Mixed HPV-related Neuroendocrine Carcinoma and HPV-related Squamous Cell Carcinoma of the Base of Tongue in a Patient With Incidental Identification of Synchronous Metastatic Papillary Thyroid Carcinoma.

BACKGROUND: While it is not uncommon in patients with head and neck cancer to present with multiple metachronous primary neoplasms, rarely do these present as a singular mass composed of intertwined, histologically distinct malignant tumors. Sometimes referred to as collision tumors, these entities are poorly understood and only appear in a handful of case studies in the literature. CASE REPORT: Here we present a 58-year-old male diagnosed with a human papillomavirus-related collision tumor consisting of oropharyngeal squamous cell carcinoma and small-cell neuroendocrine carcinoma, as well as an incidentally discovered metastatic thyroid papillary carcinoma, despite an unremarkable thyroid gland. The patient underwent transoral robotic base-of-tongue resection and partial pharyngectomy with selective neck dissection followed by chemoradiotherapy. At the 18-month follow-up the patient was doing well. His thyroid was normal and no recurrent or metastatic carcinoma was identified on the computed tomography and positron-emission tomography/computed tomography imaging findings. CONCLUSION: To the best of our knowledge, this is the first such case in English literature. This case demonstrates the importance of tumor morphology and immunohistochemical testing in HPV-related oropharyngeal carcinomas, despite the overall good prognosis of such tumors, due to the possibility of synchronous or colliding primary neoplasms.

Free Flap Reconstruction Monitoring Techniques and Frequency in the Era of Restricted Resident Work Hours.

Importance: Free flap reconstruction of the head and neck is routinely performed with success rates around 94% to 99% at most institutions. Despite experience and meticulous technique, there is a small but recognized risk of partial or total flap loss in the postoperative setting. Historically, most microvascular surgeons involve resident house staff in flap monitoring protocols, and programs relied heavily on in-house resident physicians to assure timely intervention for compromised flaps. In 2003, the Accreditation Council for Graduate Medical Education mandated the reduction in the hours a resident could work within a given week. At many institutions this new era of restricted resident duty hours reshaped the protocols used for flap monitoring to adapt to a system with reduced resident labor. Objectives: To characterize various techniques and frequencies of free flap monitoring by nurses and resident physicians; and to determine if adapted resident monitoring frequency is associated with flap compromise and outcome. Design, Setting, and Participants: This multi-institutional retrospective review included patients undergoing free flap reconstruction to the head and/or neck between January 2005 and January 2015. Consecutive patients were included from different academic institutions or tertiary referral centers to reflect evolving practices. Main Outcomes and Measures: Technique, frequency, and personnel for flap monitoring; flap complications; and flap success. Results: Overall, 1085 patients (343 women [32%] and 742 men [78%]) from 9 institutions were included. Most patients were placed in the intensive care unit postoperatively (n = 790 [73%]), while the remaining were placed in intermediate care (n = 201 [19%]) or in the surgical ward (n = 94 [7%]). Nurses monitored flaps every hour (q1h) for all patients. Frequency of resident monitoring varied, with 635 patients monitored every 4 hours (q4h), 146 monitored every 8 hours (q8h), and 304 monitored every 12 hours (q12h). Monitoring techniques included physical examination (n = 949 [87%]), handheld external Doppler sonography (n = 739 [68%]), implanted Doppler sonography (n = 333 [31%]), and needle stick (n = 349 [32%]); 105 patients (10%) demonstrated flap compromise, prompting return to the operating room in 96 patients. Of these 96 patients, 46 had complete flap salvage, 22 had partial loss, and 37 had complete loss. The frequency of resident flap checks did not affect the total flap loss rate (q4h, 25 patients [4%]; q8h, 8 patients [6%]; and q12h, 8 patients [3%]). Flap salvage rates for compromised flaps were not statistically different. Conclusions and Relevance: Academic centers rely primarily on q1h flap checks by intensive care unit nurses using physical examination and Doppler sonography. Reduced resident monitoring frequency did not alter flap salvage nor flap outcome. These findings suggest that institutions may successfully monitor free flaps with decreased resident burden.

The degree of intratumor mutational heterogeneity varies by primary tumor sub-site.

