Combined petrosal approach for resection of petroclival chondrosarcoma: Microsurgical 2-D video.

BACKGROUND: Petroclival lesions pose a significant neurosurgical challenge due to involvement or close proximity to important neurovascular structures. Chondrosarcomas are rare lesions that can affect these areas. CASE DESCRIPTION: A 24-year-old male with 3 months history of poor coordination, imbalance, left-sided face hypoesthesia, facial palsy House-Brackmann Grade 2, and 6th cranial nerve palsy with diplopia. Hearing was preserved. Preoperative images showed a 5.5 cm multilobulated enhancing extra-axial mass centered in the left petroclival region with extension into middle and posterior fossa causing severe (Stage 3) brainstem compression.[1] After a lengthy discussion of treatment options, the patient consented for the procedure. We performed a presigmoid retrolabyrinthine combined petrosal approach. We used cranial nerves monitoring (VII, VIII, IX, X, XI, XII), frameless stereotaxy, and a lumbar drain. Due to the tumor size and location (petroclival region with extension into the posterior and middle cranial fossa), we chose this approach to achieve a maximal safe resection of the tumor and preserve hearing. Alternative approaches of use are expanded middle fossa with transcavernous extension or expanded endonasal approach. The selected approach achieved wide exposure of the tumor which was highly vascular. The tumor was carefully dissected off the brainstem, cranial nerves (IV, V, VI, VII, VIII), and basilar artery trunk. A gross total resection was achieved (Multimedia 1). The patient did well after surgery and was extubated on postoperative day (POD) 1 and the lumbar drain removed on POD 5. Pathology reported low-grade chondrosarcoma (WHO grade I). At 3 months follow-up, the patient improved neurologically, including facial nerve weakness (House-Brackmann Grade 1) except for his left 6th cranial nerve palsy which mildly improved. CONCLUSION: Petroclival chondrosarcomas are rare tumors that are usually treated with surgical resection followed by stereotactic radiosurgery. The tumor size, location, and extension dictate approach selection. For lesions involving the petroclival region with extension into the middle fossa and posterior fossa, the combined petrosal approach is reasonable.

Auditory Brainstem Implantation: An Overview.

An auditory brainstem implant (ABI) is a surgically implanted central neural auditory prosthesis for the treatment of profound sensorineural hearing loss in children and adults who are not cochlear implant candidates due to a lack of anatomically intact cochlear nerves or implantable cochleae. The device consists of a multielectrode surface array which is placed within the lateral recess of the fourth ventricle along the brainstem and directly stimulates the cochlear nucleus, thereby bypassing the peripheral auditory system. In the United States, candidacy criteria for ABI include deaf patients with neurofibromatosis type 2 (NF2) who are 12 years or older undergoing first- or second-side vestibular schwannoma resection. In recent years, several non-NF2 indications for ABI have been explored, including bilateral cochlear nerve avulsion from trauma, complete ossification of the cochlea due to meningitis, or a severe cochlear malformation not amenable to cochlear implantation. In addition, growing experience with ABI in infants and children has been documented with encouraging outcomes. While cochlear implantation generally remains the first-line option for hearing rehabilitation in NF2 patients with stable tumors or post hearing preservation surgery where hearing is lost but a cochlear nerve remains accessible for stimulation, an ABI is the next alternative in cases where the cochlear nerve is absent and/or if the cochlea cannot be implanted. Herein, we review ABI device design, clinical evaluation, indications, operative technique, and outcomes as it relates to lateral skull base pathology.

Intralabyrinthine Schwannomas: Disease Presentation, Tumor Management, and Hearing Rehabilitation.

Intralabyrinthine schwannomas (ILS) are rare tumors that frequently cause sensorineural hearing loss. The development and increased use of magnetic resonance imaging in recent years have facilitated the diagnosis of these tumors that present with otherwise nondiscriminant symptoms such as tinnitus, vertigo, and hearing loss. The following is a review of the presentation, pathophysiology, imaging, and treatment with a focused discussion on auditory rehabilitation options of ILS.

Special Populations in Implantable Auditory Devices: Developmentally Challenged and Additional Disabilities.

