Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. METHODS AND FINDINGS: We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (ß2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ≤ 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFNγ staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naïve CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naïve CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available. CONCLUSIONS: CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients.

Novel Strategies for Managing Retropharyngeal Lymph Node Metastases in Head and Neck and Thyroid Cancer with Transoral Robotic Surgery (TORS).

Retropharyngeal metastases are encountered in a variety of head and neck malignancies, imposing significant surgical challenges owing to their distinct location and proximity to neurovascular structures. Radiotherapy is the recommended treatment in most cases owing to its oncological efficacy. However, retropharyngeal irradiation affects the superior pharyngeal constrictor muscles and parotid glands, with the potential for long-term dysphagia and xerostomia. A younger oropharyngeal and thyroid cancer patient demographic is trending, fueling interest in treatment de-escalation strategies. Consequently, reducing radiotoxicity and its long-term effects is of special relevance in modern head and neck oncology practice. Through its unique ability to safely extirpate these traditionally difficult-to-access retropharyngeal lymph nodes via a natural orifice, TransOral Robotic Surgery (TORS) can considerably lower the surgical morbidity of retropharyngeal lymph node dissection (RPLND), compared with current existing approaches. This review summarizes the latest developments in the field, exposing current research gaps and discusses specific clinical settings where TORS could enable treatment de-escalation. In early-stage node-negative oropharyngeal cancer, single-modality surgical treatment with TORS RPLND may improve risk stratification of metastasis and recurrence in this region. TORS RPLND is also a potentially viable treatment option in salvage of an isolated retropharyngeal node recurrence or in the primary setting of a thyroid malignancy with a single positive retropharyngeal node. In time, TORS RPLND may provide an alternative de-escalation strategy in these three scenarios. However, with the reported morbidities, further prospective trials with long-term follow-up data are required to prove oncological safety and functional benefits over existing strategies.

Improving quality of life through the routine use of the patient concerns inventory for head and neck cancer patients: main results of a cluster preference randomised controlled trial.

PURPOSE: The patient concerns inventory (PCI) is a prompt list allowing head and neck cancer (HNC) patients to discuss issues that otherwise might be overlooked. This trial evaluated the effectiveness of using the PCI at routine outpatient clinics for one year after treatment on health-related QOL (HRQOL). METHODS: A pragmatic cluster preference randomised control trial with 15 consultants, 8 'using' and 7 'not using' the PCI intervention. Patients treated with curative intent (all sites, disease stages, treatments) were eligible. RESULTS: Consultants saw a median (inter-quartile range) 16 (13-26) patients, with 140 PCI and 148 control patients. Of the pre-specified outcomes, the 12-month results for the mean University of Washington Quality of Life (UW-QOLv4) social-emotional subscale score suggested a small clinical effect of intervention of 4.6 units (95% CI 0.2, 9.0), p = 0.04 after full adjustment for pre-stated case-mix. Results for UW-QOLv4 overall quality of life being less than good at 12 months (primary outcome) also favoured the PCI with a risk ratio of 0.83 (95% CI 0.66, 1.06) and absolute risk 4.8% (- 2.9%, 12.9%) but without achieving statistical significance. Other non-a-priori analyses, including all 12 UWQOL domains and at consultant level also suggested better HRQOL with PCI. Consultation times were unaffected and the number of items selected decreased over time. CONCLUSION: This novel trial supports the integration of the PCI approach into routine consultations as a simple low-cost means of benefiting HNC patients. It adds to a growing body of evidence supporting the use of patient prompt lists more generally.

The role of multidisciplinary decision making in oropharyngeal cancer: do we follow guidelines and are treatment decisions being implemented?

PURPOSE: A multidisciplinary team (MDT) approach to cancer management is gold-standard. With an increasing disease incidence and growing research into human papillomavirus (HPV)-related oropharyngeal cancer (OPC), updated UK management guidelines were recently published. This study aimed to evaluate the MDT decision-making process among OPC patients at a tertiary centre. METHODS: MDT meetings over a 12-month period were analysed retrospectively. MDT decisions were compared with guidelines and patient records examined to identify decision implementation. Reasons behind any discordant decisions were explored. RESULTS: This study included 140 OPC patients. Thirty-three (23.6%) were not tested for HPV. Patients over 70 years with a smoking history treated palliatively were less likely to be tested (P = 0.017). Eighty-five percent of MDT decisions followed guidelines with the majority not complying (76.2%) related to patient comorbidity. Ten decisions (7.1%) were not implemented. Reasons included: Seven due to patient choice, of which four patients (57.1%) were only seen following the MDT meeting, and three due to clinician decisions as new clinical information emerged. CONCLUSION: The majority of MDT decisions followed guidelines and any discordant decisions were justifiable. Discussing management options with patients beforehand facilitates decision implementation as decisions can potentially change after seeing the patient. Progress is still needed with regards to HPV testing. Reasons for not testing could include subliminal decision-making among clinicians, and patients falling between centres. Crucially, the role of the MDT in head and neck cancer should be to ratify decisions rather than making them, hence the need to see patients prior to MDT discussion.

