Search

Introduction: Pelvic exenteration provides significant survival benefits for selected patients diagnosed with locally advanced rectal cancer. However, in-hospital postoperative morbidity such as abdominal abscess, sepsis, and anastomotic leak remain highly prevalent, which can have short/long-term impacts on patient quality of life (QoL). The aim of this study was to determine the influence of postoperative morbidity on QoL outcomes in patients following pelvic exenteration., Methods: This prospective cohort study included patients who underwent pelvic exenteration at a tertiary teaching hospital in Sydney, between 2008 and 2023. QoL measures were collected at baseline, 6, 12, 18, 24, 36, 48, and 60 months using the short-form 36 (SF-36v2) survey. The predictors included variables relating to postoperative morbidity, including hospital and ICU length of stay (LOS), post-discharge mortality and the number of postoperative complications. Mixed-effects analyses were used to determine the influence of these postoperative outcomes on physical and mental QoL trajectories., Results: This study included 674 patients, with a median age of 61 years. Shorter hospital and ICU LOS, and fewer or no postoperative complications were associated with higher physical QoL scores across all time points. Conversely, postoperative morbidity did not exhibit a significant impact on mental QoL scores. Furthermore, there was a longitudinal improvement in mental QoL outcomes compared to baseline, independent of postoperative morbidity., Conclusion: Postoperative morbidity significantly impacted physical QoL outcomes after pelvic exenteration, whereas mental QoL outcomes were not influenced. Interventions aimed at mitigating postoperative morbidity may hold the potential to enhance long-term QoL outcomes following pelvic exenteration., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Pre-operative physical status and its association with post-operative surgical outcomes is poorly understood in patients with peritoneal malignancy who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). The aims of this study were to determine the pre-operative physical function in patients having CRS-HIPEC and investigate the association between physical function and post-operative outcomes., Patients and Methods: Patients undergoing CRS-HIPEC between 2017 and 2021 were recruited at a single quaternary referral hospital in Sydney, Australia. The primary physical function measures were the 6-min walk test (6MWT) and the five-times sit to stand test (5STS). Data were collected pre-operatively and at post-operative day 10, and were analysed according to pre-operative patient characteristics and post-operative outcomes such as length of hospital stay (LOS) and complications., Results: The cohort of patients that participated in functional assessments consisted of 234 patients, with a median age of 56 years. Patients having CRS-HIPEC performed worse on the 6MWT pre-operatively compared with the general Australian population (p < 0.001). Post-operatively, these patients experienced a further deterioration in 6MWT and 5STS performance and the degree of the post-operative decline in function was associated with post-operative morbidity. A higher level of pre-operative physical function was associated with shorter LOS and minor post-operative complications., Conclusions: Patients who have undergone CRS-HIPEC were functionally impaired pre-operatively compared with the general population and experience a further deterioration of physical function post-operatively. A higher level of pre-operative physical function is associated with minor post-operative morbidity, which is highly relevant for pre-operative optimisation of patients with cancer., (© 2022. Crown.)

Background: There is clinical uncertainty regarding an association between preoperative functional capacity of cancer patients, and postoperative outcomes. The aim of this systematic review and meta-analysis is to investigate whether poor performance on preoperative six-minute walk test (6MWT) or five-times sit to stand test (5STS) is associated with worse postoperative complication rates and prolonged length of hospital stay (LOS) in cancer patients., Methods: An electronic search was performed from earliest available record to 26th February 2021 in MEDLINE, Embase and AMED. Studies investigating the association between preoperative physical function (measured using either 6MWT or 5STS) and postoperative outcomes (complications and LOS) in patients with gastrointestinal, abdominal and pelvic cancers were included. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Where possible, summary odds ratios (OR) or mean differences (MD), and 95% confidence intervals (CI) were calculated using random-effect models., Results: Five studies (379 patients) were included, of which none utilized the 5STS. Overall, studies were rated as having low to moderate risk of bias. Higher preoperative performance on the 6MWT (≥400 m) was associated with low grade postoperative complications (OR = 0.38; 95% CI = 0.15-0.95) but was not associated with a shorter LOS (MD = 3.29; 95%CI = -1.07-7.66)., Conclusion: The available evidence suggests that in cancer patients, a higher preoperative functional capacity may be associated with reduced postoperative complications. Conversely, there is no significant association between preoperative function and LOS. Further high-quality studies are needed in this area, including studies involving 5STS., (© 2022 Royal Australasian College of Surgeons.)