Children with hearing loss and additional disabilities can benefit from cochlear implants and other implantable auditory devices. Although each individual child must be evaluated, and families uniquely counseled on goals and realistic expectations, overall many gains and benefits are possible in this population. In this article, an overview of the considerations for this group is discussed and outcomes are reviewed, including auditory and speech measures as well as benefits in other skills and quality of life.

Hearing Preservation in Pediatric Recipients of Cochlear Implants.

OBJECTIVE: To determine factors that influence low-frequency hearing preservation following pediatric cochlear implantation and compare hearing preservation outcomes between 20 and 24 mm depth lateral wall electrodes. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic referral center. PATIENTS: Pediatric cochlear implant recipients (under the age of 18) who presented preoperatively with a low-frequency pure tone average (LFPTA; 125, 250 and 500 Hz) ≤ 70 dB HL. INTERVENTION: Cochlear implantation MAIN OUTCOME MEASURES:: Multiple logistic regression evaluating the influence of variables on change in LFPTA including preoperative low-frequency hearing, lateral wall or perimodiolar electrode, progressive vs stable hearing, side, time from surgery, and the presence or the absence of enlarged vestibular aqueduct. A second analysis reviews the 12-month postactivation hearing preservation of a subset of subjects implanted with modern lateral wall electrodes. RESULTS: A total of 105 subjects were included from the last 10 years for our multiple logistic regression analysis. This demonstrated a significant correlation of poorer preoperative low-frequency hearing with change in LFPTA. A significant negative effect of electrode type, specifically perimodiolar electrodes was also seen. Forty-five subjects from the last 3 years undergoing cochlear implantation with a lateral wall electrode demonstrated an overall 12-month preservation rate (LFPTA < 90 dB) of 82%. Differences in preservation rates existed between different electrodes. CONCLUSION: Preservation of low-frequency hearing following cochlear implantation is predicted both by preoperative low-frequency hearing as well as type of electrode implanted. Consistent low-frequency hearing preservation is possible in pediatric subjects receiving lateral wall electrodes, although differences exist between electrode types.

Surgical Experience and Early Outcomes With a Slim Perimodiolar Electrode.

INTRODUCTION: In 2016 the Cochlear CI532 received FDA approval and has since been the primary full-length electrode from this manufacturer implanted at our center. Our experience to date including surgical technique and early patient outcomes are reviewed here. METHODS: Since 2016, this array was used as our standard full length Cochlear array, including children with normal anatomy, with 237 total implantations. Surgical experience and clinical outcomes including low frequency hearing preservation and speech perception on CNC words were analyzed in those with at least 6 months follow-up implanted through June 2017 (n = 94). RESULTS: Speech perception scores are improving over clinical follow-up in accord with other electrode arrays. Hearing preservation is possible with a number of patients utilizing acoustic low frequency hearing in conjunction with electric stimulation from their CI. Tip fold overs were infrequent (4.6%) and always identified on intraoperative x-ray. No patients left the operating room with a tip fold over. CONCLUSIONS: Speech perception outcomes with the CI532 slim periomodiolar array are similar to other full length arrays with the added potential for at least short term preservation of residual acoustic hearing. There is a learning curve to its use and intraoperative x-rays are valuable to ensure optimal placement.

Round window electrocochleography before and after cochlear implant electrode insertion.

OBJECTIVE/HYPOTHESIS: Previous reports have documented the feasibility of utilizing electrocochleographic (ECoG) responses to acoustic signals to assess trauma caused during cochlear implantation. The hypothesis is that intraoperative round window ECoG before and after electrode insertion will help predict postoperative hearing preservation outcomes in cochlear implant recipients. STUDY DESIGN: Prospective cohort study. METHODS: Intraoperative round window ECoG responses were collected from 31 cochlear implant recipients (14 children and 17 adults) immediately prior to and just after electrode insertion. Hearing preservation was determined by postoperative changes in behavioral thresholds. RESULTS: On average, the postinsertion response was smaller than the preinsertion response by an average of 4 dB across frequencies. However, in some cases (12 of 31) the response increased after insertion. The subsequent hearing loss was greater than the acute loss in the ECoG, averaging 22 dB across the same frequency range (250-1,000 Hz). There was no correlation between the change in the ECoG response and the corresponding change in audiometric threshold. CONCLUSIONS: Intraoperative ECoG is a sensitive method for detecting electrophysiologic changes during implantation but had limited prognostic value regarding hearing preservation in the current conventional cochlear implant patient population where hearing preservation was not intended. LEVEL OF EVIDENCE: 2b Laryngoscope, 126:1193-1200, 2016.

