ABSTRACT
INTRODUCTION: This article reports on the effects of an early outbreak during the COVID-19 pandemic on visit volume and telehealth use by various specialists at a comprehensive cancer center. MATERIALS AND METHODS: The number of on-site and telehealth visits (THV) for medical and surgical specialties were obtained from scheduling software. RESULTS: Total visits were most drastically limited in April 2020 to a low point of 3139; THV made up 28% of all visits. For head and neck surgery, THV made up 54% and 30% of visits in April and May, respectively. Other specialties, such as psychiatry and palliative care, had higher levels of THV. For most specialties, the rebound in June through September did not make up for visits lost during the outbreak, and fiscal year (FY) 2020 had a 9% loss from FY 2019 with 5786 fewer total annual visits across all specialties. CONCLUSIONS: While telemedicine was a helpful part of this cancer center's response to the initial COVID-19 surge, it was not able to replace the in-person services offered at the same center. The main strategy of physicians at this cancer center was to defer care, with telemedicine being an auxiliary response.
Subject(s)
COVID-19/epidemiology , SARS-CoV-2 , Telemedicine/trends , Head and Neck Neoplasms/surgery , Humans , Telemedicine/statistics & numerical dataABSTRACT
OBJECTIVES/HYPOTHESIS: To determine the association between findings of blinded reviews of preoperative drug-induced sleep endoscopy (DISE) and outcomes of hypoglossal nerve stimulation (HNS) for obstructive sleep apnea (OSA). STUDY DESIGN: Cohort study. METHODS: A retrospective, multicenter cohort study of 343 adults who underwent treatment of OSA with HNS from 10 academic medical centers was performed. Preoperative DISE videos were scored by four blinded reviewers using the VOTE Classification and evaluation of a possible primary structure contributing to airway obstruction. Consensus DISE findings were examined for an association with surgical outcomes based on therapy titration polysomnogram (tPSG). Treatment response was defined by a decrease of ≥50% in the apnea-hypopnea index (AHI) to <15 events/hour. RESULTS: Study participants (76% male, 60.4 ± 11.0 years old) had a body mass index of 29.2 ± 3.6 kg/m2 . AHI decreased (35.6 ± 15.2 to 11.0 ± 14.1 events/hour; P < .001) on the tPSG, with a 72.6% response rate. Complete palate obstruction (vs. none) was associated with the greatest difference in AHI improvement (-26.8 ± 14.9 vs. -19.2 ± 12.8, P = .02). Complete (vs. partial/none) tongue-related obstruction was associated with increased odds of treatment response (78% vs. 68%, P = .043). Complete (vs. partial/none) oropharyngeal lateral wall-related obstruction was associated with lower odds of surgical response (58% vs. 74%, P = .042). CONCLUSIONS: The DISE finding of primary tongue contribution to airway obstruction was associated with better outcomes, whereas the opposite was true for the oropharyngeal lateral walls. This study suggests that the role for DISE in counseling candidates for HNS extends beyond solely for excluding complete concentric collapse related to the velum. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:1676-1682, 2021.