In an era where mutational profiles inform treatment options, it is critical to know the extent to which tumor biopsies represent the molecular profile of the primary and metastatic tumor. Head and neck squamous cell carcinoma (HNSCC) arise primarily in the mucosal lining of oral cavity and oropharynx. Despite aggressive therapy the 5-year survival rate is at 50%. The primary objective of this study is to characterize the degree of intratumor mutational heterogeneity in HNSCC. We used multi-region sequencing of paired primary and metastatic tumor DNA of 24 spatially distinct samples from seven patients with HNSCC of larynx, floor of the mouth (FOM) or oral tongue. Full length, in-depth sequencing of 202 genes implicated in cancer was carried out. Larynx and FOM tumors had more than 69.2% unique SNVs between the paired primary and metastatic lesions. In contrast, the oral tongue HNSCC had only 33.3% unique SNVs across multiple sites. In addition, HNSCC of the oral tongue had fewer mutations than larynx and FOM tumors. These findings were validated on the Affymetrix whole genome 6.0 array platform and were consistent with data from The Cancer Genome Atlas (TCGA). This is the first report demonstrating differences in mutational heterogeneity varying by subsite in HNSCC. The heterogeneity within laryngeal tumor specimens may lead to an underestimation of the genetic abnormalities within tumors and may foster resistance to standard treatment protocols. These findings are relevant to investigators and clinicians developing personalized cancer treatments based on identification of specific mutations in tumor biopsies.

Obesity and perioperative complications in head and neck free tissue reconstruction.

BACKGROUND: Free tissue transfer is a mainstay in reconstruction of complex head and neck defects. The purpose of this study was to determine if perioperative complications were more common in patients with body mass index (BMI) >30 kg/m(2) undergoing free flap reconstruction. METHODS: A multi-institutional retrospective cohort was created. Medical complications, surgical complications, and procedural variables were recorded. Logistic regression was used to investigate univariate and multivariate associations between outcomes and predictors. RESULTS: Of 582 cases, 128 patients (22%) had BMI >30. Surgical complications occurred in 153 cases (26.3%), with an adjusted odds ratio (OR) for association of surgical complications with BMI >30 of 0.92 (p = .71). Medical complications occurred in 178 cases (30.6%), with an adjusted OR of 0.78 (p = .26). Age and advanced comorbidity status (Adult Comorbidity Evaluation-27 [ACE-27] 2 or 3) were associated with medical complications (p < .0001). CONCLUSION: BMI >30 does not predict medical or surgical complications in patients undergoing head and neck free flap surgery. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1188-E1191, 2016.

Long-term Functional Outcomes of Total Glossectomy With or Without Total Laryngectomy.

IMPORTANCE: The optimal reconstruction of total glossectomy defects with or without total laryngectomy is controversial. Various pedicled and free tissue flaps have been advocated, but long-term data on functional outcomes are not available to date. OBJECTIVES: To compare various total glossectomy defect reconstructive techniques used by multiple institutions and to identify factors that may lead to improved long-term speech and swallowing function. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional, retrospective review of electronic medical records of patients undergoing total glossectomy at 8 participating institutions between June 1, 2001, and June 30, 2011, who had a minimal survival of 2 years. INTERVENTION: Total glossectomy with or without total laryngectomy. MAIN OUTCOMES AND MEASURES: Demographic and surgical factors were compiled and correlated with speech and swallowing outcomes. RESULTS: At the time of the last follow-up, 45% (25 of 55) of patients did not have a gastrostomy tube, and 76% (42 of 55) retained the ability to verbally communicate. Overall, 75% (41 of 55) of patients were tolerating at least minimal nutritional oral intake. Feeding tube dependence was not associated with laryngeal preservation or the reconstructive techniques used, including flap suspension, flap innervation, or type of flap used. Laryngeal preservation was associated with favorable speech outcomes, such as the retained ability to verbally communicate in 97% of those not undergoing total laryngectomy (35 of 36 patients) vs 44% (7 of 16) in those undergoing total laryngectomy (P < .001), as well as those not undergoing total laryngectomy achieving some or all intelligible speech in 85% (29 of 34 patients) compared with 31% (4 of 13) undergoing total laryngectomy achieving the same intelligibility (P < .001). CONCLUSIONS AND RELEVANCE: In patients with total glossectomy, feeding tube dependence was not associated with laryngeal preservation or the reconstructive technique, including flap innervation and type of flap used. Laryngeal preservation was associated with favorable speech outcomes such as the retained ability to verbally communicate and higher levels of speech intelligibility.