Aim: Postoperative functional outcomes following pelvic exenteration surgery for treatment of advanced or recurrent pelvic malignancies are poorly understood. The aim of this study was to determine the short-term functional outcomes following pelvic exenteration surgery using objective measures of physical function., Method: Patients undergoing pelvic exenteration surgery between January 2017 and May 2020 were recruited at a single quaternary referral hospital in Sydney, Australia. The primary measures were the 6-min walk test (6MWT) and the five times sit to stand (5STS) test. Data were collected at baseline (preoperatively), 10 days postoperatively and at discharge from hospital, and were analysed according to tumour type, extent of exenteration, sacrectomy, length of hospital stay, major nerve resection and postoperative complications., Results: The cohort of patients that participated in functional assessments consisted of 135 patients, with a median age of 61 years. Pelvic exenteration patients had a reduced 6MWT distance preoperatively compared to the general population (P < 0.001). Following surgery, we observed a further decrease in 6MWT distance (P < 0.001) and an increase in time to complete 5STS (P < 0.001) at postoperative day 10 compared to baseline, with a slight improvement at discharge. There were no differences in 6MWT and 5STS outcomes between patients based on comparisons of surgical and oncological factors., Conclusion: Pelvic exenteration patients are functionally impaired in the preoperative period compared to the general population. Surgery causes a further reduction in physical function in the short term; however, functional outcomes are not impacted by tumour type, extent of exenteration, sacrectomy or nerve resection., (© 2021 Association of Coloproctology of Great Britain and Ireland.)

Bidirectional interplay between the peripheral immune and nervous systems plays a crucial role in maintaining homeostasis and responding to noxious stimuli. This crosstalk is facilitated by a variety of cytokines, inflammatory mediators and neuropeptides. Dysregulation of this delicate physiological balance is implicated in the pathological mechanisms of various skin disorders and peripheral neuropathies. The skin is a highly complex biological structure within which peripheral sensory nerve terminals and immune cells colocalise. Herein, we provide an overview of the sensory innervation of the skin and immune cells resident to the skin. We discuss modulation of cutaneous immune response by sensory neurons and their mediators (e.g., nociceptor-derived neuropeptides), and sensory neuron regulation by cutaneous immune cells (e.g., nociceptor sensitization by immune-derived mediators). In particular, we discuss recent findings concerning neuroimmune communication in skin infections, psoriasis, allergic contact dermatitis and atopic dermatitis. We then summarize evidence of neuroimmune mechanisms in the skin in the context of peripheral neuropathic pain states, including chemotherapy-induced peripheral neuropathy, diabetic polyneuropathy, post-herpetic neuralgia, HIV-induced neuropathy, as well as entrapment and traumatic neuropathies. Finally, we highlight the future promise of emerging therapies associated with skin neuroimmune crosstalk in neuropathic pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Lowy, Makker and Moalem-Taylor.)

Peripheral nerve injuries caused by focal constriction are characterised by local nerve ischaemia, axonal degeneration, demyelination, and neuroinflammation. The aim of this study was to understand temporal changes in the excitability properties of injured motor axons in a mouse model of nerve constriction injury (NCI). The excitability of motor axons following unilateral sciatic NCI was studied in male C57BL/6J mice distal to the site of injury at the acute (6 hours-1 week) and chronic (up to 20 weeks) phases of injury, using threshold tracking. Multiple measures of nerve excitability, including strength-duration properties, threshold electrotonus, current-threshold relationship, and recovery cycle were examined using the automated nerve excitability protocol (TRONDNF). Acutely, injured motor axons developed a pattern of excitability characteristic of ischemic depolarisation. In most cases, the sciatic nerve became transiently inexcitable. When a liminal compound muscle action potential could again be recorded, it had an increase in threshold and latency, compared to both pre-injury baseline and sham-injured groups. These axons showed a greater threshold change in response to hyperpolarising threshold electrotonus and a significant upward shift in the recovery cycle. Mathematical modelling suggested that the changes seen in chronically injured axons involve shortened internodes, reduced myelination, and exposed juxtaparanodal fast K + conductances. The findings of this study demonstrate long-term changes in motor excitability following NCI (involving alterations in axonal properties and ion channel activity) and are important for understanding the mechanisms of neurapraxic injuries and traumatic mononeuropathies., (© 2021 Peripheral Nerve Society.)