The Relationship Between Cochleovestibular Orientation, Age, and Sensorineural Hearing Loss: Implications for Cochlear Implantation.

OBJECTIVES: To determine if spatial orientation of the cochlea within the temporal bone is related to age or sensorineural hearing loss (SNHL) and describe the implications for cochlear implantation. METHODS: Five angles of cochlear orientation were determined from computed tomography (CT) imaging of the temporal bones in adults with (n = 55) and without (n = 27) sensorineural hearing loss (SNHL) and children with (n = 45) and without (n = 12) SNHL: facial recess versus basal turn, posterior semicircular canal versus basal turn, round window versus basal turn (axial view), round window versus basal turn (coronal view), and the cochlear axis versus the mastoid facial nerve. RESULTS: All angles showed substantial variation between subjects and between ears. The angles between the round window and basal turn (coronal view) and the posterior semicircular canal and basal turn were significantly correlated with age for all subjects with SNHL (r = 0.22, P = .002 and r = 0.15, P = .03, respectively). Patients with SNHL had significantly more acute angles (46.6° vs 55.8°) between the round window versus basal turn (axial orientation) compared to controls (P < .001). CONCLUSIONS: Cochlear orientation within the temporal bone changes with age and the degree of SNHL. These results suggest that the approach to the round window for electrode insertion might differ between children and adults.

Electrophysiologic consequences of flexible electrode insertions in gerbils with noise-induced hearing loss.

HYPOTHESIS: Flexible electrode interaction with intracochlear structures in a noise-damaged region of the cochlea can lead to measureable electrophysiologic changes. BACKGROUND: An emerging goal in cochlear implantation is preservation of residual hearing subsequently allowing for combined electric and acoustic stimulation (EAS). However, residual hearing is at least partially lost in most patients as a result of electrode insertion. A gerbil model was used to examine changes to acoustically evoked cochlear potentials during simulated cochlear implantation. METHODS: Gerbils were partially deafened by noise exposure to mimic residual hearing in human cochlear implant candidates. After 1 month, round window and intracochlear recordings during flexible electrode insertion were made in response to 1 kHz tone burst stimuli at 80 dB SPL. After the insertion, the cochleas were histologically examined for hair cell loss because of the noise exposure and trauma because of the electrode insertion. RESULTS: Anatomic damage from the flexible electrode was not observable in most cases. However, insertions caused response declines that were, on average, greater than the controls, although some losses were similar to the controls. The CM was more sensitive than the CAP for detecting cochlear disturbance. CONCLUSION: Because response reductions occurred in the absence of anatomic damage, disturbances in the fluid at the base appear to affect responses from the apex. The losses were less than in previous experiments where the basilar membrane was penetrated.

Round window electrocochleography just before cochlear implantation: relationship to word recognition outcomes in adults.

