTs reported with cohorts using a lower dose of cisplatin, even in the expansion cohort. The study was stopped at the dose of 22.5mg/m2 in accordance with the initial study design. With 33 evaluable patients for response, the Overall Response Rate (ORR) rate was 57.6%: 9.1% Complete Responses (CR) and 48.5% Partial Responses (PR) were noted. CONCLUSIONS: The recommended phase II dose for cabazitaxel in combination with cisplatin 75mg/m2 and 5-FU 800mg/m2/d×4days is 22.5mg/m2 and for cisplatin 100mg/m2 and 5-FU 800mg/m2/d×4days is 17.5mg/m2. With a median follow-up of 39months, PFS for the entire non-metastatic population at 3years was approximately 58%.

Beyond the Cuff: MR Imaging of Labroligamentous Injuries in the Athletic Shoulder.

Shoulder disease is common in the athletic population and may arise as a consequence of a single traumatic episode or multiple repeated events. Associated labroligamentous injuries can result in substantial disability. Specific athletic and occupational activities result in predictable injury patterns. Imaging in general and magnetic resonance (MR) imaging, in particular, are vital in establishing the correct diagnosis and excluding common mimicking conditions, to ensure timely and appropriate management. In this review, the utility of MR imaging and MR arthrography will be explored in evaluation of shoulder disease, taking into account normal variants of the labroligamentous complex. Subsequently, broad categories of labral lesions and instability, external and internal impingement, as well as nerve entrapment syndromes, will be discussed, while emphasizing their imaging findings in the clinical context and illustrating key features. More recent concepts of internal impingement and secondary subacromial impingement will also be clarified.

Health related quality of life measure in systemic pediatric rheumatic diseases and its translation to different languages: an international collaboration.

BACKGROUND: Rheumatic diseases in children are associated with significant morbidity and poor health-related quality of life (HRQOL). There is no health-related quality of life (HRQOL) scale available specifically for children with less common rheumatic diseases. These diseases share several features with systemic lupus erythematosus (SLE) such as their chronic episodic nature, multi-systemic involvement, and the need for immunosuppressive medications. HRQOL scale developed for pediatric SLE will likely be applicable to children with systemic inflammatory diseases. FINDINGS: We adapted Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY©) to Simple Measure of Impact of Illness in Youngsters (SMILY©-Illness) and had it reviewed by pediatric rheumatologists for its appropriateness and cultural suitability. We tested SMILY©-Illness in patients with inflammatory rheumatic diseases and then translated it into 28 languages. Nineteen children (79% female, n=15) and 17 parents participated. The mean age was 12±4 years, with median disease duration of 21 months (1-172 months). We translated SMILY©-Illness into the following 28 languages: Danish, Dutch, French (France), English (UK), German (Germany), German (Austria), German (Switzerland), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico), Spanish (Venezuela), Turkish, Afrikaans, Arabic (Saudi Arabia), Arabic (Egypt), Czech, Greek, Hindi, Hungarian, Japanese, Romanian, Serbian and Xhosa. CONCLUSION: SMILY©-Illness is a brief, easy to administer and score HRQOL scale for children with systemic rheumatic diseases. It is suitable for use across different age groups and literacy levels. SMILY©-Illness with its available translations may be used as useful adjuncts to clinical practice and research.

Women's and residents' experiences of communication in the diagnostic mammography suite.

