Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy ...alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy.
We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition.
Among several predicted peptide epitopes, EGFR875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875-889 epitope could be detected in the blood of HNSCC patients. EGFR875-889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875-889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.
We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875-889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy.
Tendon entheses can be classed as fibrous or fibrocartilaginous according to the tissue present at the skeletal attachment site. The former can be ‘bony’ or ‘periosteal’, depending on whether the ...tendon is directly attached to bone or indirectly to it via the periosteum. At fibrocartilaginous entheses, the uncalcified fibrocartilage dissipates collagen fibre bending and tendon narrowing away from the tidemark; calcified fibrocartilage anchors the tendon to the bone and creates a diffusion barrier between the two. Where there are additional fibrocartilaginous specialisations in the tendon and/or bone next to the enthesis, an ‘enthesis organ’ is created that reduces wear and tear. Little attention has been paid to bone at entheses, despite the obvious bearing this has on the mechanical properties of the interface and the clinical importance of avulsion fractures. Disorders at entheses (enthesopathies) are common and occur in conditions such as diffuse idiopathic skeletal hyperostosis and the seronegative spondyloarthropathies. They are also commonly seen as sporting injuries such as tennis elbow and jumper's knee.
The need for graduated return to play (GRTP) following recovery from sports-induced concussions has been demonstrated. We report a case of concussion of a collegiate cycling athlete. When returning ...to daily training and competitions, we set a GRTP program taking cycling competitions and the training environment into consideration. As a result, successful recovery was possible based on the athleteʼs symptoms and degree of recovery. Nonetheless, the results of this study suggested the need to readjust GRTP from the viewpoint of cycling and student sports.
The ligamentum capitis femoris (LCF) has increased in clinical significance through the development of hip arthroscopy. The histological pathologies and molecular composition of the femoral ...attachment of the LCF and the degeneration caused by LCF disruption were investigated in the human hip joint. Twenty‐four LCFs were retrieved at surgery for femoral neck fracture (age range: 63–87 years). In the “intact” (i.e., intact throughout its length, n = 12) group, the attachment consisted of rich fibrocartilage. Fibrocartilage cells were present in the midsubstance. In contrast, the construction of the attachment in the “disrupted” (i.e., ligament no longer attached to the femoral head, n = 12) group had disappeared. The attachment in the disrupted group was not labeled for type II collagen or aggrecan, while that in the intact group was labeled for types I, II and III collagen, chondroitin 4‐sulfate, chondroitin 6‐sulfate, aggrecan, and versican. The percentage of single‐stranded DNA‐positive chondrocytes was significantly higher in the disrupted group than in the intact group. We conclude that the femoral attachment of the LCF has a characteristic fibrocartilaginous structure that is likely to adjust to the mechanical load, and suggest that its degeneration is advanced by disruption and should be regarded as a clinical pathology.
The peroneal (fibularis) tendons are held in place within the malleolar groove by the superior peroneal retinaculum. If this is torn, the tendons can subluxate or dislocate. Understanding the anatomy ...of the region is important for treating these injuries when it becomes necessary to reconstruct the malleolar groove surgically. Serial transverse sections of the groove were cut from 10 dissecting room cadavers after routine histology processing. The structure of the malleolar groove differed significantly in its proximal and distal parts. Distally, the bone is convex and the shape of the groove is determined by a thick periosteal cushion of fibrocartilage that covers the bone surface. Proximally, the groove shape is determined by the bone itself, and the periosteum is thin and fibrous. The restriction of a periosteal fibrocartilage to the distal end suggests that it serves to adapt the shape of the malleolar groove to that of the tendons within it and thus promotes stress dissipation. Paradoxically, however, it increases the risk of damage to subluxated tendons, because these can be sliced longitudinally by a sharp ridge created from periosteal fibrocartilage when the retinaculum is torn. Our results suggest that if bone‐block surgical procedures are used to reconstruct the malleolar groove, they are best restricted to its proximal part.
