Biglycan neo-epitope (BGN262), a novel biomarker for screening early changes in equine osteoarthritic subchondral bone.

OBJECTIVE: Native biglycan (BGN), which can undergo proteolytic cleavage in pathological conditions, is well known to be involved in bone formation and mineralization. This study aimed to delineate the specific cleavage fragment, a neo-epitope for BGN (BGN262), in synovial fluid (SF) from young racehorses in training, osteoarthritic (OA) joints with subchondral bone sclerosis (SCBS), and chip fracture joints. DESIGN: A custom-made inhibition ELISA was developed to quantify BGN262 in SF. Cohort 1: A longitudinal study comprising 10 racehorses undergoing long-term training. Cohort 2: A cross-sectional study comprising joints from horses (N = 69) with different stages of OA and radiographically classified SCBS. Cohort 3: A cross-sectional study comprising horses (N = 9) with chip fractures. Receiver operating characteristic (ROC) curve analysis was performed (healthy joints vs chip joints) to evaluate BGN262 robustness. RESULTS: Cohort 1: SF BGN262 levels from racehorses showed a statistical increase during the first 6 months of the training period. Cohort 2: BGN262 levels were significantly higher in the SF from severe SCBS joints. Cohort 3: SF BGN262 levels in chip fracture joints showed a significant increase compared to normal joints. The ROC analysis showed an AUC of 0.957 (95% C.I 0.868-1.046), indicating good separation between the groups. CONCLUSIONS: The data presented show that BGN262 levels increase in SF in correlation with the initiation of training, severity of SCBS, and presence of chip fractures. This suggests that BGN262 is a potential predictor and a novel biomarker for early changes in subchondral bone (SCB), aiming to prevent catastrophic injuries in racehorses.

Association between time interval from neoadjuvant chemoradiotherapy to surgery and complete histological tumor response in esophageal and gastroesophageal junction cancer: a national cohort study.

The optimal time interval from neoadjuvant therapy to surgery in the treatment of esophageal cancer is not known. The aim of this study was to investigate if a prolonged interval between completed neoadjuvant chemoradiotherapy and surgery was associated with improved histological response rates and survival in a population-based national register cohort. The population-based cohort study included patients treated with neoadjuvant chemoradiotherapy and esophagectomy due to cancer in the esophagus or gastroesophageal junction. Patients were divided into two groups based on the median time from completed neoadjuvant treatment to surgery. The primary outcome was complete histological response. Secondary outcomes were lymph node tumor response, postoperative complications, R0 resection rate, 90-day mortality, and overall survival. In total, 643 patients were included, 344 (54%) patients underwent surgery within 49 days, and 299 (47%) after 50 days or longer. The groups were similar concerning baseline characteristics except for a higher clinical tumor stage (P = 0.009) in the prolonged time to surgery group. There were no significant differences in complete histological response, R0 resection rate, postoperative complications, 90-day mortality, or overall survival. Adjusted odds ratio for ypT0 in the prolonged time to surgery group was 0.99 (95% confidence interval: 0.64-1.53). Complete histological response in the primary tumor (ypT0) was associated with significantly higher overall survival: adjusted hazard ratio: 0.55 (95% CI 0.41-0.76). If lymph node metastases were present in these patients, the survival was, however, significantly lower: adjusted hazard ratio for ypT0N1: 2.30 (95% CI 1.21-4.35). In this prospectively collected, nationwide cohort study of esophageal and junctional type 1 and 2 cancer patients, there were no associations between time to surgery and histological complete response, postoperative outcomes, or overall survival. The results suggest that it is safe for patients to postpone surgery at least 7 to 10 weeks after completed chemoradiotherapy, but no evidence was seen in favor of recommending a prolonged time to surgery after neoadjuvant chemoradiotherapy for esophageal cancer. A definitive answer to this question requires a randomized controlled trial of standard vs. prolonged time to surgery.

Phylogeny and character evolution in the Dacrymycetes, and systematics of Unilacrymaceae and Dacryonaemataceae fam. nov.