HYPOTHESES: Electrocochleography (ECoG) to acoustic stimuli can differentiate relative degrees of cochlear responsiveness across the population of cochlear implant recipients. The magnitude of the ongoing portion of the ECoG, which includes both hair cell and neural contributions, will correlate with speech outcomes as measured by results on CNC word score tests. BACKGROUND: Postoperative speech outcomes with cochlear implants vary from almost no benefit to near normal comprehension. A factor expected to have a high predictive value is the degree of neural survival. However, speech performance with the implant does not correlate with the number and distribution of surviving ganglion cells when measured postmortem. We will investigate whether ECoG can provide an estimate of cochlear function that helps predict postoperative speech outcomes. METHODS: An electrode was placed at the round window of the ear about to be implanted during implant surgery. Tone bursts were delivered through an insert earphone. Subjects included children (n = 52, 1-18 yr) and postlingually hearing impaired adults (n = 32). Word scores at 6 months were available from 21 adult subjects. RESULTS: Significant responses to sound were recorded from almost all subjects (80/84 or 95%). The ECoG magnitudes spanned more than 50 dB in both children and adults. The distributions of ECoG magnitudes and frequencies were similar between children and adults. The correlation between the ECoG magnitude and word score accounted for 47% of the variance. CONCLUSION: ECoGs with high signal-to-noise ratios can be recorded from almost all implant candidates, including both adult and pediatric populations. In postlingual adults, the ECoG magnitude is more predictive of implant outcomes than other nonsurgical variables such as duration of deafness or degree of residual hearing.

Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways.

A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals from mature single-positive thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTα, LTß, and receptor activator for NF-κB in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of single-positive thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high-affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 knockout mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development.

Intraoperative round window recordings to acoustic stimuli from cochlear implant patients.

HYPOTHESIS: Acoustically evoked neural and hair cell potentials can be measured from the round window (RW) intraoperatively in the general population of cochlear implant recipients. BACKGROUND: Cochlear implant performance varies greatly among patients. Improved methods to assess and monitor functional hair cell and neural substrate before and during implantation could potentially aid in enhanced nontraumatic intracochlear electrode placement and subsequent improved outcomes. METHODS: Subjects (1-80 yr) undergoing cochlear implantation were included. A monopolar probe was placed at the RW after surgical access was obtained. The cochlear microphonic (CM), summating potential (SP), compound action potential (CAP), and auditory nerve neurophonic (ANN) were recorded in response to tone bursts at frequencies of 0.25 to 4 kHz at various levels. RESULTS: Measurable hair cell/neural potentials were detected to 1 or more frequencies in 23 of 25 subjects. The greatest proportion and magnitude of cochlear responses were to low frequencies (<1,000 Hz). At these low frequencies, the ANN, when present, contributed to the ongoing response at the stimulus frequency. In many subjects, the ANN was small or absent, whereas hair cell responses remained. CONCLUSION: In cochlear implant recipients, acoustically evoked cochlear potentials are detectable even if hearing is extremely limited. Sensitive measures of cochlear and neural status can characterize the state of hair cell and neural function before implantation. Whether this information correlates with speech performance outcomes or can help in tailoring electrode type, placement or audiometric fitting, can be determined in future studies.

High levels of IL-7 cause dysregulation of thymocyte development.

IL-7 signaling is required for thymocyte development and its loss has a severe deleterious effect on thymus function. Thymocyte-stromal cell interactions and other mechanisms tightly regulate IL-7 expression. We show that disruption of that regulation by over-expression of IL-7 inhibits T-cell development and promotes extensive B-cell lymphopoiesis in the thymus. Our data reveal that high levels of IL-7 negate Notch-1 function in thymocytes found in IL-7 transgenic mice and in co-culture with OP9-DL1 cells. While high levels of IL-7R are present on thymocytes, increased suppressor of cytokine signaling-1 expression blunts IL-7 downstream signaling, resulting in hypo-phosphorylation of proteins in the PI3K-Akt pathway. Consequently, GSK3ß remains active and inhibits Notch-1 signaling as observed by decreased Hes-1 and Deltex expression in thymic progenitors. This is the first demonstration that high levels of IL-7 antagonize Notch-1 signaling and suggest that IL-7 may affect T- versus B-lineage choice in the thymus.

Electrophysiological properties of cochlear implantation in the gerbil using a flexible array.