Purpose: Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1-2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients., Methods: Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome., Results: Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices. Front and hind paws exhibited dose dependent and dramatic discoloration indicative of anaemia. Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia. Cytokines and chemokines within the spleen were significantly affected with temporal upregulation of IL-6, IL-1α and G-CSF and downregulation of IL-1β, IL-12p40, MIP-1β, IL-2 and RANTES. Flow cytometric analysis demonstrated alterations in splenocyte populations, including a significant reduction in CD45+ cells. Histological staining of the liver showed no evidence of sinusoidal obstructive syndrome but there were signs suggestive of extramedullary haematopoiesis., Conclusion: Chronic oxaliplatin treatment dose dependently induced haematological toxicity and splenomegaly characterised by numerous physiological and morphological changes, which occurred independently of sinusoidal obstructive syndrome., Competing Interests: The authors have declared that no competing interests exist.

Oxaliplatin chemotherapy produces acute changes in peripheral nerve excitability in humans by modulating voltage-gated Na + channel activity. However, there are few animal studies of oxaliplatin-induced neuropathy that demonstrate similar changes in excitability. In the present study, we measured the excitability of motor and sensory caudal nerve in C57BL/6 mice after oxaliplatin injections either systemically (intraperitoneal) or locally (intramuscular at the base of the tail). As opposed to intraperitoneal administration of oxaliplatin, a single intramuscular injection of oxaliplatin produced changes in both motor and sensory axons. In motor axons, oxaliplatin caused a greater change in response to long-lasting depolarization and an upward shift in the recovery cycle, particularly at 24 h [depolarizing threshold electrotonus (TEd) 10-20 ms, P = 0.0095; TEd 90-100 ms, P = 0.0056) and 48 h (TEd 10-20 ms, P = 0.02; TEd 90-100 ms, P = 0.04) posttreatment. Oxaliplatin treatment also stimulated the production of afterdischarges in motor axons. These changes were transient and showed dose dependence. Mathematical modeling demonstrated that these changes could be accounted for by slowing inactivation of voltage-gated Na + channels by 73.3% and reducing fast K + conductance by 47% in motor axons. In sensory axons, oxaliplatin caused an increase in threshold, a reduction in peak amplitude, and greater threshold changes to strong hyperpolarizing currents on days 4 and 8 . Thus, local administration of oxaliplatin produced clinically relevant changes in nerve excitability in mice and may provide an alternative approach for the study of acute oxaliplatin-induced neurotoxicity. NEW & NOTEWORTHY We present a novel mouse model of acute oxaliplatin-induced peripheral neurotoxicity that is comparable to clinical observations. Intramuscular injection of oxaliplatin produced acute changes in motor nerve excitability that were attributable to alterations in Na + and K + channel activity. Conversely, we were unable to show any significant changes in nerve excitability with systemic intraperitoneal injections of oxaliplatin. This study suggests that local intramuscular injection is a valid approach for modelling oxaliplatin-induced peripheral neuropathy in animals.

Sensory problems such as neuropathic pain are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the CNS. Regulatory T (Treg) cells are critical for maintaining immune homeostasis, but their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunized female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin-35 (IL-35) significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg-cell dependent and associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes and reduced monocyte infiltration in the trigeminal afferent pathway. We present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE independently of motor symptoms by decreasing neuroinflammation and increasing myelination. SIGNIFICANCE STATEMENT Pain is a highly prevalent symptom affecting the majority of multiple sclerosis (MS) patients and dramatically affects overall health-related quality of life; however, this is a research area that has been largely ignored. Here, we identify for the first time a role for regulatory T (Treg) cells and interleukin-35 (IL-35) in suppressing facial allodynia and facial grimacing in animals with experimental autoimmune encephalomyelitis (EAE). We demonstrate that spinal delivery of Treg cells and IL-35 reduces pain associated with EAE by decreasing neuroinflammation and increasing myelination independently of motor symptoms. These findings increase our understanding of the mechanisms underlying pain in EAE and suggest potential treatment strategies for pain relief in MS., (Copyright © 2019 the authors 0270-6474/19/392326-21$15.00/0.)