Tracheotomy tubes with suction above the cuff reduce the rate of ventilator-associated pneumonia in intensive care unit patients.

OBJECTIVES: We evaluated the effect of tracheotomy tubes that enable suction immediately above the cuff on the development of ventilator-associated pneumonia (VAP). METHODS: Patients without preexisting pneumonia who required tracheotomy were randomly assigned to receive a tracheotomy tube with or without above-the-cuff suction. The suction tube provided 10 mm Hg of continuous wall suction while the tracheotomy tube cuff was inflated. Data regarding the development of VAP, time on the ventilator, and length of stay in the intensive care unit (ICU) were recorded and compared between groups. RESULTS: Eighteen patients were randomized and prospectively evaluated. Nine patients received standard tracheotomy tubes, and 9 received suction-above-the-cuff tracheotomy tubes. The prevalences of VAP were 56% in the control group and 11% in the suction tracheotomy group (p = 0.02). The mean times on the ventilator were 18 +/- 14 days in the control group and 11 +/- 11 days in the suction group (p = 0.12). The mean lengths of ICU stay were 26 +/- 15 days in the control group and 18 +/- 15 days in the suction group (p = 0.14). CONCLUSIONS: Use of suction-above-the-cuff tracheotomy tubes significantly decreases the incidence of VAP in ICU patients. There were trends toward decreased time on the ventilator and decreased length of stay in the ICU.

Artificial muscle for reanimation of the paralyzed face: durability and biocompatibility in a gerbil model.

BACKGROUND: Current management of permanent facial paralysis centers on nerve grafting and muscle transfer; however, limitations of those procedures call for other options. OBJECTIVES: To determine the durability and biocompatibility of implanted artificial muscle in a gerbil model and the degree of inflammation and fibrosis at the host tissue-artificial muscle interface. METHODS: Electroactive polymer artificial muscle (EPAM) devices engineered in medical-grade silicone were implanted subcutaneously in 13 gerbils. The implanted units were stimulated with 1 kV at 1 Hz, 24 h/d via a function generator. Electrical signal input/output was recorded up to 40 days after implantation. The animals were euthanized between 23 and 65 days after implantation, and the host tissue-implant interface was evaluated histologically. RESULTS: The animals tolerated implantation of the EPAM devices well, with no perioperative deaths. The muscle devices created motion for a mean of 30.3 days (range, 19-40 days), with a mean of 2.6 × 106 cycles (range, 1.6 × 106 to 3.5 × 106 cycles). Histologic examination of the explanted devices revealed the development of a minimal fibrous capsule surrounding the implants, with no evidence of bacterial infection or inflammatory infiltrate. No evidence of device compromise, corrosion, or silicone breakdown was noted. CONCLUSIONS: Artificial muscle implanted in this short-term animal model was safe and functional in this preliminary study. We believe that EPAM devices will be a safe and viable option for restoration of facial motions in patients with irreversible facial paralysis.

The effects of tolerance on allograft damage caused by the innate immune system.

BACKGROUND: It is not known whether tolerance can be induced in a strong proinflammatory milieu or whether the induction of tolerance can prevent interferon (IFN)-gamma-associated graft injury. To address these questions, we studied the effects of rIFN-gamma infusion on porcine cardiac allograft survival. METHODS: Recombinant interferon (rIFN)-gamma was continuously infused into the left anterior descending artery of hearts transplanted into major histocompatibility complex-inbred miniature swine treated with a 12-day course of cyclosporine A. Group 1 recipients received a nearly syngeneic heart, group 2 recipients received a class I disparate heart, and group 3 recipients were cotransplanted with a class I-disparate heart and kidney, a procedure demonstrated to induce tolerance to both grafts. A fourth group of animals were not transplanted but received intracoronary rIFN-gamma infusion into the native heart. RESULTS: rIFN-gamma perfusion not only accelerated the acute rejection of class I-disparate hearts (mean survival time, 19+/-7.21 vs. 38+/-8.19; P=0.025) but caused near-syngeneic heart transplants, which otherwise survived indefinitely, to reject within 35 days. In contrast, rIFN-gamma perfusion had no demonstrable effects on hearts grafts in tolerant recipients or on autologous hearts. CONCLUSIONS: These results suggest that tolerance induction can occur in the presence of IFN-gamma-mediated inflammation, and that tolerance induction can prevent the tissue injury caused by the overproduction of IFN-gamma. This suggests that the beneficial effects of tolerance may include protection from nonspecific inflammatory responses, such as those produced by ischemia-reperfusion injury and brain death.