OBJECTIVE: To gain understanding of radiology residents' and women's experiences, concerns, information needs, coping strategies and perspectives about optimal communication during diagnostic mammography. METHODS: Qualitative analysis of focus groups of radiology residents and women who had undergone diagnostic mammograms. RESULTS: Five categories of themes emerged from our analysis: information needs, perspectives and ideals, emotional experiences and observations, working together, individual experiences, and others' roles. Women preferred continuous orientation, clear explanations and emotional support by physicians and radiology technologists throughout diagnostic processes. Communication about diagnostic mammogram results evoked the threat of breast cancer and was experienced as "bad news" by women, but not necessarily by all radiology residents. Lack of collaboration among radiologists, technologists and other healthcare professionals engendered confusion and anxiety in patients. Radiology residents felt inadequately prepared to meet the communication challenges of providing information and emotional support tailored to women's needs in this context. CONCLUSION: Women's experiences are influenced by the extent to which they receive clear information and support, and perceive collaboration among professionals involved in the diagnostic mammography process. PRACTICE IMPLICATIONS: Radiology education must address communication with patients and among healthcare professionals involved in the care of patients undergoing diagnostic procedures and interventions.

The "diagonal effect": a systematic error in oblique antisaccades.

Antisaccades are known to show greater variable error and also a systematic hypometria in their amplitude compared with visually guided prosaccades. In this study, we examined whether their accuracy in direction (as opposed to amplitude) also showed a systematic error. We had human subjects perform prosaccades and antisaccades to goals located at a variety of polar angles. In the first experiment, subjects made prosaccades or antisaccades to one of eight equidistant locations in each block, whereas in the second, they made saccades to one of two equidistant locations per block. In the third, they made antisaccades to one of two locations at different distances but with the same polar angle in each block. Regardless of block design, the results consistently showed a saccadic systematic error, in that oblique antisaccades (but not prosaccades) requiring unequal vertical and horizontal vector components were deviated toward the 45 degrees diagonal meridians. This finding could not be attributed to range effects in either Cartesian or polar coordinates. A perceptual origin of the diagonal effect is suggested by similar systematic errors in other studies of memory-guided manual reaching or perceptual estimation of direction, and may indicate a common spatial bias when there is uncertain information about spatial location.

Ethical debating: therapy for adolescents with eating disorders.

Groups are a common component of treatment programs for adolescents with eating disorders (EDs). This article discusses a weekly group run by nursing and psychology members of a multidisciplinary EDs team. The theme of this group was ethical debating, and it was designed for adolescent patients aged between 14 and 18 years. These ED patients were provided with basic information about five ethical principles, and they debated weekly ethical scenarios. Debate content and process, as well as its therapeutic benefits, will be discussed in this article.

Vibratory antinociception: effects of vibration amplitude and frequency.

The ability of cutaneous vibration to compromise detection of a nociceptive stimulus was examined in 2 sets of psychophysical experiments. The noxious stimulus was a 10-millisecond burst of radiant heat from a CO(2) laser; at the near-threshold levels used it generally yielded a mild pricking sensation. In both experiments, the detectability (d(e)') of the laser was measured in the presence of different vibratory stimuli and in the absence of vibration. Periods of vibration lasted 10 seconds, bracketing the time of occurrence of the laser. Vibratory and laser stimuli were presented 2.3 cm apart on the dorsal surface of the forearm. Confidence rating procedures yielded receiver operating characteristic curves from which detectability of the laser was calculated. In an amplitude study, vibrations ranging from 10 to 45 dB above threshold were used; results indicated that nociceptive sensitivity gradually declined as vibration amplitude increased. In a frequency study, vibrations ranging from 20 to 230 Hz were used; all interfered with nociception. Combining the results of the 2 studies permitted the conclusion that signals in multiple vibrotactile channels are able to modulate nociception. No one mechanoreceptive channel appears to have a privileged role.

Modulation of Porphyromonas gingivalis proteinase activity by suboptimal doses of antimicrobial agents.

