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Background: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd., Patients and Methods: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded., Results: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred., Conclusion: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration., Competing Interests: Disclosure CP reports grant funding support: Pfizer, Daiichi Sankyo, Exact Sciences, Gilead and Seagen. Honoraria for advisory boards: Pfizer, Roche, Daiichi Sankyo, Novartis, Exact Sciences, Gilead, SeaGen and Eli Lilly. Support for travel and conferences: Roche, Novartis and Gilead. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Proton beam therapy has been utilised for the treatment of uveal melanoma in the UK for over 30 years, undertaken under a single centre. In the UK, all ocular tumours are treated at one of four centres. We aimed to understand the variation in referral patterns to the UK proton service, capturing all uveal melanoma patients treated with this modality., Methods: Retrospective analysis of data regarding all patients treated at the Clatterbridge Proton service between January 2004 and December 2014., Results: A total of 1084 patients with uveal melanoma were treated. The mean age was 57 years (range 9-90 years), basal diameter of 11.5 mm (range 2.0-23.4 mm) and tumour thickness of 3.9 mm (range 0.1-15.4 mm). The majority were TNM stage I (39%) or II (36%). The distance to the optic nerve varied from 0 to 24.5 mm with 148 (14%) of patients having ciliary body involvement. There were variations in the phenotypic characteristic of the tumours treated with protons from different centres, with London referring predominantly small tumours at the posterior pole, Glasgow referring large tumours often at the ciliary body and Liverpool sending a mix of these groups., Discussion: In the UK, common indications for the use of proton treatment in uveal melanoma include small tumours in the posterior pole poorly accessible for plaque treatment (adjacent to the disc), tumours at the posterior pole affecting the fovea and large anterior tumours traditionally too large for brachytherapy. This is the first UK-wide audit enabling the capture of all patients treated at the single proton centre., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre., Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded., Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%)., Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate., Competing Interests: CP received grant from Pfizer and Daiichi Sankyo and honoraria from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, SeaGen, and Eli Lilly., (Copyright © 2022 Benjamin James Hall et al.)

Aim: To present our experience of the use of stereotactic radiosurgery and proton beam therapy to treat posterior uveal melanoma over a 10 year period., Methods and Materials: Case notes of patients treated with stereotactic radiosurgery (SRS), or Proton beam therapy (PBT) for posterior uveal melanoma were reviewed. Data collected included visual acuity at presentation and final review, local control rates, globe retention and complications. We analysed post-operative visual outcomes and if visual outcomes varied with proximity to the optic nerve or fovea., Results: 191 patients were included in the study; 85 and 106 patients received Stereotactic radiosurgery and Proton beam therapy, respectively. Mean follow up period was 39 months in the SRS group and 34 months in the PBT group. Both treatments achieved excellent local control rates with eye retention in 98% of the SRS group and 95% in the PBT group. The stereotactic radiosurgery group showed a poorer visual prognosis with 65% losing more than 3 lines of Snellen acuity compared to 45% in the PBT group. 33% of the SRS group and 54% of proton beam patients had a visual acuity of 6/60 or better., Conclusions: Stereotactic radiosurgery and proton beam therapy are effective treatments for larger choroidal melanomas or tumours unsuitable for plaque radiotherapy. Our results suggest that patients treated with proton beam therapy retain better vision post-operatively; however, possible confounding factors include age, tumour location and systemic co-morbidities. These factors as well as the patient's preference should be considered when deciding between these two therapies.

Proton beam radiotherapy of uveal melanoma can be administered as primary treatment, as salvage therapy for recurrent tumor, and as neoadjuvant therapy prior to surgical resection. The physical properties of proton beams make it possible to deliver high-doses of radiation to the tumor with relative sparing of adjacent tissues. This form of therapy is effective for a wider range of uveal melanoma than any other modality, providing exceptionally-high rates of local tumor control. This is particularly the case with diffuse iris melanomas, many of which are unresectable. The chances of survival, ocular conservation, visual preservation and avoidance of iatrogenic morbidity depend greatly on the tumor size, location and extent. When treating any side-effects and/or complications, it is helpful to consider whether these are the result of collateral damage or persistence of the irradiated tumor ('toxic tumor syndrome').