Proximal patellar tendinopathy occurs as an overuse injury in sport and is also characteristic of ankylosing spondylitis patients. It particularly affects the posteromedial part of the patellar ...tendon enthesis, although the reason for this is unclear. We investigated whether there are regional differences in the trabecular architecture of the patella or in the histology of the patellar tendon enthesis that could suggest unequal force transmission from bone to tendon. Trabecular architecture was analysed from X‐rays taken with a Faxitron radiography system of the patellae of dissecting room cadavers and in magnetic resonance images of the knees of living volunteers. Structural and fractal analyses were performed on the Faxitron digital images using MatLab software. Regional differences at the enthesis in the thickness of the uncalcified fibrocartilage and the subchondral plate were evaluated histologically in cadaveric material. The radiological studies showed that the quantity of bone and the apparent trabecular thickness in the patella were greatest medially, and that in the lateral part of the patella there were fewer trabeculae which were orientated either antero‐posteriorly or superiorly inferiorly. The histological study showed that the uncalcified fibrocartilage was most prominent medially and that the subchondral plate was thinner laterally. Overall, the results indicate that mechanical stress at the proximal patellar tendon enthesis is asymmetrically distributed and greater on the medial than on the lateral side. Thus, we suggest that the functional anatomy of the knee is closely related to regional variations in force transmission, which in turn relates to the posteromedial site of pathology in proximal patellar tendinopathy.
In this retrospective study we have assessed the results of low tibial valgus osteotomy for varus-type osteoarthritis of the ankle and its indications. We performed an opening wedge osteotomy in 25 ...women (26 ankles). The mean follow-up was for eight years and three months (2 years 3 months to 17 years 11 months). Of the 26 ankles, 19 showed excellent or good clinical results. Their mean scores for pain, walking, and activities of daily living were significantly improved but there was no change in the range of movement. In the ankles which were classified radiologically as stage 2 according to our own grading system, with narrowing of the medial joint space, and in 11 as stage 3a, with obliteration of the joint space at the medial malleolus only, the joint space recovered. In contrast, such recovery was seen in only two of 12 ankles classified as stage 3b, with obliteration of the joint space advancing to the upper surface of the dome of the talus. Low tibial osteotomy is indicated for varus-type osteoarthritis of stage 2 or stage 3a.
The anterior talofibular ligament is the most commonly injured ligament in the ankle. Despite considerable interest in the clinical outcome of treatment protocols, we do not know whether the ...distinctive pattern of localization of the injuries relates to regional differences in the structure and molecular composition of the ligament. To address this issue, ligaments were examined by histology and immunohistochemistry. Differences in the structure of its two attachments (i.e. entheses) were evaluated with quantitative, morphometric techniques, and regional differences in the distribution of collagens, glycosaminoglycans and proteoglycans were determined qualitatively by immunolabelling. Morphometric analyses showed that bone density was less at the fibular attachment, but that enthesis fibrocartilage was more prominent. Immunohistochemistry revealed the presence of a fibrocartilage (containing type II collagen and aggrecan) at the site where the ligament wraps around the lateral talar articular cartilage in a plantarflexed and inverted foot: the fibrocartilage is regarded as an adaptation to resisting compression. We propose that avulsion fractures are less common at the talar end of the ligament because (1) bone density is greater here than at the fibular enthesis, and (2) stress is dissipated away from the talar enthesis by the ‘wrap‐around’ fibrocartilaginous character of the ligament near the talar articular facet.
This study investigated the sprain factor in basketball in terms of three aspects. These were position (guard, forward, center); scene of injury (game, practice, situation); and whether there was ...contact or not (foot, and areas other than the foot). The aim was to clarify the relationship between the incidence of sprain and the above three variables. Sixty university basketball players participated in this epidemiological survey spanning three sea sons. A total of 33 games were assessed.With regard to the assessment of single factors, it was found that the forward position, game setting, and foot contact were each associated with the highest number of sprains. Regarding multiple factors: a combination of the guard position, game setting, and foot contact, was linked with the highest incidence of sprains.Since there was a difference between the single and combined factors, it is suggested that the single factors rather than the combined factors should be further investigated.
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