Subject(s)
Airway Obstruction/diagnosis , Electric Stimulation Therapy/methods , Endoscopy/methods , Hypoglossal Nerve , Sleep Apnea, Obstructive/therapy , Aged , Airway Obstruction/etiology , Airway Obstruction/therapy , Contraindications, Procedure , Counseling , Electric Stimulation Therapy/adverse effects , Electric Stimulation Therapy/instrumentation , Female , Humans , Hypnotics and Sedatives/administration & dosage , Implantable Neurostimulators , Male , Middle Aged , Oropharynx/diagnostic imaging , Palate/diagnostic imaging , Polysomnography , Preoperative Period , Retrospective Studies , Severity of Illness Index , Sleep/drug effects , Sleep Apnea, Obstructive/complications , Sleep Apnea, Obstructive/diagnosis , Tongue/diagnostic imaging , Treatment OutcomeABSTRACT
OBJECTIVE: To compare patients with moderate-severe obstructive sleep apnea (OSA) undergoing traditional single and multilevel sleep surgery to those undergoing upper airway stimulation (UAS). STUDY DESIGN: Case control study comparing retrospective cohort of patients undergoing traditional sleep surgery to patients undergoing UAS enrolled in the ADHERE registry. SETTING: 8 multinational academic medical centers. SUBJECTS AND METHODS: 233 patients undergoing prior single or multilevel traditional sleep surgery and meeting study inclusion criteria were compared to 465 patients from the ADHERE registry who underwent UAS. We compared preoperative and postoperative demographic, quality of life, and polysomnographic data. We also evaluated treatment response rates. RESULTS: The pre and postoperative apnea hypopnea index (AHI) was 33.5 and 15 in the traditional sleep surgery group and 32 and 10 in the UAS group. The postoperative AHI in the UAS group was significantly lower. The pre and postoperative Epworth sleepiness scores (ESS) were 12 and 6 in both the traditional sleep surgery and UAS groups. Subgroup analysis evaluated those patients undergoing single level palate and multilevel palate and tongue base traditional sleep surgeries. The UAS group had a significantly lower postoperive AHI than both traditional sleep surgery subgroups. The UAS group had a higher percentage of patients reaching surgical success, defined as a postoperative AHI <20 with a 50% reduction from preoperative severity. CONCLUSION: UAS offers significantly better control of AHI severity than traditional sleep surgery. Quality life improvements were similar between groups.
Subject(s)
Electric Stimulation Therapy , Otorhinolaryngologic Surgical Procedures , Postoperative Complications , Quality of Life , Sleep Apnea, Obstructive , Airway Management/methods , Case-Control Studies , Comparative Effectiveness Research , Electric Stimulation Therapy/adverse effects , Electric Stimulation Therapy/methods , Female , Humans , Male , Middle Aged , Otorhinolaryngologic Surgical Procedures/adverse effects , Otorhinolaryngologic Surgical Procedures/methods , Outcome and Process Assessment, Health Care/statistics & numerical data , Palate/surgery , Polysomnography/methods , Polysomnography/statistics & numerical data , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/physiopathology , Sleep Apnea, Obstructive/therapy , Tongue/surgeryABSTRACT
Objective To present 5-year outcomes from a prospective cohort of patients with obstructive sleep apnea (OSA) who were treated with upper airway stimulation (UAS) via a unilateral hypoglossal nerve implant. Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical trial. Methods From a cohort of 126 patients, 97 completed protocol, and 71 consented to a voluntary polysomnogram. Those having continuous positive airway pressure failure with moderate to severe OSA, body mass index <32 kg/m2, and no unfavorable collapse on drug-induced sleep endoscopy were enrolled in a phase 3 trial. Prospective outcomes included apnea-hypopnea index (AHI), oxygen desaturation index, and adverse events, as well as measures of sleepiness, quality of life, and snoring. Results Patients who did and did not complete the protocol differed in baseline AHI, oxygen desaturation index, and Functional Outcomes of Sleep Questionnaire scores but not in any other demographics or treatment response measures. Improvement in sleepiness (Epworth Sleepiness Scale) and quality of life was observed, with normalization of scores increasing from 33% to 78% and 15% to 67%, respectively. AHI response rate (AHI <20 events per hour and >50% reduction) was 75% (n = 71). When a last observation carried forward analysis was applied, the responder rate was 63% at 5 years. Serious device-related events all related to lead/device adjustments were reported in 6% of patients. Conclusions Improvements in sleepiness, quality of life, and respiratory outcomes are observed with 5 years of UAS. Serious adverse events are uncommon. UAS is a nonanatomic surgical treatment with long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure.