The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics.

Although much is known about the migration of T cells from blood to lymph nodes, less is known about the mechanisms regulating the migration of T cells from tissues into lymph nodes through afferent lymphatics. Here we investigated T cell egress from nonlymphoid tissues into afferent lymph in vivo and developed an experimental model to recapitulate this process in vitro. Agonism of sphingosine 1-phosphate receptor 1 inhibited the entry of tissue T cells into afferent lymphatics in homeostatic and inflammatory conditions and caused the arrest, mediated at least partially by interactions of the integrin LFA-1 with its ligand ICAM-1 and of the integrin VLA-4 with its ligand VCAM-1, of polarized T cells at the basal surface of lymphatic but not blood vessel endothelium. Thus, the increased sphingosine 1-phosphate present in inflamed peripheral tissues may induce T cell retention and suppress T cell egress.

Sphingosine 1-phosphate receptor modulators: a new class of immunosuppressants.

In this review, we summarize how FTY720 came from the lab bench to the bedside by examining its structural similarities to natural occurring sphingosine analogues, the mechanism of action, and clinical applicability to not only transplantation but also autoimmune, oncological, and neurobiological fields. FTY720, a sphingosine 1-phosphate (S1P) analogue, promotes the survival of human and animal allografts by sequestering T lymphocytes within peripheral lymphoid tissue. The mechanism of sequestration is three-fold: (1) T lymphocytes are driven into peripheral lymph nodes in a chemokine dependent manner by FTY720; (2) FTY720 downregulates sphingosine 1-phosphate receptors (S1PRs) on the T lymphocyte surface, rendering it unable to migrate along a S1P gradient; and (3) FTY720 closes stromal gates on the abluminal side of the lymphatic endothelium. Future areas of investigation include developing S1P analogues that have specific agonist binding to S1PRs avoiding side effects seen in non-specific binding.

Combination treatment with donor-specific transfusions and cyclosporine a induces long-term survival of cardiac allografts in miniature Swine.

BACKGROUND: To evaluate whether pretransplant donor-specific transfusions (DST) can induce tolerance to cardiac allografts in large animals, heterotopic cardiac transplants were performed across a class I MHC barrier in inbred miniature swine. METHODS: Experimental animals received two DSTs, each containing 1.4x10 viable peripheral blood mononuclear cells, 14 and 7 days prior to transplantation together with a 12-day course of cyclosporine (CyA) (13 mg/kg IV) starting on postoperative day (POD) 0. RESULTS: Untreated (n=2) and DST-only (n=2) treated control animals rejected between POD 6 and 8. Animals treated with CyA alone (n=3) exhibited graft survival to 53, 52 and 59 days. In contrast, the combination of DST and CyA (n=3) led to stable graft function for >200 days. Long-term survivors maintained peripheral CML response against donor antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased (P=0.011), and a significant number of CD8+ T cells underwent apoptosis (10.1% on POD 0; 5.2% on POD -14; P=0.04). None of the DST-treated animals developed donor-specific antibodies. CONCLUSIONS: These results are the first to demonstrate the ability of DST to induce operational tolerance to cardiac allografts in large animals, and they suggest that peripheral mechanisms of tolerance mediate this effect.

Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine.

The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection.

Genes, germs, and schizophrenia: an evolutionary perspective.

Literature on schizophrenia and other mental illnesses has emphasized the compatibility of evidence with genetic causation without adequately considering alternative hypotheses of disease causation. Although some studies from the mid-20th century reported associations between certain pathogens and schizophrenia, only recently has the possibility of infectious causation of schizophrenia again become an active focus of research. Infectious causation of schizophrenia is still, however, generally regarded as less well demonstrated than genetic causation. This article evaluates the evidence that has been used to support genetic and infectious causation. Our consideration of infectious causation focuses on the protozoan Toxoplasma gondii but also assesses other pathogens that may contribute to the development of some of the illnesses currently categorized as schizophrenia. Although evidence generally accepted as demonstrating genetic causation can be readily explained by hypotheses of infectious causation, some of the evidence implicating infectious causation cannot be similarly explained by genetic causation. This asymmetry indicates that a scientific approach to the causation of schizophrenia needs to put a greater emphasis on tests that distinguish hypotheses of genetic causation from those of infectious causation.