We present a multilocus phylogeny of the class Dacrymycetes, based on data from the 18S, ITS, 28S, RPB1, RPB2, TEF-1α, 12S, and ATP6 DNA regions, with c. 90 species including the types of most currently accepted genera. A variety of methodological approaches was used to infer phylogenetic relationships among the Dacrymycetes, from a supermatrix strategy using maximum likelihood and Bayesian inference on a concatenated dataset, to coalescence-based calculations, such as quartet-based summary methods of independent single-locus trees, and Bayesian integration of single-locus trees into a species tree under the multispecies coalescent. We evaluate for the first time the taxonomic usefulness of some cytological phenotypic characters, i.e., vacuolar contents (vacuolar bodies and lipid bodies), number of nuclei of recently discharged basidiospores, and pigments, with especial emphasis on carotenoids. These characters, along with several others traditionally used for the taxonomy of this group (basidium shape, presence and morphology of clamp connections, morphology of the terminal cells of cortical/marginal hyphae, presence and degree of ramification of the hyphidia), are mapped on the resulting phylogenies and their evolution through the class Dacrymycetes discussed. Our analyses reveal five lineages that putatively represent five different families, four of which are accepted and named. Three out of these four lineages correspond to previously circumscribed and published families (Cerinomycetaceae, Dacrymycetaceae, and Unilacrymaceae), and one is proposed as the new family Dacryonaemataceae. Provisionally, only a single order, Dacrymycetales, is accepted within the class. Furthermore, the systematics of the two smallest families, Dacryonaemataceae and Unilacrymaceae, are investigated to the species level, using coalescence-based species delimitation on multilocus DNA data, and a detailed morphological study including morphometric analyses of the basidiospores. Three species are accepted in Dacryonaema, the type, Da. rufum, the newly combined Da. macnabbii (basionym Dacrymyces macnabbii), and a new species named Da. macrosporum. Two species are accepted in Unilacryma, the new U. bispora, and the type, U. unispora, the latter treated in a broad sense pending improved sampling across the Holarctic.

Juvenile osteochondritis dissecans of the knee is a result of failure of the blood supply to growth cartilage and osteochondrosis.

OBJECTIVE: Juvenile osteochondritis dissecans (JOCD) is similar to osteochondrosis dissecans (OCD) in animals, which is the result of failure of the cartilage canal blood supply, ischemic chondronecrosis and delayed ossification, or osteochondrosis. The aim of the current study was to determine if osteochondrosis lesions occur at predilection sites for JOCD in children. METHOD: Computed tomographic (CT) scans of 23 knees (13 right, 10 left) from 13 children (9 male, 4 female; 1 month to 11 years old) were evaluated for lesions consisting of focal, sharply demarcated, uniformly hypodense defects in the ossification front. Histological validation was performed in 11 lesions from eight femurs. RESULTS: Thirty-two lesions consisting of focal, uniformly hypodense defects in the ossification front were identified in the CT scans of 14 human femurs (7 left, 7 right; male, 7-11 years old). Defects corresponded to areas of ischemic chondronecrosis in sections from all 11 histologically validated lesions. Intra-cartilaginous secondary responses comprising proliferation of adjacent chondrocytes and vessels were detected in six and two lesions, whereas intra-osseous responses including accumulation of chondroclasts and formation of granulation tissue occurred in 10 and six lesions, respectively. One CT cyst-like lesion contained both a pseudocyst and a true cyst in histological sections. CONCLUSION: Changes identical to osteochondrosis in animals were detected at predilection sites for JOCD in children, and confirmed to represent failure of the cartilage canal blood supply and ischemic chondronecrosis in histological sections.

The prognostic value of pre-treatment thrombocytosis in two cohorts of patients with non-small cell lung cancer treated with curatively intended chemoradiotherapy.

