CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

A thematic literature review of innovative strategies to prepare nursing students for aged-care.

BACKGROUND: The exponential rise in people living longer but requiring residential care is adding pressure to already overstretched aged care nurses. Consequently, a person-centred care culture in residential care remains aspirational, rather than a reality. For nursing students in Australia and elsewhere, clinical placements in aged care facilities are under-utilised due to negative perceptions about the likelihood for learning. Creative strategies to engage students to safely challenge ageist thinking and to inspire enthusiasm for learning in this context are needed. OBJECTIVES: The purpose of this thematic review of the literature is to better understand challenges related to learning in aged care settings and identify innovative strategies to enhance nursing student learning experiences in residential aged care placements. REVIEW METHODS: A literature review was undertaken in 2019 using CINAHL, PUBMED, Elsevier, Medline, ProQuest and Google Scholar. The search was limited to papers that were peer reviewed, in English, and published between 2001 and the date of review (mid-2019) in order to situate the review in the new millennium. RESULTS: 47 articles and books were included in the review that introduce solutions and innovative strategies that could be used to improve students' attitudes to learning in aged care and from older people. The literature review was categorized into three main themes, including: barriers to working with older people; the need for pedagogical change to foster empathy; and innovative strategies to address barriers. CONCLUSION: These themes are useful to consider in designing engaging learning and teaching for nursing students to be effective in working in aged care.

Hypofractionated Concomitant Chemoradiation in Inoperable Locally Advanced Non-small Cell Lung Cancer: A Report on 100 Patients and a Systematic Review.

AIMS: Concomitant chemoradiation is the standard of care in patients with inoperable non-small cell lung cancer. The purpose of this study was to analyse the survival outcome and toxicity data of using hypofractionated chemoradiation. MATERIALS AND METHODS: One hundred patients were treated from June 2011 to November 2016. Treatment consisted of 55 Gy in 20 daily fractions concurrently with split-dose cisplatin vinorelbine chemotherapy over 4 weeks followed by two cycles of cisplatin vinorelbine only. Survival was estimated using Kaplan-Meier and Cox regression was carried out for known prognostic factors. A systematic search of literature was conducted using Medline, Embase and Cochrane databases and relevant references included. RESULTS: In total, 97% of patients completed radiotherapy and 73% of patients completed all four cycles of chemotherapy. One patient died of a cardiac event during consolidative chemotherapy. There were two cases of grade 4 toxicities (one sepsis, one renal impairment). Grade 3 toxicities included nausea/vomiting (17%), oesophagitis (15%), infection with neutropenia (12%) and pneumonitis (4%). Clinical benefit was seen in 86%. Two-year progression-free survival and overall survival rates were 49% and 58%, respectively. The median progression-free survival and overall survival were 23.4 and 43.4 months, respectively. The only significant prognostic factor was the number of chemotherapy cycles received (P = 0.02). The systematic review identified 13 relevant studies; a variety of regimens were assessed with variable reporting of outcomes and toxicity but with overall an improvement in survival over time. CONCLUSION: Our experience compared with the original phase II trial showed improved treatment completion rates and survival with acceptable morbidity. With appropriate patient selection this regimen is an effective treatment option for locally advanced non-small cell lung cancer. This study helps to benchmark efficacy and toxicity rates while considering the addition of new agents to hypofractionated concurrent chemoradiotherapy. The agreement of a standard regimen for assessment in future trials would be beneficial.

Interferon-gamma response to the treatment of active pulmonary and extra-pulmonary tuberculosis.

BACKGROUND: Interferon-gamma (IFN-γ) release assays (IGRAs) are used to diagnose tuberculosis (TB) but not to measure treatment response. OBJECTIVE: To measure IFN-γ response to active anti-tuberculosis treatment. DESIGN: Patients from the Henan Provincial Chest Hospital, Henan, China, with TB symptoms and/or signs were enrolled into this prospective, observational cohort study and followed for 6 months of treatment, with blood and sputum samples collected at 0, 2, 4, 6, 8, 16 and 24 weeks. The QuantiFERON® TB-Gold assay was run on collected blood samples. Participants received a follow-up telephone call at 24 months to determine relapse status. RESULTS: Of the 152 TB patients enrolled, 135 were eligible for this analysis: 118 pulmonary (PTB) and 17 extra-pulmonary TB (EPTB) patients. IFN-γ levels declined significantly over time among all patients (P = 0.002), with this decline driven by PTB patients (P = 0.001), largely during the initial 8 weeks of treatment (P = 0.019). IFN-γ levels did not change among EPTB patients over time or against baseline culture or drug resistance status. CONCLUSION: After 6 months of effective anti-tuberculosis treatment, IFN-γ levels decreased significantly in PTB patients, largely over the initial 8 weeks of treatment. IFN-γ concentrations may offer some value for monitoring anti-tuberculosis treatment response among PTB patients.

