Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.

INTRODUCTION: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. PATIENTS AND METHODS: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. RESULTS: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. CONCLUSIONS: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.

The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study.

BACKGROUND: This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel. METHODS: Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m(-2) docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated. RESULTS: In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of > or =6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of >or =3 mg kg(-1). Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had > or =5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from > or =5 to <5 CTCs and 9 out of 10 (90%) had a > or =30% decline in CTCs after therapy. CONCLUSIONS: Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.

Development of the human Achilles tendon enthesis organ.

The attachment of the Achilles tendon is part of an 'enthesis organ' that reduces stress concentration at the hard-soft tissue interface. The organ also includes opposing sesamoid and periosteal fibrocartilages, a bursa and Kager's fat pad. In addition, the deep crural and plantar fasciae contribute to Achilles stress dissipation and could also be regarded as components. Here we describe the sequence in which these various tissues differentiate. Serial sections of feet from spontaneously aborted foetuses (crown rump lengths 22-322 mm) were examined. All slides formed part of an existing collection of histologically sectioned embryological material, obtained under Spanish law and housed in the Universidad Complutense, Madrid. From the earliest stages, it was evident that the Achilles tendon and plantar fascia had a mutual attachment to the calcaneal perichondrium. The first components of the enthesis organ to appear (in the 45-mm foetus) were the retrocalcaneal bursa and the crural fascia. The former developed by cavitation within the mesenchyme that later gave rise to Kager's fat pad. The tip of the putative fat pad protruded into the developing bursa in the 110-mm foetus and fully differentiated adipocytes were apparent in the 17-mm foetus. All three fibrocartilages were first recognisable in the 332-mm foetus--at which time adipogenesis had commenced in the heel fat pad. The sequence in which the various elements became apparent suggests that bursal formation and the appearance of the crural fascia may be necessary to facilitate the foot movements that subsequently lead to fibrocartilage differentiation. The later commencement of adipogenesis in the heel than in Kager's pad probably reflects the non-weight environment in utero. The direct continuity between plantar fascia and Achilles tendon that is characteristic of the adult reflects the initial attachment of both structures to the calcaneal perichondrium rather than to the skeletal anlagen itself.

Follow-up schedules after treatment for malignant melanoma.

BACKGROUND: Existing follow-up guidelines after treatment for melanoma are based largely on dated literature and historical precedent. This study aimed to calculate recurrence rates and establish prognostic factors for recurrence to help redesign a follow-up schedule. METHODS: Data were retrieved from the Sydney Melanoma Unit database for all patients with a single primary melanoma and American Joint Committee on Cancer (AJCC) stage I-II disease, who had received their first treatment between 1959 and 2002. Recurrence rates, timing and survival were recorded by substage, and predictive factors were analysed. RESULTS: Recurrence occurred in 18.9 per cent (895 of 4748) of patients overall, 5.2 per cent (95 of 1822) of those with stage IA disease, 18.4 per cent (264 of 1436) with IB, 28.7 per cent (215 of 750) with IIA, 40.6 per cent (213 of 524) with IIB and 44.3 per cent (86 of 194) with IIC disease. Overall, the median disease-free survival time was 2.6 years, but there were marked differences between AJCC subgroups. Primary tumour thickness, ulceration and tumour mitotic rate were important predictors of recurrence. CONCLUSION: A new follow-up schedule was proposed: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB-IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.

Detection of second primary cutaneous melanomas.

AIMS: There have been few studies investigating the value of follow-up in the detection of second primary melanomas (SPMs) and there is scant information on the role of self-surveillance by the patient. The aim of this study was to assess the frequency of patient detection of both first primary melanomas (FPMs) and SPMs. PATIENTS AND METHODS: Patients were interviewed to determine who detected their FPM and SPM (in situ or invasive). The associations between clinical and pathological factors and the person who identified the FPM and SPM were examined using multivariate analysis. RESULTS: One hundred and twelve patients with a recently diagnosed SPM were treated at the Sydney Melanoma Unit (July 2001 to March 2003). Patients detected 59% of the FPMs as compared with 46% of the SPMs. Female gender, greater Breslow tumour thickness and younger age were significant predictors for a patient-detected FPM (Odds Ratio: 4.9 (Confidence Interval 1.5-16.0), 3.2 (1.65-6.04), and 0.9 (0.9-1.0), respectively). Greater tumour thickness and ready visibility of the lesion to the patient were predicting factors for patient detection of a SPM (Odds Ratio: 1.9 (Confidence Interval 1.1-3.3) and 3.6 (1.4-9.1), respectively). CONCLUSIONS: A history of melanoma does not increase the ability of patients to detect new or thinner primary melanomas themselves. Therefore, patients may benefit from regular clinical review by clinicians, who play an important role in the detection of new melanomas.

Adipose tissue at entheses: the innervation and cell composition of the retromalleolar fat pad associated with the rat Achilles tendon.

