Antiplatelet and Wound Healing Implications of Immunotherapy and Targeted Cancer Therapies in the Perioperative Period.

The traditional paradigm of oncologic treatment centered on cytotoxic chemotherapy has undergone tremendous advancement during the last 15 yr with the advent of immunotherapy and targeted cancer therapies. These agents, including small molecule inhibitors, monoclonal antibodies, and immune-checkpoint inhibitors, are highly specific to individual tumor characteristics and can prevent cell growth and tumorigenesis by inhibiting specific molecular targets or single oncogenes. While generally better tolerated than traditional chemotherapy, these therapies are associated with unique constellations of adverse effects. Of particular importance in the perioperative and periprocedural settings are hematologic abnormalities, particularly antiplatelet effects with increased risk of bleeding, and implications for wound healing. This narrative review discusses targeted cancer therapies and provides recommendations for physicians managing these patients' care as it relates to procedural or surgical interventions.

Dorsal Versus Ventral Intrathecal Catheter Tip Location and Effect on Dose Escalation and Opioid Use in Patients With Cancer Pain.

OBJECTIVES: In the practice of intrathecal drug delivery, consensus exists regarding the cephalad to caudad location of the catheter tip relative to dermatomal distribution of pain. However, data are lacking on the importance of dorsal vs ventral tip location relative to the spinal cord. We hypothesize that a dorsally placed catheter tip improves efficacy because of closer proximity to nociceptive pathways. MATERIALS AND METHODS: A retrospective review of 298 patients with cancer with intrathecal drug delivery systems implanted at the Huntsman Cancer Institute from May 2014 to June 2020 was performed. Patients were stratified by catheter tip location zones based on available radiographic studies. Patient-controlled intrathecal medication dose requirements and rate of change were compared with catheter zone and other variables, including the presence of adjuncts such as bupivacaine and ziconotide. RESULTS: A total of 158 patients were suitable for analysis demonstrating a dorsal tip in 63.9% (n = 101) and ventral tip in 36.1% (n = 57), with a median follow-up of 17 days (interquartile range [IQR], 10-24). There was no difference in daily dose change from implant to discharge between the dorsal group 8.2% (IQR, 0.0-41.5) and ventral group 20.8% (IQR, 0.0-66.7; p = 0.12). Daily dose change from discharge to follow-up was 2.6% (IQR, 0.0-7.1) in the dorsal group and 1.8% (IQR, 0.0-5.7) in the ventral group (p = 0.92). Catheter tip location had no impact on systemic opioid use. CONCLUSIONS: We did not find significant associations between dorsal vs ventral catheter tip location and measures of pain relief, including change in intrathecal dose or systemic opioid use.

Controversies in intrathecal drug delivery for cancer pain.

Pain and suffering related to cancer are challenging issues that continue to deserve consideration for treatment optimization. Advances in analgesic management and control of the underlying cancer have improved symptom management, yet many patients still suffer from uncontrolled pain. Intrathecal drug delivery has an established role in the management of refractory cancer pain, but there are significant knowledge gaps in our understanding and application of this therapy. This review addresses several areas of controversy, including the importance of intrathecal catheter tip location, the necessity of an intrathecal trial and the role of intrathecal ziconotide and local anesthetics. In each area, the evidence is discussed, with an emphasis on presenting practical clinical guidance and highlighting deficiencies in our knowledge that are worthy of future investigation.

Initial Intrathecal Dose Titration and Predictors of Early Dose Escalation in Patients With Cancer Using a 100:1 Oral to Intrathecal Morphine Conversion Ratio.

OBJECTIVE: Pain is common in patients with advanced cancer, and intrathecal drug delivery (IDD) has been successfully used for recalcitrant pain. We report on our experience using a 100:1 oral-to-intrathecal morphine conversion ratio for initial dosing and factors predictive of early dose escalation. MATERIALS AND METHODS: Retrospective review of an intrathecal drug delivery system (IDDS) data base at the Huntsman Cancer Institute-University of Utah in cancer patients initiated on IDD with morphine or hydromorphone. Demographic characteristics, preoperative opioid use, and initial and hospital discharge IDD settings were collected. RESULTS: A total of 275 patients were identified between June 2014 and May 2020. The median oral-to-intrathecal morphine conversion ratio for initial IDD dosing was 105.5:1 (interquartile range [IQR] 90-120, range 75-150). No serious adverse effects including respiratory depression or sedation were noted and the median length of stay was one night (IQR 1-2, range 1-22). Ninety-six percent of patients discontinued opioids immediately following IDDS implant. Initial IDD dosing was adequate in 42% of patients. Dose reduction was required in 4% prior to discharge due to nausea, patient request, weakness, pruritus, or urinary retention. Dose escalation was required in 54%, with a median dose increase of 66.7% (IQR 33-150%, range 5-1150%). Patients in the highest quartile of dose escalation, ≥70% between IDD initiation and discharge, had associations with younger age, higher preoperative opioid use, and inpatient status. No significant associations were found in patients who required dose reduction as compared to other patients. CONCLUSIONS: An oral-to-intrathecal morphine conversion ratio of approximately 100:1 for initiation of IDD in patients with cancer pain was safe and well tolerated and may facilitate rapid elimination of systemic opioids. Dose reduction was rare, while a majority of patients required further dose escalation prior to discharge.