Myogenic transcription factors regulate pro-metastatic miR-182.

Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression.

Second toe proximal phalanx interposition bone graft to correct a failed Keller's arthroplasty. A new technique.

We present a case report of a novel salvage technique for a failed Keller's arthroplasty using nonvascularised phalanx transfer from the second toe to the hallux on the same foot. The technique restores length, function and relieves pain.

Validation of novel imaging methodologies for use as cancer clinical trial end-points.

The success or failure of a clinical trial, of any phase, depends critically on the choice of an appropriate primary end-point. In the setting of phases II and III cancer clinical trials, imaging end-points have historically, and continue presently to play a major role in determining therapeutic efficacy. The primary goal of this paper is to discuss the validation of imaging-based markers as end-points for phase II clinical trials of cancer therapy. Specifically, we outline the issues that must be considered, and the criteria that would need to be satisfied, for an imaging end-point to supplement or potentially replace RECIST- defined tumour status as a phase II clinical trial end-point. The key criteria proposed to judge the utility of a new end-point primarily relate to its ability to accurately and reproducibly predict the eventual phase III end-point for treatment effect, which is usually assessed by a difference between two arms on progression free or overall survival, both at the patient and more importantly at the trial level. As will be demonstrated, the level of evidence required to formally and fully validate a new imaging marker as an appropriate end-point for phase II trials is substantial. In many cases, this level of evidence will only become available by conducting a series of coordinated prospectively designed multicentre clinical trials culminating in a formal meta-analysis. We also include a discussion of situations where flexibility may be required, relative to the ideal rigorous evaluation, to accommodate inevitable real-world feasibility constraints.

Lessons learned from independent central review.

Independent central review (ICR) is advocated by regulatory authorities as a means of independent verification of clinical trial end-points dependent on medical imaging, when the data from the trials may be submitted for licensing applications [Food and Drug Administration. United States food and drug administration guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Rockville, MD: US Department of Health and Human Services; 2007; Committee for Medicinal Products for Human Use. European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) guideline on the evaluation of anticancer medicinal products in man. London, UK: European Medicines Agency; 2006; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-492 (oxaliplatin). Rockville, MD: US Department of Health and Human Services; 2002; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 21-923 (sorafenib tosylate). Rockville, MD: US Department of Health and Human Services; 2005; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-065 (ixabepilone). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Drug Evaluation and Research. Approval package for application number NDA 22-059 (lapatinib ditosylate). Rockville, MD: US Department of Health and Human Services; 2007; United States Food and Drug Administration Center for Biologics Evaluation and Research. Approval package for BLA numbers 97-0260 and BLA Number 97-0244 (rituximab). Rockville, MD: US Department of Health and Human Services; 1997; United States Food and Drug Administration. FDA clinical review of BLA 98-0369 (Herceptin((R)) trastuzumab (rhuMAb HER2)). FDA Center for Biologics Evaluation and Research; 1998; United States Food and Drug Administration. FDA Briefing Document Oncology Drugs Advisory Committee meeting NDA 21801 (satraplatin). Rockville, MD: US Department of Health and Human Services; 2007; Thomas ES, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. JCO 2007(November):5210-7]. In addition, clinical trial sponsors have used ICR in Phase I-II studies to assist in critical pathway decisions including in-licensing of compounds [Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. JCO 2007(November):5180-6; Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. JCO 2007(August):3407-14; Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. JCO 2007(June):2171-7; Ghassan KA, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. JCO 2006(September):4293-300; Boué F, Gabarre J, GaBarre J, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. JCO 2006(September):4123-8; Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. JCO 2006(July):3354-60; Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. JCO 2006(June):2502-12; Jaffer AA, Lee FC, Singh DA, et al. Multicenter phase II trial of S-1 plus cisplatin in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma. JCO 2006(February):663-7; Bouché O, Raoul JL, Bonnetain F, et al. Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Fédération Francophone de Cancérologie Digestive Group Study-FFCD 9803. JCO 2004(November):4319-28]. This article will focus on the definition and purpose of ICR and the issues and lessons learned in the ICR setting primarily in Phase II and III oncology studies. This will include a discussion on discordance between local and central interpretations, consequences of ICR, reader discordance during the ICR, operational considerations and the need for specific imaging requirements as part of the study protocol.

