Role of Adjuvant Chemotherapy After Curative Resection in Stage II and III Rectal Cancer.

INTRODUCTION: Patients with resected locally advanced rectal cancer (LARC) and an incomplete total mesorectal excision (TME) have worse oncologic outcomes. The associations between TME grade, adjuvant therapy receipt, and oncologic outcomes have not been well-studied. We aimed to determine the association between adjuvant chemotherapy and oncologic outcomes in patients who underwent neoadjuvant chemoradiation (CRT) or short-course radiotherapy (SCRT) followed by proctectomy and to evaluate this association stratified by TME grade. MATERIALS AND METHODS: We analyzed a retrospective multi-institutional cohort of primary LARC patients diagnosed between 2010 and 2018 who received neoadjuvant CRT/SCRT followed by proctectomy. Complete TME was defined as complete mesorectal excision, and noncomplete TME was defined as near-complete or incomplete TME. We used adjusted Cox proportional hazards regression to test the association between adjuvant chemotherapy and mortality or locoregional recurrence (LRR) across groups. RESULTS: We identified 746 eligible patients. On final pathology, 101 (13.5%) had noncomplete and 645 (86.5%) had complete TME. Rates of adjuvant chemotherapy receipt were similar between noncomplete and complete TME groups (70.3% and 69.5%, respectively). Mean follow-up interval was 35 mo. Adjuvant chemotherapy was associated with lower risk of mortality (HR 0.27, 95% CI 0.19-0.39, P < 0.001); the same association existed when stratifying patients by TME grade. For patients with a complete TME, adjuvant chemotherapy was associated with lower LRR (HR 0.08, 95% CI 0.01-0.56, P = 0.01). The LRR model for the noncomplete TME group did not converge due to few captured recurrences. CONCLUSIONS: These data show an association between adjuvant chemotherapy and positive outcomes in LARC patients receiving neoadjuvant CRT/SCRT followed by proctectomy.

Comparative proteomic analysis of ventricular and cisternal cerebrospinal fluid in haemorrhagic stroke patients.

BACKGROUND: Analysis of cerebrospinal fluid (CSF) using mass spectrometry is a relatively novel analytical tool, and comparisons of ventricular and cisternal proteomes are yet to be performed. This may have implications for clinical medicine, particularly in demonstrating continuity of the ventricular system with preserved flow in the presence of ventricular blood. Other uses include the identification of novel biomarkers, including for diagnosis of subarachnoid haemorrhage and of aetiology. The primary objective was therefore to characterise and compare the proteomes of ventricular and CSF after haemorrhagic stroke. METHODS: Paired CSF samples were prospectively collected from the optico-carotid cistern and the frontal horn of the lateral ventricle at the time of craniotomy and clipping in 8 patients with haemorrhagic stroke. Six patients had an aneurysmal subarachnoid haemorrhage (aSAH) from a ruptured saccular aneurysm, one patient had an aSAH after rupture of a mycotic aneurysm and one patient had a spontaneous intracerebral haemorrhage (IPH) with an adjacent unruptured saccular aneurysm. Samples were processed and proteins identified and quantified using data-dependent liquid chromatography tandem mass spectrometry (DDA LC-MSMS). RESULTS: There was no systematic difference between the cisternal and ventricular proteomes. However, blinded principal component analysis (PCA) of the cisternal and ventricular samples separated patients according to pathophysiology. Additionally CSF D-Dimer levels were not detected in the IPH patient but were reliably measured in aSAH patients. CONCLUSIONS: Ventricular CSF is representative of cisternal CSF after aSAH. CSF proteomic PCA analysis can distinguish between haemorrhage types. CSF D-dimer levels may represent a novel diagnostic marker for aSAH. Label free DDA LC-MSMS CSF analysis may inform possible biomarkers.

Trace residue identification, characterization, and longitudinal monitoring of the novel synthetic opioid ß-U10, from discarded drug paraphernalia.

Empirical data regarding dynamic alterations in illicit drug supply markets in response to the COVID-19 pandemic, including the potential for introduction of novel drug substances and/or increased poly-drug combination use at the "street" level, that is, directly proximal to the point of consumption, are currently lacking. Here, a high-throughput strategy employing ambient ionization-mass spectrometry is described for the trace residue identification, characterization, and longitudinal monitoring of illicit drug substances found within >6,600 discarded drug paraphernalia (DDP) samples collected during a pilot study of an early warning system for illicit drug use in Melbourne, Australia from August 2020 to February 2021, while significant COVID-19 lockdown conditions were imposed. The utility of this approach is demonstrated for the de novo identification and structural characterization of ß-U10, a previously unreported naphthamide analog within the "U-series" of synthetic opioid drugs, including differentiation from its α-U10 isomer without need for sample preparation or chromatographic separation prior to analysis. Notably, ß-U10 was observed with 23 other drug substances, most commonly in temporally distinct clusters with heroin, etizolam, and diphenhydramine, and in a total of 182 different poly-drug combinations. Longitudinal monitoring of the number and weekly "average signal intensity" (ASI) values of identified substances, developed here as a semi-quantitative proxy indicator of changes in availability, relative purity and compositions of street level drug samples, revealed that increases in the number of identifications and ASI for ß-U10 and etizolam coincided with a 50% decrease in the number of positive detections and an order of magnitude decrease in the ASI for heroin.