Spreading depression (SD), whether elicited by local application of high K(+) medium to the cortical surface or by other stimuli, can increase the brain's tolerance to a subsequent, severe ischaemic insult in vivo, a phenomenon termed preconditioning. Herein, we have developed and validated a robust in vitro protocol for high-K(+)-preconditioning of cultured neurones. This new model is especially appropriate to unravel the molecular mechanisms underlying neuronal preconditioning and subsequent ischaemic tolerance. With this new, optimised preparation, preconditioning was found to be dependent upon culture day in vitro, cell density, K(+) concentration and duration of treatment. Finally, preconditioning was shown to be dependent upon N-methyl-d-aspartate (NMDA), CAM-kinase II signalling and alpha7-nicotinic (alpha7 nACh) receptor function, which is analogous to in vivo preconditioning induced by various stimuli.

The main aims of this article are to report the overall and disease-specific survival of a consecutive series of patients presenting with oral cancer from 1992 to 2002 and to relate survival to clinical and pathological factors. The article uses population-based age-sex mortality rates in the North-West of England to highlight differences in overall and disease-specific survival. 541 patients with oral squamous cell carcinoma presented to the Regional Maxillofacial Unit from 1992 to 2002. Curative treatment favoured radical primary surgery, 10% (52) received primary radiotherapy. These patients were on average 8 years older with more advanced tumours and overall poorer survival at 5 years, 23% (SE 7%). The remainder of the results refer to 489 patients who had primary curative surgery, 40% (194) of whom received adjuvant radiotherapy. The overall survival (OS) was 56% (SE 2%) and the disease-specific survival (DSS) was 74% (SE 2%). There was a local recurrence rate of 10% (50) and the loco-regional recurrence rate was 21% (103). The second primary rate was 7% (35). Survival figures had improved over the 10-year period from 63% DSS for the first 4 years of the study (1992-1995) compared to 81% for the last 3 years (2000-2002). In stepwise Cox regression the two predictors selected for disease-specific survival were pN status and margins (both p<0.001). Age-sex mortality rates for the North-West indicate that 15.0% of the 489 primary surgery patients might have been expected to die within 5 years if they were typical of the general population and the observed difference between all causes and oral-cancer specific survival was 18.3%. These data emphasise the value of disease-specific survival as an indicator of successful treatment in a cohort that tends to be elderly, from social deprived backgrounds, with life styles and comorbidity that influence overall survival.

We present the case of a 42-year-old male who presented with a hot, tender swelling in the left supraclavicular fossa. He was pyrexial on presentation with a mildly elevated leucocyte count of 12.4x10(9)/l. Clinical examination, including full ear, nose and throat assessment, proved unremarkable. The medical history revealed that 2 years earlier the patient had been diagnosed with a testicular seminoma for which he underwent a right inguinal orchidectomy and abdominal radiotherapy. CT scan highlighted a 6 cm para-laryngeal mass, of mixed attenuation, with an adjacent region of inflammation. Overall appearance was suggestive of an infective mass. Ultrasound-guided fine needle aspiration cytology revealed a metastatic seminomatous deposit. Imaging of the chest and abdomen revealed this as the only site of metastasis. He is currently undergoing chemotherapy, and is responding well. We review the pathology of testicular seminoma. This case highlights the myriad of pathologies that may present as a lump in the neck.

In this paper we outline a class of fully parametric proportional hazards models, in which the baseline hazard is assumed to be a power transform of the time scale, corresponding to assuming that survival times follow a Weibull distribution. Such a class of models allows for the possibility of time varying hazard rates, but assumes a constant hazard ratio. We outline how Bayesian inference proceeds for such a class of models using asymptotic approximations which require only the ability to maximize the joint log posterior density. We apply these models to a clinical trial to assess the efficacy of neutron therapy compared to conventional treatment for patients with tumours of the pelvic region. In this trial there was prior information about the log hazard ratio both in terms of elicited clinical beliefs and the results of previous studies. Finally, we consider a number of extensions to this class of models, in particular the use of alternative baseline functions, and the extension to multi-state data.