Non-invasive nerve excitability techniques have provided valuable insight into the understanding of neurological disorders. The widespread use of mice in translational research on peripheral nerve disorders and by pharmaceutical companies during drug development requires valid and reliable models that can be compared to humans. This study established a novel experimental protocol that enables comparative assessment of the excitability properties of motor and sensory axons at the same site in mouse caudal nerve, compared the mouse data to data for motor and sensory axons in human median nerve at the wrist, and constructed a mathematical model of the excitability of mouse axons. In a separate study, ischaemia was employed as an experimental manoeuvre to test the translational utility of this preparation. The patterns of mouse sensory and motor excitability were qualitatively similar to human studies under normal and ischaemic conditions. The most conspicuous differences between mouse and human studies were observed in the recovery cycle and the response to hyperpolarization. Modelling showed that an increase in temperature in mouse axons could account for most of the differences in the recovery cycle. The modelling also suggested a larger hyperpolarization-activated conductance in mouse axons. The kinetics of this conductance appeared to be much slower raising the possibility that an additional or different hyperpolarization-activated cyclic-nucleotide gated (HCN) channel isoform underlies the accommodation to hyperpolarization in mouse axons. Given a possible difference in HCN isoforms, caution should be exercised in extrapolating from studies of mouse motor and sensory axons to human nerve disorders., (© 2018 Peripheral Nerve Society.)

Introduction: Muscle wasting is a frequent, debilitating complication of cancer. The impact of colorectal cancer chemotherapeutic oxaliplatin on the development of muscle loss and associated molecular changes is of clinical importance., Methods: C57BL/6J male mice were treated with oxaliplatin. Total body weights were measured and behavioral studies performed. Hindlimb muscle weights (gastrocnemius and soleus) were recorded in conjunction with gene and protein expression analysis., Results: Oxaliplatin-treated mice displayed reduced weight gain and behavioral deficits. Mice treated over a shorter course had significantly increased STAT3 phosphorylation in gastrocnemius muscles. Mice receiving extended oxaliplatin treatment demonstrated reduced hindlimb muscle mass with upregulation of myopathy-associated genes Foxo3, MAFbx, and Bnip3., Discussion: The findings suggest that oxaliplatin treatment can directly disrupt skeletal muscle homeostasis and promote muscle loss, which may be clinically relevant in the context of targeting fatigue and weakness in cancer patients. Muscle Nerve 57: 650-658, 2018., (© 2017 Wiley Periodicals, Inc.)

Connexin43 (Cx43) hemichannels in spinal cord astrocytes are implicated in the maintenance of neuropathic pain following peripheral nerve injury. Peptide5 is a Cx43 mimetic peptide that blocks hemichannels. In this study, we investigated the effects of spinal delivery of Peptide5 on mechanical pain hypersensitivity in two mouse models of neuropathic pain, peripheral nerve injury and chemotherapy-induced peripheral neuropathy (CIPN). We demonstrated that 10days following a chronic constriction injury (CCI) of the sciatic nerve, Cx43 expression, co-localised predominantly with astrocytes, was increased in the ipsilateral L3-L5 lumbar spinal cord. An intrathecal injection of Peptide5 into nerve-injured mice, on day 10 when pain was well-established, caused significant improvement in mechanical pain hypersensitivity 8h after injection. Peptide5 treatment resulted in significantly reduced Cx43, and microglial and astrocyte activity in the dorsal horn of the spinal cord, as compared to control saline-treated CCI mice. Further in vitro investigations on primary astrocyte cultures showed that 1h pre-treatment with Peptide5 significantly reduced adenosine triphosphate (ATP) release in response to extracellular calcium depletion. Since ATP is a known activator of the NOD-like receptor protein 3 (NLRP3) inflammasome complex, a key mediator of neuroinflammation, we examined the effects of Peptide5 treatment on NLRP3 inflammasome expression. We found that NLRP3, its adaptor apoptosis-associated spec-like protein (ASC) and caspase-1 protein were increased in the ipsilateral spinal cord of CCI mice and reduced to naïve levels following Peptide5 treatment. In the models of oxaliplatin- and paclitaxel-induced peripheral neuropathy, treatment with Peptide5 had no effect on mechanical pain hypersensitivity. Interestingly, in these CIPN models, although spinal Cx43 expression was significantly increased at day 13 following chemotherapy, NLRP3 expression was not altered. These results suggest that the analgesic effect of Peptide5 is specifically achieved by reducing NLRP3 expression. Together, our findings demonstrate that blocking Cx43 hemichannels with Peptide5 after nerve injury attenuates mechanical pain hypersensitivity by specifically targeting the NLRP3 inflammasome in the spinal cord., (Copyright © 2017 Elsevier Inc. All rights reserved.)