Chemoradiotherapy is the standard of care for inoperable stage III non-small cell lung cancer (NSCLC). This treatment, however, offers only a small chance of cure and is associated with many side effects. Little research has been made concerning which patients benefit most/least from the treatment. The present study evaluates the prognostic value of anemia, leukocytosis and thrombocytosis at diagnosis in this treatment setting. In the present study, data were collected retrospectively for 222 patients from two different phase II studies conducted between 2002-2007 in Sweden with patients treated with chemoradiotherapy for stage IIIA-IIIB NSCLC. Clinical data and the serum values of hemoglobin (Hgb), White blood cells (WBC) and Platelets (Plt) at enrollment were collected for all patients and studied in relation to overall survival using Kaplan-Meier product-limit estimates and a multivariate Cox proportional hazards regression model. The results showed that patients with thrombocytosis (Plt > 350 x 109/L) had a shorter median overall survival (14.5 months) than patients with normal Plt at baseline (23.7 months). Patients with leukocytosis (WBC > 9 x 109/L) had a shorter median survival (14.9 months) than patients with a normal WBC at baseline (22.5 months). However, in a multivariate model including all lab parameters and clinical factors, only thrombocytosis and performance status displayed a prognostic significance. In Conclusion, thrombocytosis showed to be an independent prognostic marker associated with shorter overall survival in stage III NSCLC treated with curatively intended chemoradiotherapy. This knowledge can potentially be used together with established prognostic factors, such as performance status when choosing the optimal therapy for the individual patient in this clinical setting.

Osteochondrosis, Synovial Fossae, and Articular Indentations in the Talus and Distal Tibia of Growing Domestic Pigs and Wild Boars.

Articular osteochondrosis (OC) often develops in typical locations within joints, and the characterization of OC distribution in the pig tarsus is incomplete. Prevalence of OC is high in domestic pigs but is presumed to be low in wild boars. Postmortem and computed tomography (CT) examinations of the talus and distal tibia from 40 domestic pigs and 39 wild boars were evaluated for the locations and frequencies of OC, synovial fossae, and other articular indentations, and frequency distribution maps were made. All domestic pigs but only 5 wild boars (13%) had OC on the talus. In domestic pigs, OC consistently affected the axial aspect of the medial trochlea tali in 11 (28%) joints and the distomedial talus in 26 (65%) joints. In wild boars, all OC lesions consistently affected the distomedial talus. On the articular surface of the distal tibia, all domestic pigs and 34 wild boars (87%) had synovial fossae and 7 domestic pigs (18%) had superficial cartilage fibrillation opposite an OC lesion (kissing lesion). Other articular indentations occurred in the intertrochlear groove of the talus in all domestic pigs and 13 wild boars (33%) and were less common on the trochlea tali. The prevalence of tarsal OC in wild boars is low. In domestic pigs and wild boars, OC is typically localized to the distomedial talus and in domestic pigs also to the medial trochlea tali. Further investigations into the reasons for the low OC prevalence in wild boars may help in developing strategies to reduce OC incidence in domestic pigs.

Cardiovascular safety of the glucagon-like peptide-1 receptor agonist taspoglutide in people with type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials.

AIMS: To study the short-term cardiovascular effects of the once-weekly glucagon-like peptide-1 receptor agonist taspoglutide. METHODS: We conducted a meta-analysis of individual-participant data from nine randomized controlled trials in the T-Emerge programme, which assessed the efficacy and safety of taspoglutide in type 2 diabetes. Our primary outcome was a composite of death from cardiovascular disease (CVD) and acute myocardial infarction, stroke and hospitalization for unstable angina. RESULTS: Overall, 7056 individuals were included in the analysis, and there were 67 primary endpoint events during 7478 person-years of follow-up (40 vs 27 events in the intervention vs control groups, respectively). The odds ratio for the composite endpoint among people randomized to taspoglutide was 0.94 (95% confidence interval 0.57-1.56), which was robust across multiple subgroups. Longer-term data were not available as the development of taspoglutide was stopped because of gastrointestinal intolerance and serious hypersensitivity reactions. CONCLUSIONS: The available data suggest that short-term, once-weekly administration of taspoglutide was not associated with an excess risk of CVD, and provide insights relevant to the development of other novel once-weekly incretin mimetics.

Osteochondrosis Can Lead to Formation of Pseudocysts and True Cysts in the Subchondral Bone of Horses.