Subject(s)
Electric Stimulation Therapy , Hypoglossal Nerve , Implantable Neurostimulators , Sleep Apnea, Obstructive/therapy , Female , Humans , Male , Middle Aged , Prospective Studies , Time Factors , Treatment OutcomeABSTRACT
Objective To assess patient-based outcomes of participants in a large cohort study-the STAR trial (Stimulation Therapy for Apnea Reduction)-48 months after implantation with an upper airway stimulation system for moderate to severe obstructive sleep apnea. Study Design A multicenter prospective cohort study. Setting Industry-supported multicenter academic and clinical setting. Subjects Participants (n = 91) at 48 months from a cohort of 126 implanted participants. Methods A total of 126 participants received an implanted upper airway stimulation system in a prospective phase III trial. Patient-reported outcomes at 48 months, including Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), and snoring level, were compared with preimplantation baseline. Results A total of 91 subjects completed the 48-month visit. Daytime sleepiness as measured by ESS was significantly reduced ( P = .01), and sleep-related quality of life as measured by FOSQ significantly improved ( P = .01) when compared with baseline. Soft to no snoring was reported by 85% of bed partners. Two patients required additional surgery without complication for lead malfunction. Conclusion Upper airway stimulation maintained a sustained benefit on patient-reported outcomes (ESS, FOSQ, snoring) at 48 months in select patients with moderate to severe obstructive sleep apnea.
Subject(s)
Electric Stimulation Therapy , Sleep Apnea, Obstructive/therapy , Disorders of Excessive Somnolence/therapy , Follow-Up Studies , Humans , Hypoglossal Nerve , Implantable Neurostimulators , Male , Middle Aged , Patient Reported Outcome Measures , Prospective Studies , Quality of Life , Self Report , Snoring/therapyABSTRACT
OBJECTIVES/HYPOTHESIS: To estimate the incidence of patients presenting to emergency departments (EDs) for facial trauma sustained from participation in combat sports and evaluate injury patterns and patient demographics. METHODS: The National Electronic Injury Surveillance System (NEISS) was evaluated for facial injuries from wrestling, boxing, and martial arts leading to ED visits from 2008 to 2013. Relevant entries were examined for injury mechanism, location, type, as well as other patient characteristics. RESULTS: There were 1143 entries extrapolating to an estimated 42â 395 ED visits from 2008 to 2013. Injury rates for boxing, marital arts, and wrestling were, respectively, 44, 56, and 120 injuries per 100â 000 participants. Males comprised the majority (93.7%). A plurality of injuries involved lacerations (46.0%), followed by fractures (26.2%) and contusions/abrasions (19.3%). The proportion of fractures was highest among boxers (36.9%). Overall, the most common mechanisms of injury were punching, kicking, and head butting. CONCLUSIONS: The significant number of ED visits resulted from combat sports facial trauma, reinforcing the importance of familiarity with injury patterns among practitioners managing facial trauma. As most injuries involve individuals younger than 19 despite guidelines suggesting children and adolescents avoid combat sports, these findings may be used for patient education and encouragement of the use of personal protective equipment. Furthermore, injury patterns reported in this analysis may serve as an adjunct for enhancing clinical history taking and physical examination.
Subject(s)
Boxing/injuries , Contusions/epidemiology , Facial Injuries/epidemiology , Lacerations/epidemiology , Martial Arts/injuries , Skull Fractures/epidemiology , Wrestling/injuries , Adolescent , Adult , Databases, Factual , Emergency Service, Hospital , Facial Bones/injuries , Female , Humans , Male , Mandibular Fractures/epidemiology , Nasal Bone/injuries , Orbital Fractures/epidemiology , Sex Distribution , United States/epidemiology , Young AdultABSTRACT
OBJECTIVES: To evaluate the long-term (24-mo) effect of cranial nerve upper airway stimulation (UAS) therapy on patient-centered obstructive sleep apnea (OSA) outcome measures. METHODS: Prospective, multicenter, cohort study of 126 patients with moderate to severe OSA who had difficulty adhering to positive pressure therapy and received the surgically implanted UAS system. Outcomes were measured at baseline and postoperatively at 12 mo and 24 mo, and included self- and bedpartner-report of snoring intensity, Epworth Sleepiness Scale (ESS), and Functional Outcomes of Sleep Questionnaire (FOSQ). Additional analysis included FOSQ subscales, FOSQ-10, and treatment effect size. RESULTS: Significant improvement in mean FOSQ score was observed from baseline (14.3) to 12 mo (17.3), and the effect was maintained at 24 mo (17.2). Similar improvements and maintenance of effect were seen with all FOSQ subscales and FOSQ-10. Subjective daytime sleepiness, as measured by mean ESS, improved significantly from baseline (11.6) to 12 mo (7.0) and 24 mo (7.1). Self-reported snoring severity showed increased percentage of "no" or "soft" snoring from 22% at baseline to 88% at 12 mo and 91% at 24 mo. UAS demonstrated large effect size (> 0.8) at 12 and 24 mo for overall ESS and FOSQ measures, and the effect size compared favorably to previously published effect size with other sleep apnea treatments. CONCLUSIONS: In a selected group of patients with moderate to severe OSA and body mass index ≤ 32 kg/m2, hypoglossal cranial nerve stimulation therapy can provide significant improvement in important sleep related quality-of-life outcome measures and the effect is maintained across a 2-y follow-up period.