Improving quality of life through the routine use of the patient concerns inventory for head and neck cancer patients: baseline results in a cluster preference randomised controlled trial.

PURPOSE: The main aim of this paper is to present baseline demographic and clinical characteristics and HRQOL in the two groups of the Patient Concerns Inventory (PCI) trial. The baseline PCI data will also be described. METHODS: This is a pragmatic cluster preference randomised control trial with 15 consultant clusters from two sites either 'using' (n = 8) or 'not using' (n = 7) the PCI at a clinic for all of their trial patients. The PCI is a 56-item prompt list that helps patients raise concerns that otherwise might be missed. Eligibility was head and neck cancer patients treated with curative intent (all sites, stage of disease, treatments). RESULTS: From 511 patients first identified as eligible when screening for the multi-disciplinary tumour board meetings, 288 attended a first routine outpatient baseline study clinic after completion of their treatment, median (IQR) of 103 (71-162) days. At baseline, the two trial groups were similar in demographic and clinical characteristics as well as in HRQOL measures apart from differences in tumour location, tumour staging and mode of treatment. These exceptions were cluster (consultant) related to Maxillofacial and ENT consultants seeing different types of cases. Consultation times were similar, with PCI group times taking about 1 min longer on average (95% CL for the difference between means was from - 0.7 to + 2.2 min). CONCLUSION: Using the PCI in routine post-treatment head and neck cancer clinics do not elongate consultations. Recruitment has finished but 12-month follow-up is still ongoing.

Measuring Harm in Hospitalized Children via a Trigger Tool.

BACKGROUND: The 1999 report To Err Is Human published by the Institute of Medicine estimated that between 44,000 and 98,000 deaths occur each year in US hospitals due to medical errors. However, processes to detect medically induced harm remain inaccurate and inconsistent. Hospitalized pediatric patients are at high risk for adverse events, with published rates ranging between 1% and 11% of all hospitalizations. OBJECTIVE: The study aimed to use the Global Assessment of Pediatric Patient Safety (GAPPS) tool to detect adverse events in a pediatric inpatient setting of an academic medical center children's hospital and compare to internal incident reporting methods. METHODS: Nurse reviewers used the GAPPS tool during a retrospective chart review of 100 patients discharged from the children's hospital. Among the total 100 cases, 20 adverse events were discovered with the tool. Adverse events were validated by physician reviewers, and the severity of harm and preventability were assigned. The number of adverse events was then compared to internal incident reporting for the same time frame. RESULTS: The detection rate is 4.87% within 411 patient-days. In contrast, the hospital had only 1.22% incident reports. CONCLUSIONS: The GAPPS tool can detect four times more adverse events than the hospital incident reporting system. The results are likely to be replicated for other children's hospitals to increase identification of adverse events and harm to patients.

Electroless Deposition of Nickel on Photografted Polymeric Microscale Patterns.

This report demonstrates the electroless deposition of Ni onto micropatterns of poly (acrylic acid) (PAA) photografted to phthalimide-terminated self-assembled monolayers (SAMs). PAA is spin-coated onto phthalimide SAMs and covered with a photomask. UV irradiation selectively binds PAA to exposed regions of the surface, allowing PAA on unexposed regions to be rinsed off. A Pd catalyst is then selectively adsorbed to regions of the surface where PAA is bound. The adsorbed catalyst selectively initiates Ni plating upon immersion of the substrate into a Ni(SO4 ) bath.

Transoral laser microsurgery for early and moderately advanced laryngeal cancers: outcomes from a single centralised United Kingdom centre.

Transoral laser microsurgery (TLM) represents an important treatment for selected laryngeal cancers. Utilisation of TLM, however, is highly variable between United Kingdom (UK) centres, and published data relating to its use in the UK is scarce. We report outcomes from our tertiary referral centre, and highlight lessons learned. Patients undergoing primary TLM for laryngeal cancer with curative intent (2007-2011) were studied retrospectively. Survival analyses were evaluated using the Kaplan-Meier method and log-rank statistics used to examine the influence of several variables. Overall, 170 cases were included-153 glottic and 17 supraglottic. Median follow-up was 39 months (range 14-79 months). Respective 3-year local control (LC), overall survival (OS), disease-specific survival (DSS), and disease-free survival were 92, 92, 98, and 86 % for glottic carcinomas. Three-year LC and OS were both 88 % for supraglottic carcinomas. For glottic cases, a significant impact of pT stage on DSS was observed, and of age on OS. Median hospital stay was one and 19 days for glottic and supraglottic cases respectively, with respective 3-year laryngeal preservation rates of 97 and 94 %, and tracheostomy rates of 0 and 29 %. One patient in the glottic group and four in the supraglottic group failed to regain swallowing function post-operatively, remaining either PEG dependent or undergoing functional total laryngectomy. Our series confirms the oncological and functional efficacy of TLM, offering a unique large-scale UK perspective. Our experience indicates, however, that treatment of larger supraglottic tumours should be considered carefully, as functional outcomes may be compromised.