Osteochondrosis arises as a result of focal failure of the blood supply to growth cartilage. The current aim was to examine the pathogenesis of pseudocysts and true cysts in subchondral bone following failure of the blood supply to the articular-epiphyseal cartilage complex in horses. Cases were recruited based on identification of lesions (n = 17) that were considered likely to progress to or to represent pseudocysts or true cysts in epiphyseal bone in histological sections and included 10 horses ranging in age from 48 days to 5 years old. Cases comprised 3 warmbloods, 3 Standardbreds, 1 Quarter horse and 1 Arabian with spontaneous lesions and 2 Fjord ponies with experimentally induced lesions. Seven lesions consisted of areas of ischemic chondronecrosis and were compatible with pseudocysts. Two lesions were located at intermediate depth in epiphyseal growth cartilage, 2 lesions were located in the ossification front, 2 lesions were located in epiphyseal bone and 1 lesion was located in the metaphyseal growth plate (physis). Ten lesions contained dilated blood vessels and were compatible with true cysts. In 2 lesions the dilated blood vessels were located within the lumina of failed cartilage canals. In the 8 remaining lesions areas of ischemic chondronecrosis were associated with granulation tissue in the subjacent bone and dilated vessels were located within this granulation tissue. Failure of the blood supply and ischemic chondronecrosis can lead to formation of pseudocysts or dilatation of blood vessels and formation of true cysts in the epiphyseal bone of horses.

An Update on the Pathogenesis of Osteochondrosis.

Osteochondrosis is defined as a focal disturbance in endochondral ossification. The cartilage superficial to an osteochondrosis lesion can fracture, giving rise to fragments in joints known as osteochondrosis dissecans (OCD). In pigs and horses, it has been confirmed that the disturbance in ossification is the result of failure of the blood supply to epiphyseal growth cartilage and associated ischemic chondronecrosis. The earliest lesion following vascular failure is an area of ischemic chondronecrosis at an intermediate depth of the growth cartilage (osteochondrosis latens) that is detectable ex vivo, indirectly using contrast-enhanced micro- and conventional computed tomography (CT) or directly using adiabatic T1ρ magnetic resonance imaging. More chronic lesions of ischemic chondronecrosis within the ossification front (osteochondrosis manifesta) are detectable by the same techniques and have also been followed longitudinally in pigs using plain CT. The results confirm that lesions sometimes undergo spontaneous resolution, and in combination, CT and histology observations indicate that this occurs by filling of radiolucent defects with bone from separate centers of endochondral ossification that form superficial to lesions and by phagocytosis and intramembranous ossification of granulation tissue that forms deep to lesions. Research is currently aimed at discovering the cause of the vascular failure in osteochondrosis, and studies of spontaneous lesions suggest that failure is associated with the process of incorporating blood vessels into the advancing ossification front during growth. Experimental studies also show that bacteremia can lead to vascular occlusion. Future challenges are to differentiate between causes of vascular failure and to discover the nature of the heritable predisposition for osteochondrosis.

Osteochondral lesions in distal tarsal joints of Icelandic horses reveal strong associations between hyaline and calcified cartilage abnormalities.

Osteochondral lesions in the joints of the distal tarsal region of young Icelandic horses provide a natural model for the early stages of osteoarthritis (OA) in low-motion joints. We describe and characterise mineralised and non-mineralised osteochondral lesions in left distal tarsal region joint specimens from twenty-two 30 ±1 month-old Icelandic horses. Combinations of confocal scanning light microscopy, backscattered electron scanning electron microscopy (including, importantly, iodine staining) and three-dimensional microcomputed tomography were used on specimens obtained with guidance from clinical imaging. Lesion-types were described and classified into groups according to morphological features. Their locations in the hyaline articular cartilage (HAC), articular calcified cartilage (ACC), subchondral bone (SCB) and the joint margin tissues were identified and their frequency in the joints recorded. Associations and correlations between lesion-types were investigated for centrodistal joints only. In centrodistal joints the lesion-types HAC chondrocyte loss, HAC fibrillation, HAC central chondrocyte clusters, ACC arrest and ACC advance had significant associations and strong correlations. These lesion-types had moderate to high frequency in centrodistal joints but low frequencies in tarsometatarsal and talocalcaneal-centroquartal joints. Joint margin lesion-types had no significant associations with other lesion-types in the centrodistal joints but high frequency in both the centrodistal and tarsometatarsal joints. The frequency of SCB lesion-types in all joints was low. Hypermineralised infill phase lesion-types were detected. Our results emphasise close associations between HAC and ACC lesions in equine centrodistal joints and the importance of ACC lesions in the development of OA in low-motion compression-loaded equine joints.