In this tutorial paper we give a simple Bayesian analysis of data that arise in clinical trials. We consider the case when there are two treatment groups and the response in each group can be assumed to be binomially distributed. We also assume that prior beliefs about the rate parameter in each group can be adequately expressed by a Beta distribution. Using such a model approximate posterior inferences can then be made about the odds ratio between the two groups. We illustrate this methodology by analyzing a randomized trial to assess the benefits of treating patients with carcinoma of the pelvic region (rectum, bladder, colon, cervix) using high-energy fast neutrons as opposed to conventional megavoltage x-rays (photons). In this trial there was prior information about the relative efficacy of neutron therapy based on the beliefs of 10 clinicians. Some of the deficiencies of this simple approach are high-lighted and other approaches to analysis indicated. The paper facilitates practical consideration of a Bayesian approach without the complexities that a fuller analysis necessitates.

alpha B crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1-10 of alpha B crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Pick's disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimer's disease with large numbers of ballooned neurons, two cases of motor neuron disease, four cases of cortico-basal degeneration, and four cases with areas of brain showing swollen neurons adjacent to recent cerebral infarcts. The anti-alpha B crystallin showed strong diffuse cytoplasmic immunoreactivity of swollen cortical neurons in all the diseases. Astrocytes and oligodendroglial cells were also stained in normal tissues as previously described. Weak diffuse immunoreactivity with an antibody to ubiquitin-conjugates was also seen in the swollen neurons from cases of neurodegenerative disease but not following infarction. Ballooned neurons have been shown to contain phosphorylated neurofilament epitopes not normally present in the perikaryonal region. The presence of alpha B crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that alpha B crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of alpha B crystallin in neurons at the edge of areas of cerebral infarction is likely to reflect cells which are regenerating following damage; its detection may therefore be a marker for such cells. On a practical level, the antibody greatly facilitates the localization of such abnormal neurons in diagnostic histology.

Human liver mRNA isolated from subjects phenotyped as homozygous PiMM or PiZZ alpha 1-antitrypsin, was translated in a reticulocyte cell-free system, and alpha 1-antitrypsin identified by immunoprecipitation. In the presence of dog pancreas membranes the translated alpha 1-antitrypsin appeared as a larger product. Treatment with endo-beta-N-glucosaminidase yielded a protein smaller than the reticulocyte translated product, presumably due to removal of the N-terminal signal sequence by membranes and sugar residues by endo-beta-N-glucosaminidase. Quantitation of alpha 1-antitrypsin translated from PiMM and PiZZ livers suggests that both mRNA species were present at the same cellular concentration, and that processing to the core glycosylation stage proceeded at identical rates.

Microinjection of human liver mRNA from a patient homozygous for alpha 1-antitrypsin deficiency (PiZZ) into Xenopus oocytes led to a 2--10-fold increase in lysosomal activity. Stimulation of lysosomal activity was not observed when mRNA from a normal human liver (alpha 1-antitrypsin PiMM), or water was injected into the oocyte. This lysosomal activity was oocyte derived and was not due to translation products of the human liver mRNA. Thus a protein that accumulates intracellularly in the secretory pathway is capable of stimulating lysosomal activity.

mRNA was prepared from autopsy liver samples from a homozygote for alpha 1-antitrypsin deficiency (PiZZ) and from a normal (PiMM) subject. Both preparations gave equivalent synthesis of alpha 1-antitrypsin in a wheat germ cell-free system. This suggests that the deficiency of plasma alpha 1-antitrypsin associated with the Z variant is due to a failure of processing and secretion of the protein rather than of its synthesis. It is likely that it is the resultant intracellular accumulation of the Z protein rather than a deficiency of protease inhibitor that is the primary cause of the liver pathology associated with this variant.

Injection of equivalent amounts of normal (PiMM) or abnormal (PiZZ) alpha 1-antitrypsin mRNA into Xenopus oocytes resulted in secretion of both the normal and abnormal alpha 1-antitrypsin. A much lower proportion of the abnormal protein was secreted, and the Z alpha 1-antitrypsin that was not secreted accumulated within the cell in a high-mannose form. The time taken for secretion of the normal and abnormal proteins was identical. Both the secreted and intracellular alpha 1-antitrypsin synthesized by oocytes were functionally active.