New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

BACKGROUND: Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. FUTURE WORK: A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.

Recommendations for the assessment of progression in randomised cancer treatment trials.

Progression-free survival (PFS) is an increasingly important end-point in cancer drug development. However, several concerns exist regarding the use of PFS as a basis to compare treatments. Unlike survival, the exact time of progression is unknown, so progression times might be over-estimated (or under-estimated) and, consequently, bias may be introduced when comparing treatments. In addition, the assessment of progression is subject to measurement variability which may introduce error or bias. Ideally trials with PFS as the primary end-point should be randomised and, when feasible, double-blinded. All patients eligible for study should be evaluable for the primary end-point and thus, in general, have measurable disease at baseline. Appropriate definitions should be provided in the protocol and data collected on the case-report forms, if patients with only non-measurable disease are eligible and/or clinical, or symptomatic progression are to be considered progression events for analysis. Protocol defined assessments of disease burden should be obtained at intervals that are symmetrical between arms. Independent review of imaging may be of value in randomised phase II trials and phase III trials as an auditing tool to detect possible bias.

Evaluation of delivery of enhanced diabetes care to patients of South Asian ethnicity: the United Kingdom Asian Diabetes Study (UKADS).

AIMS: We tested the hypothesis that enhanced care for diabetes, tailored to the needs of the South Asian community with Type 2 diabetes, would improve risk factors for diabetic vascular complications and ultimately reduce morbidity and mortality. PATIENTS AND METHODS: The study was a cluster randomized controlled trial (RCT) with general practice the unit of randomization. Six West Midlands general practices with a high proportion of South Asian patients were randomized to 'enhanced care' using Asian link workers and extra community diabetes specialist nurse sessions (intervention) or continued standard practice care (control). RESULTS: Of 401 patients recruited to the study, 361 (90%), comprising 178 from Coventry and 183 from Birmingham were eligible and included in the analyses. The mean age at baseline (standard deviation, SD) was 58.9 (11.7 years) with median (interquartile range; IQR) duration of diabetes 6.5 (3-11) years. At one year follow-up there was a significant difference in reduction of systolic (4.6 mmHg, P = 0.035) and diastolic blood pressure (3.4 mmHg, P = 0.003) and total cholesterol (0.4 mmol/l, P = 0.005), comparing the intervention and control groups. After adjusting for baseline measurement and age, only differential reduction in diastolic blood pressure remained significant. There was no significant change in HbA(1c) and no difference between the groups. CONCLUSIONS: Using link workers and extra community diabetes specialist nurse input together with treatment protocols in primary care might prove a useful strategy in working towards NSF targets for diabetes management. In this study, small reductions in blood pressure and cholesterol were achieved. Improvement in glycaemic control may require longer and possibly different strategies. Further research is required to evaluate fully the effectiveness, including the costs and longer term sustainability of culturally sensitive initiatives.

Factors affecting the extent of dermal absorption of solvent vapours: a human volunteer study.

OBJECTIVES: We have previously reported that solvent vapours can be absorbed through the skin and that the extent varies markedly and depends on the chemical. For some chemicals, the extent of absorption is significant, e.g. for 1-methoxy-2-propanol dermal absorption accounts for up to 14% of the total absorbed dose after 8 h exposure at the OES. We have conducted a second study using 2-butoxyethanol to investigate the influence of temperature, humidity and clothing on the dermal absorption of vapours. As for the first study, the extent of dermal absorption was determined by biological monitoring to measure the resultant body burden of the chemical. METHODS: Four volunteers were exposed on nine occasions. For eight of these exposures they wore air-fed half-masks to supply clean air for the inhalation route. The 'baseline' conditions (one 'whole body' and one 'skin only' exposure) were 25 degrees C, 40% relative humidity with volunteers wearing shorts and T-shirt. For each subsequent exposure, a single parameter was changed: humidity (60%, 65%), temperature (20 degrees C, 30 degrees C) or clothing (minimal and overalls). Finally, a 'industrial scenario' was conducted where volunteers wore overalls over their shorts and T-shirts and environmental conditions reflected high temperature and high humidity (30 degrees C, 60%), such as might be encountered in a tank-cleaning operation or similar. RESULTS: Results show that 'baseline' dermal absorption of 2-butoxyethanol vapour was, on average, 11% of the total absorbed dose. Higher temperature (30 degrees C, mean 14%, P = 0.03) and greater humidity (65% RH, mean 13%, P = 0.1) increased dermal absorption. The wearing of whole-body overalls did not attenuate absorption (mean 10%). By combining several factors together in the 'industrial scenario', dermal absorption of vapours was significantly increased with a mean of 39% of the total absorbed dose. CONCLUSIONS: The work has shown that dermal absorption of vapours can be significant and that environmental conditions may affect the absorption. Some types of protective clothing may not be suitable to reduce absorption. The possibility of dermal absorption of vapours should be considered particularly for workers in high vapour concentration conditions where control of exposure relies on respiratory protection.