Transection of vessels in epiphyseal cartilage canals leads to osteochondrosis and osteochondrosis dissecans in the femoro-patellar joint of foals; a potential model of juvenile osteochondritis dissecans.

OBJECTIVE: To transect blood vessels within epiphyseal cartilage canals and observe whether this resulted in ischaemic chondronecrosis, an associated focal delay in enchondral ossification [osteochondrosis (OC)] and pathological cartilage fracture [osteochondrosis dissecans (OCD)] in the distal femur of foals, with potential translational value to the pathogenesis of juvenile osteochondritis dissecans (JOCD) in children. METHOD: Ten Norwegian Fjord Pony foals were operated at the age of 13-15 days. Two vessels supplying the epiphyseal growth cartilage of the lateral trochlear ridge of the left distal femur were transected in each foal. Follow-up examination was carried out from 1 to 49 days post-operatively and included plain radiography, macroscopic and histological examination. RESULTS: Transection of blood vessels within epiphyseal cartilage canals resulted in necrosis of vessels and chondrocytes, i.e., ischaemic chondronecrosis, in foals. Areas of ischaemic chondronecrosis were associated with a focal delay in enchondral ossification (OC) in foals examined 21 days or more after transection, and pathological cartilage fracture (OCD) in one foal examined 42 days after transection. CONCLUSION: The ischaemic hypothesis for the pathogenesis of OC has been reproduced experimentally in foals. There are several similarities between OCD in animals and JOCD in children. It should be investigated whether JOCD also occurs due to a focal failure in the cartilage canal blood supply, followed by ischaemic chondronecrosis.

Articular osteochondrosis: a comparison of naturally-occurring human and animal disease.

BACKGROUND: Osteochondrosis (OC) is a common developmental orthopedic disease affecting both humans and animals. Despite increasing recognition of this disease among children and adolescents, its pathogenesis is incompletely understood because clinical signs are often not apparent until lesions have progressed to end-stage, and examination of cadaveric early lesions is not feasible. In contrast, both naturally-occurring and surgically-induced animal models of disease have been extensively studied, most notably in horses and swine, species in which OC is recognized to have profound health and economic implications. The potential for a translational model of human OC has not been recognized in the existing human literature. OBJECTIVE: The purpose of this review is to highlight the similarities in signalment, predilection sites and clinical presentation of naturally-occurring OC in humans and animals and to propose a common pathogenesis for this condition across species. STUDY DESIGN: Review. METHODS: The published human and veterinary literature for the various manifestations of OC was reviewed. Peer-reviewed original scientific articles and species-specific review articles accessible in PubMed (US National Library of Medicine) were eligible for inclusion. RESULTS: A broad range of similarities exists between OC affecting humans and animals, including predilection sites, clinical presentation, radiographic/MRI changes, and histological appearance of the end-stage lesion, suggesting a shared pathogenesis across species. CONCLUSION: This proposed shared pathogenesis for OC between species implies that naturally-occurring and surgically-induced models of OC in animals may be useful in determining risk factors and for testing new diagnostic and therapeutic interventions that can be used in humans.

Dendrodacrys: a new genus for species with branched hyphidia in Dacrymyces s.l., with the description of four new species.