Quantitative Assessment of the Incidence of Persistent Orthostatic Hemodynamic Changes After Celiac Plexus Neurolysis: A Prospective Case Series.

Celiac plexus neurolysis has been associated with orthostatic hypotension but has not been quantified prospectively or evaluated for persistence after the immediate postprocedural period. Our objective was to quantify persistent hemodynamic changes induced by celiac plexus neurolysis. In this case series of 16 patients with cancer, 8 (50%) had orthostatic hypotension alone, 3 (18.75%) developed an exaggerated postural heart rate increase (>30 beats per min), and 1 (6.25%) had both orthostatic hypotension and an increased heart rate. While the analgesic benefit of celiac plexus neurolysis is clear, the observed hemodynamic changes may be poorly tolerated in some individuals.

The Effect of Measured Radiotherapy Dose on Intrathecal Drug Delivery System Function.

OBJECTIVES: Radiation therapy (RT) and intrathecal drug delivery systems (IDDS) are often used concurrently to optimize pain management in patients with cancer. Concern remains among clinicians regarding the potential for IDDS malfunction in the setting of RT. Here we assessed the frequency of IDDS malfunction in a large cohort of patients treated with RT. MATERIALS AND METHODS: Cancer patients with IDDS and subsequent RT at our institution from 2011 to 2019 were eligible for this study. Patients were excluded in the rare event that their IDDS was managed by an outside clinic and follow-up documentation was unavailable. Eighty-eight patients aged 22-88 years old (43% female, 57% male) representing 106 separate courses of RT were retrospectively identified. Patients received varying levels of radiation for treatment of cancer and cumulative dose to the IDDS was calculated. IDDS interrogation was subsequently performed by a pain specialist. Malfunction was recorded as deviation from the expected drug volume and/or device errors reported upon interrogation as defined by the manufacturer. RESULTS: Total measured RT dose to the IDDS ranged from 0 to 18.0 Gy (median = 0.2 Gy) with median dose of 0.04 Gy/fraction (range, 0-3.2 Gy/fraction). Ten pumps received a total dose >2 Gy and three received ≥5 Gy. Eighty-two percentage of patients had follow-up with a pain specialist for IDDS interrogation and all patients underwent follow-up with a healthcare provider following RT. There were zero incidences of IDDS malfunction related to RT. No patient had clinical evidence of radiation related pump malfunction at subsequent encounters. CONCLUSIONS: We found no evidence that RT in patients with IDDS led to device failure or dysfunction. While radiation oncologists and pain specialists should coordinate patient care, it does not appear that RT dose impacts the function of the IDDS to warrant significant clinical concern.

Observation of Complement Protein Gene Expression Before and After Surgery in Opioid-Consuming and Opioid-Naive Patients.

Opioids may influence inflammation. We compared genes associated with pain and inflammation in patients who consumed opioids (3-120 mg of oral morphine equivalents per day) with those who did not for differential expression. White blood cells were assayed in 20 patients presenting for total lower extremity joint replacement. We focused on messenger ribonucleic acid expression of complement proteins. We report that the expression of a complement inhibitor, complement 4 binding protein A, was reduced, and the expression of a complement activator, complement factor D, was increased in opioid-consuming patients. We conclude that opioid consumption may influence expression of complement activators and inhibitors.

Initiation of Intrathecal Drug Delivery Dramatically Reduces Systemic Opioid Use in Patients With Advanced Cancer.