Subject(s)
Electric Stimulation Therapy/methods , Hypoglossal Nerve/physiology , Self Report , Sleep Apnea, Obstructive/therapy , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prospective Studies , Sleep Apnea, Obstructive/physiopathology , Surveys and Questionnaires , Treatment OutcomeABSTRACT
OBJECTIVE: To describe the 36-month clinical and polysomnography (PSG) outcomes in an obstructive sleep apnea (OSA) cohort treated with hypoglossal cranial nerve upper airway stimulation (UAS). STUDY DESIGN: A multicenter prospective cohort study. SETTING: Industry-supported multicenter academic and clinical setting. SUBJECTS: Participants (n = 116) at 36 months from a cohort of 126 implanted participants. METHODS: Participants were enrolled in a prospective phase III trial evaluating the efficacy of UAS for moderated to severe OSA. Prospective outcomes included apnea-hypopnea index, oxygen desaturation index, other PSG measures, self-reported measures of sleepiness, sleep-related quality of life, and snoring. RESULTS: Of 126 enrolled participants, 116 (92%) completed 36-month follow-up evaluation per protocol; 98 participants additionally agreed to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the a priori definition of success with the primary outcomes of apnea-hypopnea index, reduced from the median value of 28.2 events per hour at baseline to 8.7 and 6.2 at 12 and 36 months, respectively. Similarly, self-reported outcomes improved from baseline to 12 months and were maintained at 36 months. Soft or no snoring reported by bed partner increased from 17% at baseline to 80% at 36 months. Serious device-related adverse events were rare, with 1 elective device explantation from 12 to 36 months. CONCLUSION: Long-term 3-year improvements in objective respiratory and subjective quality-of-life outcome measures are maintained. Adverse events are uncommon. UAS is a successful and appropriate long-term treatment for individuals with moderate to severe OSA.
Subject(s)
Cranial Nerves , Electric Stimulation Therapy , Sleep Apnea, Obstructive/therapy , Cohort Studies , Female , Humans , Implantable Neurostimulators , Male , Middle Aged , Prospective Studies , Time Factors , Treatment OutcomeABSTRACT
Acute kidney injury (AKI) is a well-known complication of cisplatin-based chemotherapy; however, its impact on long-term patient survival is unclear. We sought to determine the incidence and risk factors for development of cisplatin-associated AKI and its impact on long-term renal function and patient survival. We identified 233 patients who received 629 cycles of high-dose cisplatin (99±9mg/m2) for treatment of head and neck cancer between 2005 and 2011. These subjects were reviewed for development of AKI. Cisplatin nephrotoxicity (CN) was defined as persistent rise in serum creatinine, with a concomitant decline in serum magnesium and potassium, in absence of use of nephrotoxic agents and not reversed with hydration. All patients were hydrated per protocol and none had baseline glomerular filtration rate (GFR) via CKD-EPI<60mL/min/1.73m2. The patients were grouped based on development of AKI and were staged for levels of injury, per KDIGO-AKI definition. Renal function was assessed via serum creatinine and estimated glomerular filtration rate (eGFR) via CKD-EPI at baseline, 6- and 12-months. Patients with AKI were screened for the absence of nephrotoxic medication use and a temporal decline in serum potassium and magnesium levels. Logistic regression models were constructed to determine risk factors for cisplatin-associated AKI. Twelve-month renal function was compared among groups using ANOVA. Kaplan-Maier curves and Cox proportional hazard models were constructed to study its impact on patient survival. Of 233 patients, 158(68%) developed AKI; 77 (49%) developed stage I, 55 (35%) developed stage II, and 26 (16%) developed stage III AKI. Their serum potassium and magnesium levels correlated negatively with level of injury (p<0.05). African American race was a significant risk factor for cisplatin-associated AKI, OR 2.8 (95% CI 1.3 to 6.3) and 2.8 (95% CI 1.2 to 6.7) patients with stage III AKI had the lowest eGFR value at 12 months (p = 0.05) and long-term patient survival (HR 2.1; p<0.01) than patients with no or lower grades of AKI. Most common causes of death were recurrent cancer (44%) or secondary malignancy elsewhere (40%). Cisplatin-associated severe AKI occurs in 20% of the patients and has a negative impact on long-term renal function and patient survival. PEG tube placement may be protective and should be considered in high risk-patients.