A new genus named Dendrodacrys is proposed for a monophyletic group in Dacrymycetaceae, containing species with pulvinate to depressed basidiocarps, distinctly branched hymenial hyphidia, and up to 3-septate mature basidiospores. Four taxa in this group, occurring in Europe, are proposed as new species, viz. De. ciprense, De. concrescens, De. ellipsosporum, and De. oblongisporum, based both on morphological and DNA data (nrDNA, RPB1, RPB2, TEF-1α, 12S). These new species are all described in detail, illustrated, and compared with other published taxa that with which they can be confounded. The new combination De. paraphysatum is proposed after revising the type material of Dacrymyces paraphysatus, but other combinations or potentially new non-European species descriptions are postponed pending further studies of additional specimens. Citation: Zamora JC, Savchenko A, González-Cruz Á, Prieto-García F, Olariaga I, Ekman S (2022). Dendrodacrys: a new genus for species with branched hyphidia in Dacrymyces s.l., with the description of four new species. Fungal Systematics and Evolution 9: 27-42. doi: 10.3114/fuse.2022.09.04.

Early lesions of articular osteochondrosis in the distal femur of foals.

Failure of the cartilage canal blood supply to epiphyseal growth cartilage has been implicated in the pathogenesis of articular osteochondrosis in horses and other animal species. In a previous study of the developmental pattern of the blood supply in the tarsus of foals, early lesions of osteochondrosis were consistently found in regions where the cartilage canal vessels traversed the chondro-osseous junction. The developmental pattern of blood vessels has also been described in the distal femoral epiphysis; however, the group of foals examined in that study did not have lesions of osteochondrosis in this location. Therefore, the relationship between the occurrence of early lesions of osteochondrosis and the developmental pattern of the blood supply to epiphyseal growth cartilage in this site in foals has not been examined. Distal femora were collected from 30 fetuses and foals (up to 11 months old) submitted for postmortem examination. Sections from the lateral trochlear ridge and medial femoral condyle of both hind limbs were examined histologically. Sixteen cartilage lesions were found in 7 of the 30 fetuses and foals. All lesions contained evidence of cartilage canal necrosis and ischemic chondronecrosis. The lesions were located in regions where cartilage canal vessels traversed the chondro-osseous junction, as previously observed in the tarsus. The location and morphology of lesions indicated that a subclinical stage of ischemic chondronecrosis existed that preceded and predisposed to the development of osteochondrosis dissecans and subchondral bone cysts.

Nerve growth factor in the equine joint.

Nerve growth factor (NGF) is a neurotrophin with many functions. In humans, it is involved in inflammation, nerve growth, apoptosis and pain signalling. Increased concentrations of NGF in synovial fluid has been shown in humans and dogs with osteoarthritis. Despite osteoarthritis being a common problem in horses, no studies have previously been published on NGF in the equine joint. The aim of this study was to quantify NGF in equine synovial fluid from healthy joints, acutely inflamed septic joints and joints with structural changes associated with osteoarthritis. A secondary aim was to identify the localisation of NGF and its two receptors, TrkA and p75NTR, in healthy and osteoarthritic articular cartilage. NGF concentrations in synovial fluid from osteoarthritic joints (n = 27), septic joints (n = 9) and healthy joints (n = 16) were determined by ELISA. In addition, articular cartilage from osteoarthritic and healthy joints was examined for NGF, TrkA and p75NTR using immunohistochemistry staining. NGF was present in equine synovial fluid and articular cartilage. Compared to synovial fluid from healthy joints, NGF concentration was higher in synovial fluid from joints with structural osteoarthritic changes (P = 0.032) or acute septic inflammation (P = 0.006). In articular cartilage with severe osteoarthritic changes, there was more abundant positive immunohistochemistry staining for NGF and its receptors than in normal articular cartilage. Further studies should focus on identifying precursor forms of NGF, and on receptor expression and downstream signalling of TrkA and P75NTR in health and disease.

Life experiences after stroke among Iranian stroke survivors.