Extended vertical hemilaryngectomy and reconstruction with a neovascularised tracheal autograft for advanced unilateral laryngeal tumours: a learning curve.

Extended vertical hemilaryngectomy and reconstruction with a neovascularised tracheal autograft is a two-stage procedure for advanced unilateral tumours of the larynx. The purpose of this study was to review our early experience of this technique by reporting our clinical outcomes and highlighting some key learning points. Patients were identified from the Liverpool Head and Neck Cancer electronic database. Case notes were reviewed for demographic data, tumour stage, treatment, complications and outcomes. Eleven patients (all males) were identified. The mean age of the cohort was 58.2 years (range 37-78 years). The overall average follow-up period was 41.5 months (range 14 days-75 months). Of the 11 cases, 3 had completed stage 1 only. The most common complications following stage 1 procedure are related to the surgical neck wound (36% of cases). Of the remaining eight patients who completed the first two surgical stages, closure of tracheostomy stoma was possible in seven; all seven subsequently resumed a normal oral diet. All these patients have subsequently remained free of disease at latest follow-up. There were two cases of post-operative pneumonia and one case of radial forearm free-flap failure. In contrast, only one case of post-operative pneumonia was recorded following the stage 2 procedure. In total, three patients in this cohort were dead at follow-up. This technique has a role in the management of a select group of fit patients presenting with unilateral tumours of the glottis and who are otherwise destined for a total laryngectomy. Whilst the technique is complex, we have shown that its introduction is possible in a suitably specialised and motivated surgical unit.

Effect of State Legislation on Opioid Prescribing Practices After Surgery at a Pediatric Hospital.

OBJECTIVE: As abuse of prescription narcotics continues to create a growing healthcare crisis throughout the United States, states have passed legislation designed to alter narcotic prescribing habits. West Virginia State Bill 273 limited the quantity of narcotics practitioners were able to prescribe. Our objective was to determine the effect of this bill on narcotic prescribing practices for pediatric surgical patients. METHODS: A hospital-wide database at a pediatric trauma center was queried to identify all pediatric patients undergoing surgery between January 1, 2017 and December 9, 2019 and all medications prescribed to this cohort. Narcotic prescriptions written for these patients in the 2 months following surgery were isolated. The percent of patients receiving a postoperative narcotic prescription and the morphine milligram equivalents (MME) per prescription were compared before and after the law's implementation. RESULTS: The number of pediatric patients identified as having surgery in the study period was 10,176; 6069 were before the law passed and 4107 were after. The percentage of patients receiving a narcotic prescription was 46.0% before the law was passed, decreasing to 36.8% after the law (P < .0001). Adjusted for age, the average MME of each prescription before the law's implementation was 104.0, which decreased to 79.2 after the law (P < .0001). CONCLUSIONS: The amount of narcotic per prescription written for pediatric patients after surgery and the percentage of patients receiving a prescription decreased after West Virginia State Bill 273 was implemented. This law was associated with decreased narcotics written by providers, providing an example for future legislation targeting opioid prescribing and abuse.

SARS-CoV-2 mRNA vaccination exposes progressive adaptive immune dysfunction in patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients have lower seroconversion rates and antibody titers following SARS-CoV-2 vaccination, but the reasons for this diminished response are poorly understood. Here, we studied humoral and cellular responses in 95 CLL patients and 30 healthy controls after two BNT162b2 or mRNA-2173 mRNA immunizations. We found that 42% of CLL vaccinees developed SARS-CoV-2-specific binding and neutralizing antibodies (NAbs), while 32% had no response. Interestingly, 26% were seropositive, but had no detectable NAbs, suggesting the maintenance of pre-existing endemic human coronavirus-specific antibodies that cross-react with the S2 domain of the SARS-CoV-2 spike. These individuals had more advanced disease. In treatment-naïve CLL patients, mRNA-2173 induced 12-fold higher NAb titers and 1.7-fold higher response rates than BNT162b2. These data reveal a graded loss of immune function, with pre-existing memory being preserved longer than the capacity to respond to new antigens, and identify mRNA-2173 as a superior vaccine for CLL patients.