BACKGROUND: Antimicrobial agents are sometimes used as adjuncts for the treatment of aggressive and refractory forms of periodontitis. In this study, we used a culture plate assay to investigate the effect of suboptimal doses of antimicrobial agents on proteinase activity of Porphyromonas gingivalis. METHODS: A culture plate assay using gelatin as the substrate, which allows a semiquantitative determination of proteinase activity, was developed. Suboptimal inhibitory concentrations of tetracycline, minocycline, doxycycline, metronidazole, penicillin G, or chlorhexidine were added to the medium, and proteolysis zones were determined following the growth of three strains of P. gingivalis. The effect of antimicrobials on outer membrane vesicle-associated gingipains also was determined. RESULTS: The gelatin plate assay was a convenient, simple procedure for investigating the effect of suboptimal inhibitory concentrations of antimicrobial agents on proteinases produced by P. gingivalis. The largest reduction (> 75%) in the proteolysis zones produced by three strains of P. gingivalis was obtained with minocycline. Tetracycline and doxycycline also reduced the proteolysis zones. A suboptimal inhibitory concentration of chlorhexidine increased the proteolysis zones by up to 70%. Metronidazole and penicillin G produced no noticeable effect. The suboptimal inhibitory concentrations of minocycline, tetracycline, and doxycyline did not reduce the activity of outer membrane vesicle-associated Arg- and Lys-gingipains. CONCLUSION: Results from this study suggest that sublethal concentrations of some antimicrobial agents in subgingival sites have the potential to affect the physiology of P. gingivalis, notably by increasing or decreasing the proteolytic activity of the bacteria.

Thermosensory intensity and affect throughout the perceptible range.

The thermosensory system was evaluated psychophysically in 12 healthy volunteers, spanning the full range of tolerable temperatures. Subjects provided ratings of (1) perceived thermal intensity, (2) perceived pleasantness or unpleasantness, and (3) perceived pain intensity after placing either one hand or foot in a temperature controlled water bath. Of particular interest were the interrelationships among the three perceptual measures, and differences between heat and cold. The relationship between perceived intensity and (un)pleasantness was different for hot vs cold stimuli. Specifically, for a given perceived thermal intensity, cold stimuli were rated as less pleasant or more unpleasant than hot stimuli. Similarly, for a given pain intensity, cold stimuli were rated as more unpleasant than hot stimuli. As warm temperatures increased and as cold temperatures decreased, stimuli were perceived as being unpleasant before they were perceived as being painful. The difference in transition temperatures for unpleasantness vs pain for heat averaged 1.4 degrees C, while the same difference for cold averaged 5.6 degrees C. Thus, there was a fourfold difference in the range of unpleasant but non-painful cold vs hot temperatures. Pain intensity and unpleasantness ratings were significantly higher for heat stimuli applied to the foot vs hand. In contrast, there was no significant body site difference for pain intensity or unpleasantness ratings of cold stimuli. All of these results reveal important differences in the processing of cold vs hot stimuli. These differences could be exploited to differentiate processing relevant to discriminative vs affective components of somesthetic perception, in both the innocuous and noxious ranges.

Reduction of TMD pain by high-frequency vibration: a spatial and temporal analysis.

Under some conditions, vibration delivered to the skin can reduce pain (vibratory analgesia). Previous studies of this phenomenon in a clinical context have been somewhat variable in terms of stimulus control, and have not examined the way in which the spatial distribution of pain is affected. In the present study, we used rigorously controlled conditions to examine vibratory analgesia in participants (N=17) with painful temporomandibular disorders (TMD). Results of 20- and 100-Hz vibration were compared with data from a no-vibration control condition. The results document for the first time that vibratory analgesia occurs in TMD chronic pain conditions. We measured its time course using continuous visual analog scale (VAS) recording, and its spatial aspects by asking subjects to indicate painful regions on standardized drawings. VAS ratings and drawings both showed that pain is reduced by 100-Hz, but not by 20-Hz, vibration. The effectiveness of the high-frequency vibration cannot be attributed to a mechanism involving Pacinian corpuscles, since these receptors are lacking in the skin of the orofacial region. Spatial analyses revealed that ipsilateral and contralateral effects of vibration were statistically equivalent, suggesting that vibratory analgesia relies at least in part on central nervous system processes rather than local mechanisms.