BACKGROUND: Stroke is a major cause of disability worldwide. It is a life-threatening and life-altering event, which leaves many physical and mental disabilities, thus creating major social and economic burdens. Experiencing a stroke and its aftermath can be devastating for patients and their families. In Iran, many services are not available for those who lack property; this may result in many difficulties and long-term problems for stroke survivors and their family members who are usually the main caregivers in Iranian cultural. Despite its effect on their lives, little is known about how the survivors perceive stroke in the Iranian context, therefore, knowing more about this process may enhance problem identification and problem solving. AIM: To illuminate how stroke survivors experience and perceive life after stroke. METHOD: A grounded theory approach was recruited using semi-structured interviews with 10 stroke survivors. FINDINGS: The survivors perceived that inadequate social and financial support, lack of an educational plan, lack of access to rehabilitative services, physical and psychological problems led them to functional disturbances, poor socio-economical situation and life disintegration. The core concept of life after stroke was functional disturbances. CONCLUSIONS: The study shows the need to support the stroke survivors in their coping process with their new situation by providing appropriate discharge plans, social and financial support, social insurances and training programmes for the stroke survivors and their families.

Immune checkpoint blockade for non-small cell lung cancer: What is the role in the special populations?

In recent years, non-small cell lung cancer (NSCLC) entered in a new era of anticancer treatments with the success of checkpoint inhibitors (CPIs). These are now part of daily practice from locally advanced to metastatic NSCLC. However, the registration phase III trials are highly selective and not fully representative of the patients seen in real-world clinical practice. This is particularly obvious for older and frail patients, which represent the majority of NSCLC cases worldwide. The median age of the patients enrolled in clinical trials is 10 years younger than what is seen in clinic and patients with performance status (PS) ≥2 were excluded from registration studies. No strong conclusions can be drawn from the available trials where older and frail patients have been excluded. The majority of data on efficacy according to age are derived from underpowered subgroup analysis and there are no age-specific safety data published. Current data suggest that older patients may derive a similar benefit with no increased toxicity when compared with younger patients. However, the recent development of immunotherapychemotherapy combinations and the potential higher incidence of toxicity, raise additional concerns for these populations where adequate patient selection is paramount. CPI is not recommended for patients with PS 3-4 and should be considered with caution for those with PS 2. The evidence for patients with pre-existing autoimmune disease (AID), organ transplant or chronic viral infections (such us viral hepatitis B and C or human immunodeficiency virus) is less clear and low level. Although CPI are potentially safe in selected patients with AID with minimal activity and well-controlled chronic viral infections, patients with solid organ transplant face a significant risk of graft loss and death. Therefore, a decision to treat these groups of patients should always be discussed at a multidisciplinary level.

Hsp90 is expressed and represents a therapeutic target in human oesophageal cancer using the inhibitor 17-allylamino-17-demethoxygeldanamycin.

Heat shock protein 90 (Hsp90) has been demonstrated to protect oncogenic variants of signalling molecules from degradation and may consequently serve as a therapeutic target for the treatment of oesophageal cancer for which adequate therapy is often lacking. We studied the expression of Hsp90 in tumour tissues of human oesophageal cancer and the impact of Hsp90 inhibition on oesophageal cancer cell lines using the drug 17-allylamino-17-demethoxygeldanamycin (17-AAG). Quantitative immunohistochemistry was performed on formalin-fixed paraffin-embedded tissues from patients with oesophageal cancer. In squamous cell carcinoma, a marked upregulation of Hsp90 could be noted in dysplastic epithelium and invasive cancer compared with normal epithelium. In adenocarcinoma, Hsp90 was expressed in neoplastic epithelium and also in normal non-neoplastic glands weakly. The inhibition of Hsp90 using 17-AAG led to a significant decrease in cell proliferation and viability in human oesophageal cancer cell lines. Using a clonogenic cell survival assay, Hsp90 inhibition significantly sensitised the cells for gamma-photon irradiation. Heat shock protein 90 was found to be critical for proper signalling induced by both epidermal growth factor and insulin-like growth factor-1, in which the inhibition of signalling by 17-AAG correlated with the observed reduction in cell proliferation and viability. These results showed that Hsp90 was selectively expressed in oesophageal cancer tissue compared with the corresponding normal tissue, and the inhibition of Hsp90 resulted in decreased proliferation and viability as well as radiosensitisation of oesophageal cancer cells. Heat shock protein 90 represents a potential therapeutic target in the treatment of patients with oesophageal cancer, alone or in combination with radiotherapy.