OBJECTIVES: Cochlear implants (CI) perform especially well if residual acoustic hearing is retained and combined with the CI in the same ear (also termed hybrid or electric-acoustic stimulation). However, in most CI patients, residual hearing is at least partially compromised during surgery, and in some it is lost completely. At present, clinicians have no feedback on the functional status of the cochlea during electrode insertion. Development of an intraoperative physiological recording algorithm during electrode insertion could serve to detect reversible cochlear trauma and optimal placement relative to surviving hair cells. In this report, an animal model was used to assist in determining physiological markers for these conditions using a flexible electrode similar to human surgery. DESIGN: The animal model was the normal-hearing gerbil. The flexible electrodes had 1 to 2 platinum-iridium contacts embedded in a 200 µm diameter silastic carrier. As control experiments some insertions were also made with much smaller (50 µm diameter) rigid electrodes. In either case, the electrode was positioned at or just inside the round window membrane and subsequently advanced into the scala tympani longitudinally in 50 to 100 µm increments. After each advancement, acoustic stimulation was used to elicit a cochlear microphonic (CM) and compound action potential (CAP). Stimuli were suprathreshold tone bursts of 1 to 16 kHz in octave steps with 2 msec rise and fall times and a 10 msec plateau. Anatomical integrity of the cochlea was subsequently assessed using a whole-mount preparation. RESULTS: In contrast with the CAP, which was relatively stable during insertion, the CM showed a variety of changes related to electrode movement. To tone bursts of 1 to 8 kHz the CM typically remained stable or increased during the insertion before contact with cochlear structures. After contact, the potentials often dropped dramatically. The CM to 16 kHz was the most variable; in some cases it increased but in other cases it decreased early in the insertion and later showed large and abrupt increases. In some instances, this pattern was seen to progressively lower frequencies as well. Histological analysis and the gerbil frequency map indicate that electrode travel was limited to the basal turn (~4 mm from the hook) and did not intrude into the characteristic frequency regions of most frequencies used. CONCLUSIONS: First, the CM provides a more sensitive indication of cochlear trauma than does the CAP. Second, stable or steady increases in the CM are a physiological marker for unimpeded travel through the scala tympani as the electrode approaches responding hair cells. Third, abrupt reductions in the CM across frequency are a physiological marker of contact with cochlear structures. Fourth, abrupt increases after a decline, which occurred primarily to 16 kHz but to a lesser degree to other frequencies as well, are a physiological marker for a release from contact. The interpretation is that as the tip of the electrode bends the shaft can move in the mediolateral dimension, sometimes contacting the basilar membrane and sometimes not. Overall, the results indicate that recordings during cochlear implantations can provide valuable feedback to the surgeon regarding electrode position and the integrity of surviving hair cells.

Detection of intracochlear damage during cochlear implant electrode insertion using extracochlear measurements in the gerbil.

OBJECTIVES/HYPOTHESIS: An intraoperative monitoring algorithm during cochlear implant electrode insertion could be used to detect trauma and guide electrode placement relative to surviving hair cells. The aim of this report was to assess the feasibility of using extracochlear recording sites to monitor acoustically evoked responses from surviving hair cells and neural elements during implantation in an animal model. STUDY DESIGN: Animal experiments. METHODS: The normal-hearing gerbil was used. Two recording methods, one using a lock-in amplifier and another using Fourier analysis of recorded signals, were used to obtain frequency-specific information about the responses to tones. Amplitude and threshold determinations were made at the round window and at three extracochlear sites. To induce intracochlear damage, a platinum-iridium wire was inserted through the round window. The wire was advanced, and changes in the potentials were correlated with cochlear contact. Anatomic integrity was assessed using cochlea whole mount preparations. RESULTS: In general, the lock-in amplifier showed greater sensitivity and lower thresholds at higher frequencies relative to the Fourier method. Also, the lock-in amplifier was more resistant to masking effects. Both systems were able to detect loss of cochlear potentials secondary to intracochlear trauma. Histologic damage was seen in all cases and corresponded to electrophysiologic changes. CONCLUSIONS: Impact of electrodes on cochlear structures affecting cochlear performance could be detected from several extracochlear sites. The lock-in amplifier demonstrated greater sensitivity and resistance to noise when compared to the fast Fourier transform recording paradigm. The latter showed greater flexibility of detecting and separating hair cell and neural potentials.

Detection of intracochlear damage with cochlear implantation in a gerbil model of hearing loss.