Subject(s)
Acute Kidney Injury/chemically induced , Antineoplastic Agents/adverse effects , Cisplatin/adverse effects , Acute Kidney Injury/mortality , Adult , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Cohort Studies , Creatinine/blood , Female , Head and Neck Neoplasms/drug therapy , Humans , Kidney Function Tests , Male , Middle Aged , Retrospective Studies , Risk FactorsABSTRACT
OBJECTIVE: To assess the efficacy and durability of upper airway stimulation via the hypoglossal nerve on obstructive sleep apnea (OSA) severity including objective and subjective clinical outcome measures. STUDY DESIGN: A randomized controlled therapy withdrawal study. SETTING: Industry-supported multicenter academic and clinical setting. SUBJECTS: A consecutive cohort of 46 responders at 12 months from a prospective phase III trial of 126 implanted participants. METHODS: Participants were randomized to either therapy maintenance ("ON") group or therapy withdrawal ("OFF") group for a minimum of 1 week. Short-term withdrawal effect as well as durability at 18 months of primary (apnea hypopnea index and oxygen desaturation index) and secondary outcomes (arousal index, oxygen desaturation metrics, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, snoring, and blood pressure) were assessed. RESULTS: Both therapy withdrawal group and maintenance group demonstrated significant improvements in outcomes at 12 months compared to study baseline. In the randomized assessment, therapy withdrawal group returned to baseline, and therapy maintenance group demonstrated no change. At 18 months with therapy on in both groups, all objective respiratory and subjective outcome measures showed sustained improvement similar to those observed at 12 months. CONCLUSION: Withdrawal of therapeutic upper airway stimulation results in worsening of both objective and subjective measures of sleep and breathing, which when resumed results in sustained effect at 18 months. Reduction of obstructive sleep apnea severity and improvement of quality of life were attributed directly to the effects of the electrical stimulation of the hypoglossal nerve.
Subject(s)
Electric Stimulation Therapy , Sleep Apnea, Obstructive/therapy , Electric Stimulation Therapy/methods , Female , Humans , Hypoglossal Nerve , Male , Middle Aged , Prospective Studies , Time Factors , Treatment Outcome , Withholding TreatmentABSTRACT
OBJECTIVES/HYPOTHESIS: Previous feasibility studies have shown that electrical stimulation of the hypoglossal nerve can improve obstructive sleep apnea (OSA). The current study examined the safety and preliminary effectiveness of a second generation device, the Upper Airway Stimulation (UAS) system, and identified baseline predictors for therapy success. STUDY DESIGN: Two consecutive open prospective studies. METHODS: UAS systems were implanted in patients with moderate to severe OSA who failed or were intolerant of continuous positive airway pressure (CPAP). The study was conducted in 2 parts. In part 1, patients were enrolled with broad selection criteria. Apnea hypopnea index (AHI) was collected using laboratory-based polysomnography at preimplant and postimplant visits. Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ) were also collected. In part 2, patients were enrolled using selection criteria derived from the experience in part 1. RESULTS: In part 1, 20 of 22 enrolled patients (two exited the study) were examined for factors predictive of therapy response. Responders had both a body mass index ≤32 and AHI ≤50 (P < .05) and did not have complete concentric palatal collapse. Part 2 patients (n = 8) were selected using responder criteria and showed an improvement on AHI from baseline, from 38.9 ± 9.8 to 10.0 ± 11.0 (P < .01) at 6 months postimplant. Both ESS and FOSQ improved significantly in part 1 and 2 subjects. CONCLUSIONS: The current study has demonstrated that therapy with upper airway stimulation is safe and efficacious in a select group of patients with moderate to severe OSA who cannot or will not use CPAP as primary treatment.