Early Warning System for Illicit Drug Use at Large Public Events: Trace Residue Analysis of Discarded Drug Packaging Samples.

Inspired by Locard's exchange principle, which states "every contact leaves a trace", a trace residue sampling strategy has been developed for the analysis of discarded drug packaging samples (DPS), as part of an early warning system for illicit drug use at large public events including music/dance festivals. Using direct analysis in real time/mass spectrometry and tandem mass spectrometry, rapid and high-throughput identification and characterization of a wide range of illicit drugs and adulterant substances was achieved, including in complex polydrug mixtures and at low relative ion abundances. A total of 1362 DPS were analyzed either off-site using laboratory-based instrumentation or on-site and in close to real time using a transportable mass spectrometer housed within a mobile analytical laboratory, with each analysis requiring less than 1 min per sample. Of the DPS analyzed, 92.2% yielded positive results for at least one of 15 different drugs and/or adulterants, including cocaine, MDMA, and ketamine, as well as numerous novel psychoactive substances (NPS). Also, 52.6% of positive DPS were found to contain polydrug mixtures, and a total of 42 different drug and polydrug combinations were observed throughout the study. For analyses performed on-site, reports to key stakeholders including event organizers, first aid and medical personnel, and peer-based harm reduction workers could be provided in as little as 5 min after sample collection. Following risk assessment of the potential harms associated with their use, drug advisories or alerts were then disseminated to event staff and patrons and subsequently to the general public when substances with particularly toxic properties were identified.

Advanced chronic liver disease in the last year of life: a mixed methods study to understand how care in a specialist liver unit could be improved.

OBJECTIVE: To identify the limitations in palliative care provision in the last year of life for people with liver cirrhosis and potential barriers to and enablers of palliative care. DESIGN: Mixed methods, including a retrospective case note review, qualitative focus groups and individual interviews. SETTING: A tertiary referral liver centre in the south of England (UK). PARTICIPANTS: Purposively selected case notes of 30 people with cirrhosis who attended the tertiary referral liver centre and died during an 18-month period; a purposive sample of 22 liver health professionals who participated in either focus groups or individual interviews. PRIMARY AND SECONDARY OUTCOMES: Data collected from case notes included hospital admissions, documented discussions of prognosis and palliative care provision. Qualitative methods explored management of people with cirrhosis, and barriers to and enablers of palliative care. RESULTS: Participants had high rates of hospital admissions and symptom burden. Clinicians rarely discussed prognosis or future care preferences; they lacked the skills and confidence to initiate discussions. Palliative care provision occurred late because clinicians were reluctant to refer due to their perception that reduced liver function is reversible, poor understanding of the potential of a palliative approach; palliative care was perceived negatively by patients and families. CONCLUSIONS: People dying with cirrhosis have unpredictable trajectories, but share a common pathway of frequent admissions and worsening symptoms as death approaches. The use of clinical tools to identify the point of irreversible deterioration and joint working between liver services and palliative care may improve care for people with cirrhosis.

Palliative care for cirrhosis: a UK survey of health professionals' perceptions, current practice and future needs.

OBJECTIVE: To determine the knowledge and practice patterns of a UK cohort of relevant healthcare professionals (HCPs) about delivering palliative care in cirrhosis, and to inform priorities for future research. DESIGN: An on-line questionnaire survey with closed and open responses. SETTING: HCPs identified from the mailing list of special interest groups in hepatology and gastroenterology (liver), general practice and specialist palliative care (SPC) across the UK. RESULTS: Of the 6181 potential contacts identified, 517 HCPs responded. Most believed a role exists for SPC in caring for people with cirrhosis, but many SPC HCPs felt ill prepared to provide good care to those facing death. Further training was needed in managing liver-related symptoms, symptom control and end of life issues. All HCP groups wished to increase community provision of palliative care support, but many general practitioners felt unable to manage advanced cirrhosis in the community. There were differences in the optimal trigger for SPC referral with liver HCPs less likely to refer at symptom deterioration. Prognostication, symptom management and service configuration were key areas identified for future research. CONCLUSIONS: All who responded acknowledged the role of SPC in caring for those dying with cirrhosis and need for further training to improve confidence and enable joint working between SPC, general practice and liver teams. Low response rates make it difficult to generalise these findings, which require further validation.

Narratives of continuity among older people with late stage chronic kidney disease who decline dialysis.