OBJECTIVES: Pain is common in cancer, affecting more than 70% of patients with advanced disease. Intrathecal drug delivery systems (IDDS) are a well-established treatment for patients with refractory cancer pain, improving pain control and reducing associated side effects. To date, details of systemic opioid use before and after IDDS implant have not been reported. MATERIALS AND METHODS: We conducted a retrospective review of patients at Huntsman Cancer Institute-University of Utah treated with IDDS for cancer pain from May 2014 to May 2018. Oral, transdermal, and parenteral opioid use before IDDS implant was compared to use 30 days postoperatively. RESULTS: A total of 173 patients were included, 93% with stage IV disease. The pre-implant median daily oral morphine equivalent (OME) was 240 mg (interquartile range 130-390, range 0-2616 mg). OME doses >200 mg/day were required by 57% of patients, and >500 mg OME by 19% of patients. The post-implant median OME was 0 mg (interquartile range 0-0, range 0-480 mg) and 82.6% of patients discontinued systemic opioids completely. 11.0% of patients used <100 mg OME, and only 1.7% of patients used >200 mg OME. Mean OME decreased by 94% following IDDS implant (p < 0.0001) and all patients who continued to use systemic opioids required a lower OME compared to pre-implant. CONCLUSIONS: In the largest cohort of patients with advanced cancer and refractory pain treated with IDDS, implantation was associated with a dramatic reduction in systemic opioid use 30 days postoperatively, with a large majority of patients discontinuing systemic opioids. Those patients that continued systemic opioids utilized significantly lower doses as compared to their pre-implant dose.

Gene Variants in Hepatic Metabolism, Gamma-Aminobutyric Acid-ergic Reward, and Prostaglandin Pathways in Opioid-Consuming and Opioid-Naïve Patients Presenting for Lower Extremity Total Joint Replacement.

Gene variants may contribute to individual differences in the experience of pain and the efficacy and reward of treatments. We explored gene variation in opioid-naïve and opioid-consuming patients undergoing elective lower extremity total joint replacement. We focused on 3 gene pathways including prostaglandin, gamma-aminobutyric acid (GABA)-ergic reward, and hepatic metabolism pathways. We report that for genes with possible or probable deleterious impact in these 3 pathways, opioid consumers had more gene variants than opioid-naïve patients (median 3 vs 1, P = .0092). We conclude that chronic opiate users may have genetic susceptibility to altered responses in reward/dependency and pain/inflammation pathways.

Epigenetics of pain mediators.

PURPOSE OF REVIEW: The field of epigenetics continues its influential rise as a means to better understand an organism's unique developmental identity over a lifespan. Whereas a genome is constant and unchanging, an epigenome is dynamic and alterable. Epigenetic changes are in response to innumerable internal and external influences including environmental changes such as diet, exercise, disease, toxins, and stress. Epigenetics is of particular interest in the medical research community both for the potential to cause disease and as a target for therapeutic interventions. This article provides a succinct explanation of the potential for epigenetics to influence the understanding of pain as well as a review of relevant research on the topic. RECENT FINDINGS: Studies on epigenetics and pain remain largely preclinical and investigate the theoretical ability of epigenetics to alter the nociceptive pathways both in the periphery and centrally. Significant evidence now exists for the ability of epigenetics to modify broadly categorized pain types, including inflammatory, neuropathic, visceral, and cancer related. SUMMARY: Both patients and providers recognize that novel medications for the treatment of both acute and chronic pain conditions are sorely needed. The understanding of epigenetics and its influence on nociception remains in relative infancy but early evidence is strong for potential therapeutic benefits to treat these conditions.

C4B null alleles are not associated with genetic polymorphisms in the adjacent gene CYP21A2 in autism.

BACKGROUND: Research indicates that the etiology of autism has a strong genetic component, yet so far the search for genes that contribute to the disorder, including several whole genome scans, has led to few consistent findings. However, three studies indicate that the complement C4B gene null allele (i.e. the missing or nonfunctional C4B gene) is significantly more frequent in individuals with autism. Due to the close proximity of the CYP21A2 gene to the C4B locus (3 kb) it was decided to examine samples from autistic subjects, including many with known C4B null alleles for common CYP21A2 mutations. METHODS: Samples from subjects diagnosed with autism and non-autistic controls (controls) previously typed for C4B null alleles were studied. Allele specific polymerase chain reaction (PCR) methods were used to determine 8 of the most common CYP21A2 genetic mutations, known to completely or partially inhibit 21-hydroxylase, the enzyme encoded by the CYP21A2 gene. RESULTS: Although the combined autism and control study subjects had 50 C4B null alleles only 15 CYP21A2 mutations were detected in over 2250 genotypes. Eight mutations were detected in the autistic samples and 7 in the controls. The frequency of CYP21A2 mutations was similar between the autism and control samples. Only one individual (autistic) carried a chromosome containing both C4B null allele and CYP21A2 mutations.