Subject(s)
Electric Stimulation Therapy/instrumentation , Implantable Neurostimulators , Sleep Apnea, Obstructive/therapy , Feasibility Studies , Female , Humans , Male , Middle Aged , Prospective StudiesABSTRACT
OBJECTIVE: To identify protein-tyrosine kinases (PTKs) that may be involved in the development and progression of head and neck squamous cell carcinoma (HNSCC). DESIGN: Messenger RNA from 7 HNSCC specimens was reverse transcribed to complementary DNA, and selective amplification of PTK complementary DNA was achieved using polymerase chain reaction (PCR) with degenerate PTK primers. The resulting PTK PCR products from these 7 HNSCC specimens were then cloned and randomly selected for sequencing. The PTKs that were represented multiple times in these randomly selected clones were selected as candidate PTKs that may be overexpressed in HNSCC. Antibodies against these candidate PTKs were then used for immunohistochemical studies on 8 other HNSCC specimens not used in the original selection of the candidate PTKs. RESULTS: Three known (EphA1, Brk, and Ron) and 2 novel (KIAA0728 and KIAA0279) PTKs were found to be highly expressed in the 7 HNSCC samples studied, based on the technique of reverse transcriptase-PCR with degenerate primers. Immunohistochemical studies with antibodies against the 3 known PTKs in 8 other HNSCC specimens not used in the previous reverse transcriptase-PCR reaction demonstrated overexpression of EphA1, Brk, and Ron in 12.5%, 37.5%, and 75% of these specimens. CONCLUSIONS: In this study, we identified 5 PTKs that were overexpressed in HNSCC using a reverse transcriptase-PCR technique and confirmed the overexpression of 3 known PTKs in some of the 8 archival HNSCC specimens studied. Our finding suggests that the signaling pathways mediated through EphA1, Brk, and Ron may be involved in the development and progression of HNSCC.
Subject(s)
Carcinoma, Squamous Cell/enzymology , Head and Neck Neoplasms/enzymology , Protein-Tyrosine Kinases/metabolism , Humans , Immunohistochemistry , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
OBJECTIVE: To study the effect of allogeneic, syngeneic, and autologous blood transfusion on the growth rate of the KHT tumor in a C3H murine model. DESIGN: Prospective, randomized, and controlled animal study. SUBJECTS: Sixty-one C3H female mice. INTERVENTIONS: The C3H female mice were implanted with 2 x 10(5) cells of KHT, a murine sarcoma. Ten days later, 0.3 mL of blood was removed from a retro-orbital site to simulate surgical blood loss. This blood loss was replaced by blood transfusion through a tail vein with the use of allogeneic (major histocompatibility complex incompatible), syngeneic (major histocompatibility complex compatible), or autologous blood. Tumor growth was measured daily for 14 days. The tumor growth curve for each of the animals was constructed and the mean slope of growth calculated for each group. RESULTS: There were statistically significant differences in tumor growth rate (P =.001) when the allogeneic group (mean slope = 0.232, n = 14), the syngeneic group (mean slope = 0.190, n = 17), and the autologous group (mean slope = 0.202, n = 14) were compared. A t test confirmed that there was no significant difference in the tumor growth rate between the groups transfused with syngeneic and autologous blood (P =.26). However, the rate of tumor growth in the allogeneic group was found to be significantly higher when independently compared with the syngeneic group (P<.001) and the autologous group (P =.02). CONCLUSIONS: In this experimental model of a solid murine sarcoma, allogeneic blood transfusion was associated with an increased rate of tumor growth compared with syngeneic and autologous blood transfusion, likely reflecting immunomodulatory effects incurred by the introduction of major histocompatibility complex-incompatible antigens.