Chronic and life-threatening conditions are widely thought to shatter the lives of those affected. In this article, we examine the accounts of 19 older people diagnosed with late stage chronic kidney disease who declined dialysis. Accounts were collected through in-depth interview in the United Kingdom (March-November, 2010). Drawing on a phenomenological approach, we focus particularly on the embodied and lived experience of the condition and on how participants constructed treatment modalities and approached treatment choice. We look toward contemporary elaborations of the conceptual framework of biographical disruption to illustrate how participants managed to contain the intrusion of illness and maintain continuity in their lives. We argue that three interactive phenomena mitigated the potential for disruption and allowed participants to maintain continuity: (a) the framing of illness as "old age"; (b) the prior experience of serious illness; and (c) the choice of the treatment with the least potential for disruption. We conclude that a diagnosis of chronic illness in late life does not inevitably shatter lives or engender biographical disruption. Instead, people are able to construct continuity owing to complex narrative interpretations of diagnosis, sensation and treatment choices.

The experiences of close persons caring for people with chronic kidney disease stage 5 on conservative kidney management: contested discourses of ageing.

Chronic kidney disease stage 5 is a global health challenge in the context of population ageing across the world. The range of treatment options available to patients at all ages has increased and includes transplantation and dialysis. However, these options are often seen as inappropriate for older frailer patients who are now offered the option of conservative kidney management, which is presented as a non-invasive alternative to dialysis, involving symptom management and addressing psychosocial needs. In this study, we conducted qualitative interviews with 26 close persons caring for someone with chronic kidney disease stage 5 in the United Kingdom to investigate how conservative kidney management interacted with implicit ideas of ageing, in both the experience of conservative kidney management and the understanding of the prognosis and future care of the kidney disease. Our findings highlighted participant confusion about the nature of conservative kidney management, which stems from an initial lack of clarity about how conservative kidney management differed from conventional treatments for chronic kidney disease stage 5. In particular, some respondents were not aware of the implicit palliative nature of the intervention or indeed the inevitable end-of-life issues. Although these findings can be situated within the context of communication failure, we would further argue that they also bring to the surface tensions in the discourses surrounding ageing and old age, drawing on the use of a 'natural' and a 'normal' paradigm of ageing. In the context of chronic kidney disease stage 5, more patients are being dialysed at older ages, but conservative kidney management is being advanced as a better option than dialysis in terms of quality of life and experience. However, in doing so, conservative kidney management implicitly draws on a notion of older age that echoes natural ageing rather than advocate a more interventionist approach. The role of discourses of ageing in the provision of treatments for conservative kidney management has not previously been acknowledged, and this article addresses this gap.

Rehabilitation in advanced, progressive, recurrent cancer: a randomized controlled trial.

CONTEXT: Two million people across the U.K. are living with cancer, often experienced as a long-term condition. They may have unmet needs after active treatment. Rehabilitation aims to address these needs, maximize psychological and physical function, and enable minimum dependency regardless of life expectancy. OBJECTIVES: We aimed to test, in a randomized controlled trial, the clinical and cost effectiveness of a rehabilitation intervention for patients with advanced, recurrent cancer. METHODS: We conducted a two-arm, wait-list control, randomized trial of a complex rehabilitation intervention delivered by a hospice-based multidisciplinary team vs. usual care for active, progressive, recurrent hematological and breast malignancies, with a follow-up at three months. The primary outcome was the psychological subscale of the Supportive Care Needs Survey (SCNS). Secondary outcomes were other domains of the SCNS, psychological status, continuity of care, quality of life, and resource use. RESULTS: Forty-one participants were enrolled and 36 completed the trial. The primary outcome was significantly lower in the intervention arm (adjusted difference -16.8, 95% CI -28.34 to -5.3; P = 0.006). The SCNS physical and patient care subscales (-14.2, 95% CI -26.2 to -2.2; P = 0.02 and -7.4, 95% CI -13.7 to -1.1; P = 0.02, respectively) and self-reported health state (12.8, 95% CI 3.2 to 22.4; P = 0.01) also differed significantly. The incremental cost-effectiveness ratio was £19,390 per quality-adjusted life year. CONCLUSION: This intervention significantly reduced the unmet needs of cancer survivors and it is likely that it is cost-effective. Despite small numbers, the main effect size was robust. We recommend implementation alongside evaluation in wider clinical settings and patient populations.

Food for life, love and hope: an exemplar of the philosophy of palliative care in action.

The World Health Organization's (1990) definition of palliative care describes an holistic approach to care for patients with advanced progressive illness. Issues relating to nutrition, lack of appetite and the subsequent weight loss the individuals may experience present a challenge to all concerned with providing both formal and informal care to this patient group. The philosophy of palliative care requires a multidisciplinary approach to the constellation of issues and problems related to food that are faced by both patients and carers in receipt of palliative care. The literature in this area is mainly related to those patients with a cancer diagnosis. The developing role of palliative care in patients with non-malignant disease provides further challenges for health care professionals. The present paper aims to reflect an entire philosophical approach to care through an examination of one area of practice.