Elective management of regional nodal basins in cutaneous squamous cell carcinoma of the head and neck: Controversies and contemporary perspectives.

Non-melanoma skin cancer (NMSC) is among the most common cancers worldwide, with an incidence that continues to rise. Although cutaneous squamous cell carcinoma (cSCC) constitutes only approximately 20% of such cases, it represents the most common cause of NMSC mortality, owing largely to the propensity for development of regional lymph node metastases (LNM), which, when present, carry a dismal prognosis. Whilst overall rates of LNM are low, there are a number of patient and tumour factors that likely confer considerably higher risks, which has led several investigators to propose more proactive elective management of regional nodal basins in selected high-risk cases. Current international guidelines, however, do not recommend any elective treatment or sampling of regional nodal basins in the absence of clinically apparent disease. The purpose of this review is to explore in detail the fundamental issues underlying this controversy, focusing specifically on cSCC of the head and neck (cSCCHN). In particular the rationale for more a proactive elective approach to regional nodal basins, including the evidence-base underlying identification of potentially high-risk factors for development of LNM is discussed, along with oncological outcomes for those patients that do go onto suffer LNM. We also provide contemporary perspectives and evidence for approaches to electively managing regional nodal basins, and offer insight into how these may develop both in the clinical and research arenas.

Early versus late oral feeding following total (pharyngo)laryngectomy: Systematic review and meta-analysis.

Timing of oral feeding following total laryngectomy is a contentious issue with highly varied practices. Multiple database search was performed to identify studies comparing outcomes of early (≤5 days) versus late (>5 days) oral feeding. Bias assessment was carried out using Cochrane bias tool. Random-effects meta-analysis was used. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The rate of pharyngocutaneous fistula (PCF) in randomized control trials (RCTs) in early versus late feeding was 15.2% versus 11.7% (RR 1.35, 95%CI [0.68-2.7], p = 0.40). The rate of PCF in the cohort studies was 14.1% versus 20.5% (RR 1.0, 95%CI [0.76-1.3], p = 0.98). The length of hospital stay was significantly shorter in the early feeding group (mean difference (days) -4.68 (-6.2 to -3.1, p < 0.0001). Early oral feeding appears to be safe and is associated with shorter hospital stay. However, the quality of evidence is low and the patient characteristics are not representative of current practices.

Visual teaching aids improve patient understanding and reduce anxiety prior to a colectomy.

BACKGROUND: Informed consent forms consist of large blocks of written information that may be difficult for patients to understand. Visual teaching aids are promising, however, they have not been studied as a pre-operative educational tool for common surgical procedures. We pilot tested the use of a visual teaching aid during the informed consent process for a colectomy. METHODS: A randomized pilot study was performed. Participants were randomized into the visual teaching aid group or standard care. Following the consent process, participants were questioned about potential surgical complications, anxiety, satisfaction, and understanding. RESULTS: 30 participants were enrolled. Potential complication recall and patient-reported understanding were improved in the visual group (p = 0.01, p = 0.03). Anxiety levels were reduced in the visual group (p = 0.02). No statistically significant data were found for satisfaction (p = 0.75). CONCLUSIONS: Utilizing a visual teaching aid during the consent process for colectomy increases patient recall of risks, reduces anxiety, and improves understanding.

Pain Medication Disposal Rates After Pediatric Surgery.

OBJECTIVES: To investigate prescription opiate usage, disposal rates, and methods of disposal after pediatric surgery. METHODS: This was a retrospective chart review of patients <18 years of age who underwent a surgical procedure at our institution and were given a postoperative opiate prescription between April 2017 and June 2018. A follow-up phone survey was conducted between 60 and 90 days postoperatively to ask about prescription opiate usage and disposal. RESULTS: A total of 290 patients with a mean age of 9.0 ± 4.7 years (62.8% male) met inclusion criteria. Sixty patients (20.7%) reported using all of their prescription opiate medication, whereas 230 patients (79.3%) did not use all of their pain medication. Of these 230 patients, 141 (61.3%) disposed of their leftover prescription opiates via flushing (56.4%), trash (28.6%), or take-back center (15.0%). At the time of phone survey between 60 and 90 days postoperatively, 88 patients (38.3%) still had leftover pain medication. By 7 days postoperatively, 234 of 290 patients (80.7%) had taken their last prescription opioid. CONCLUSIONS: In our study, 79.3% of patients were overprescribed opiate pain medication after pediatric surgery. Disposal rates at 60 to 90 days for leftover pain medication after pediatric surgery was just >60%. Pediatric patients are often overprescribed prescription opiates after surgery and typically only require a one-week supply of pain medication.