Fine needle aspiration cytology of mucinous cystadenocarcinoma of the lung: report of a case with radiographic and histologic correlation.

BACKGROUND: Mucinous cystadenocarcinoma of the lung is an uncommon tumor. Because it contains relatively few neoplastic cells relative to the amount of mucin produced, diagnosis of this entity, particularly on small specimens, is exceedingly difficult. CASE: The diagnosis of adenocarcinoma was made on transthoracic fine needle aspiration from a patient with a right upper lobe lung mass. Abundant mucoid material suggested a mucin-producing neoplasm. Histopathology revealed a mucinous cystadenocarcinoma with focal mucinous bronchoalveolar carcinoma. CONCLUSION: The presence of copious extracellular mucin in fine needle aspirates from the lung otherwise diagnostic of adenocarcinoma should raise the possibility of a mucinous tumor. In particular, the diagnosis of mucinous cystadenocarcinoma may be suggested in cases that have a cystic appearance on imaging studies.

Fine-needle aspiration diagnosis of medulloblastoma metastatic to the pelvis.

A 25-yr-old male presented with a cerebellar mass, underwent a suboccipital craniotomy, and was diagnosed with medulloblastoma. Six months later he developed a large mass in the right iliac crest. Fine-needle aspiration biopsy (FNAB) confirmed the diagnosis of metastatic medulloblastoma. The diagnosis of metastatic medulloblastoma is usually suspected clinically or radiographically, and is uncommonly confirmed by cytologic evaluation. Here we report on a rare case of FNAB used to diagnose metastatic medulloblastoma.

Diagnosis of hematopoietic processes by fine-needle aspiration in conjunction with flow cytometry: A review of 127 cases.

Although fine-needle aspiration (FNA) is accepted as the method of choice for the initial evaluation of lymph nodes for metastatic carcinomas, its utility as the initial diagnostic procedure for hematopoietic processes is less established. We review our experience over a 3-year period with 127 FNA cases accompanied by flow cytometric (FC) analysis from 117 patients. Fifty cases had subsequent histologic examination. A hematopoietic process was identified in 85 cases, a reactive process in 27 cases, and a nonhematopoietic process in 15 cases. All non-Hodgkin lymphomas (NHL) were B-cell processes except for one T-cell lymphoma. By FNA/FC, 44 NHL had sufficient findings to be subtyped; of these, 27 had subsequent histologic examination. The correlation between the FNA/FC and histologic classification in these cases of NHL was 100%. One case was insufficient for diagnosis by FNA and six cases were inadequate for FC. We conclude that FNA in conjunction with FC can be used as the initial diagnostic approach for both primary and recurrent hematopoietic processes.

Fine-needle aspiration cytology of pseudosarcomatous lesions of soft tissue.

Pseudosarcomatous lesions are benign neoplasms of the musculoskeletal system that are likely to be misdiagnosed as malignant, based on clinical and histologic features. These include soft-tissue "tumors" considered reactive or reparative lesions such as nodular fasciitis and myositis ossificans. Also included in the "pseudosarcoma" category are benign neoplasms which show "pseudoanaplastic" cytologic atypia. The latter include lipoma, leiomyoma, angiomyolipoma, and benign peripheral nerve-sheath tumors. These neoplasms, particularly the reparative processes and the nerve sheath tumors, are increasingly being subjected to initial diagnosis by fine-needle aspiration cytology. Even by conventional cytology this group of lesions represents a well-known pitfall for the diagnostic pathologist. We review some cytologic features: repair-like change, cohesion of cellular fragments, and presence of "normal" elements in the aspirate, which may help the cytopathologist avoid misdiagnosis of these notoriously difficult entities.