This study set out to determine whether the fat pad at the attachment of the Achilles tendon has features enabling it to function as an immune organ and a mechanosensory device, and to be a source of pain in insertional tendon injuries. Sections for histology and immunohistochemistry were cut from the Achilles tendon enthesis organ of 1 day old, 1 month, 4 month and 24 month old rats. For fluorescence and peroxidase immunohistochemistry, cryosections were labelled with primary antibodies directed against PGP9.5, substance P, neurofilament 200, calcitonin gene related peptide, CD68, CD36, myeloid related protein 14, actin and vinculin. The fat pad contained not only adipocytes, but also fibrous tissue, mast cells, macrophages, fibroblasts and occasional fibrocartilage cells. It was richly innervated with nerve fibres, some of which were likely to be nociceptive, and others mechanoreceptive (myelinated fibres, immunoreactive for neurofilament 200). The fibres lay between individual fat cells and in association with blood vessels. In marked contrast, the enthesis itself and all other components of the enthesis organ were aneural at all ages. The presence of putative mechanoreceptive and nociceptive nerve endings between individual fat cells supports the hypothesis that the fat pad has a proprioceptive role monitoring changes in the insertional angle of the Achilles tendon and that it may be a source of pain in tendon injuries. The abundance of macrophages suggests that the adipose tissue could have a role in combating infection and/or removing debris from the retrocalcaneal bursa.

Structure-function relationships of entheses in relation to mechanical load and exercise.

Entheses are regions of high-stress concentration that are commonly affected by overuse injuries in sport. This review summarizes current knowledge of their structure-function relationships - at the macroscopic, microscopic and molecular levels. Consideration is given to how stress concentration is reduced at fibrocartilaginous entheses by various adaptations which ensure that stress is dissipated away from the hard-soft tissue interface. The fundamental question of how a tendon or ligament is anchored to bone is addressed - particularly in relation to the paucity of compact bone at fibrocartilaginous entheses. The concept of an "enthesis organ" is reviewed - i.e. the idea of a collection of tissues adjacent to the enthesis itself, which jointly serve a common function - stress dissipation. The archetypal enthesis organ is that of the Achilles tendon and the functional importance of its subtendinous bursa, with its fibrocartilaginous walls and protruding fat pad, is emphasized. The distribution of adipose tissue elsewhere at entheses is also explained and possible functions of insertion-site fat are evaluated. Finally, a brief consideration is given to enthesopathies, with attention drawn to the possibility of degenerative changes affecting other regions of an enthesis organ, besides the enthesis itself.

Secretion of alpha-tocopherol in VLDL is decreased by dietary protein insufficiency in young growing rats.

The concentrations of alpha-tocopherol in plasma and most peripheral tissues were shown previously to be low in young growing rats fed a low protein diet. To examine the secretion rates of VLDL alpha-tocopherol and triglycerides, and lipoprotein lipase activity, weanling rats were fed a low protein (LP, 8 g/100 g lactalbumin) or a normal protein (NP, 20 g/100 g lactalbumin) diet for 6 wk. The absolute secretion rate of VLDL triglyceride (micromol/h) of the LP group was not significantly different from that of the NP group (P: > 0.05), but was significantly higher (P: < 0.05) when expressed relative to body weight [micromol/(h. kg)]. The secretion rates of VLDL alpha-tocopherol were significantly lower (P: < 0.05) in the LP group than in the NP group. The activities of hepatic lipase, lipoprotein lipase and total heparin-releasable lipase in plasma of the LP group were only 50-60% those of the NP group (P: < 0.05). The results demonstrated that the secretion rate of VLDL alpha-tocopherol and activities of lipases in postheparin plasma were significantly lower in rats fed a low protein diet. Thus, the redistribution of alpha-tocopherol from liver to peripheral tissues appears to have been impaired by dietary protein insufficiency.

Interval nodes: the forgotten sentinel nodes in patients with melanoma.

BACKGROUND: Any sentinel lymph node that receives lymph drainage directly from a primary melanoma site, regardless of its location, may contain metastatic disease. This is true even if the sentinel node does not lie in a recognized node field. Interval (in-transit) nodes that lie along the course of a lymphatic vessel between a primary melanoma site and a recognized node field are sometimes seen during lymphatic mapping for sentinel node biopsy. If drainage to such interval nodes is ignored by the surgeon during sentinel node biopsy, metastatic melanoma will be missed in some patients. HYPOTHESIS: When lymph drains directly from a cutaneous melanoma site to an interval node, that sentinel node has the same chance of harboring micrometastatic disease as a sentinel node in a recognized node field. DESIGN: Preoperative lymphoscintigraphy with technetiumTc 99m antimony trisulfide colloid was performed to define lymphatic drainage patterns and, since 1992, to locate the sentinel lymph nodes for surgical biopsy or for permanent skin marking of their location with point tattoos. SETTING: Melanoma unit of a university teaching hospital. PATIENTS: A total of 2045 patients with cutaneous melanoma were studied in 13 years. RESULTS: Interval nodes were found in 148 patients (7.2%). The incidence of interval nodes varied with the site of the primary melanoma. Interval nodes were more common with melanomas on the trunk than with those on the lower limbs. Micrometastatic disease was found in 14% of interval nodes that underwent biopsy as sentinel nodes. This incidence is similar to that found in sentinel nodes located in recognized node fields, confirming the potential clinical importance of interval nodes. CONCLUSIONS: Interval nodes should be removed surgically along with any additional sentinel nodes in standard node fields if the sentinel node biopsy procedure is to be complete. In some patients, an interval node will be the only lymph node that contains metastatic disease.