HYPOTHESIS: Cochlear trauma due to electrode insertion can be detected in acoustic responses to low frequencies in an animal model with a hearing condition similar to patients using electroacoustic stimulation. BACKGROUND: Clinical evidence suggests that intracochlear damage during cochlear implantation negatively affects residual hearing. Recently, we demonstrated the usefulness of acoustically evoked potentials to detect cochlear trauma in normal-hearing gerbils. Here, gerbils with noise-induced hearing loss were used to investigate the effects of remote trauma on residual hearing. METHODS: Gerbils underwent high-pass (4-kHz cutoff) noise exposure to produce sloping hearing loss. After 1 month of recovery, each animal's hearing loss was determined from auditory brainstem responses and baseline intracochlear recording of the cochlear microphonic and compound action potential (CAP) obtained at the round window. Subsequently, electrode insertions were performed to produce basal trauma, whereas the acoustically generated potentials to a 1-kHz tone-burst were recorded after each step of electrode advancement. Hair cell counts were made to characterize the noise damage, and cochlear whole mounts were used to identify cochlear trauma due to the electrode. RESULTS: The noise exposure paradigm produced a pattern of hair cell, auditory brainstem response, and intracochlear potential losses that closely mimicked that of electrical and acoustic stimulation patients. Trauma in the basal turn, in the 15- to 30-kHz portion of the deafened region, remote from preserved hair cells, induced a decline in intracochlear acoustic responses to the hearing preserved frequency of 1 kHz. CONCLUSION: The results indicate that a recording algorithm based on physiological markers to low-frequency acoustic stimuli can identify cochlear trauma during implantation. Future work will focus on translating these results for use with current cochlear implant technology in humans.

Exogenous insulin-like growth factor 1 enhances thymopoiesis predominantly through thymic epithelial cell expansion.

Insulin-like growth factor 1 (IGF-1) enhances thymopoiesis but given the broad distribution of IGF-1 receptors (IGF-1Rs), its mechanism of action has remained unclear. To identify points of thymic regulation by IGF-1, we examined its effects on T-cell precursors, thymocytes, and thymic epithelial cells (TECs) in normal and genetically altered mice. In thymus-intact but not thymectomized mice, IGF-1 administration increased peripheral naive and recent thymic emigrant (RTE) populations, demonstrating its effect on T-cell production, not peripheral expansion. IGF-1 administration increased bone marrow LSK (lineage(-), Sca-1(+), c-kit(+)) precursor proliferation and peripheral LSK populations, increased thymocyte populations in a sequential wave of expansion, and proportionately expanded TEC subpopulations and enhanced their chemokine expression. To separate IGF-1's effects on thymocytes and TECs, we generated mice lacking IGF-1R on thymocytes and T cells. Thymocyte and RTE numbers were decreased in these mice, but IGF-1 treatment produced comparable thymocyte numbers to similarly treated wild-type mice. We additionally separated thymic- from LSK-specific effects by demonstrating that IGF-1 increased thymocyte numbers despite impaired early thymic progenitor (ETP) importation in PSGL-1KO mice. These results indicate the critical point thymic function regulation by IGF-1 involves TEC expansion regulating thymocyte precursor entry and facilitating thymocyte development.

Regulated costimulation in the thymus is critical for T cell development: dysregulated CD28 costimulation can bypass the pre-TCR checkpoint.

Expression of CD28 is highly regulated during thymic development, with CD28 levels extremely low on immature thymocytes but increasing dramatically as CD4- CD8- cells initiate expression of TCRbeta. B7-1 and B7-2, the ligands for CD28, have a restricted distribution in the thymic cortex where immature thymocytes reside and are more highly expressed in the medulla where the most mature thymocytes are located. To determine the importance of this regulated CD28/B7 expression for T cell development, we examined the effect of induced CD28 signaling of immature thymocytes in CD28/B7-2 double-transgenic mice. Strikingly, we found that differentiation to the CD4+ CD8+ stage in CD28/B7-2 transgenics proceeds independent of the requirement for TCRbeta expression manifest in wild-type thymocytes, occurring even in Rag- or CD3epsilon- knockouts. These findings indicate that signaling of immature thymocytes through CD28 in the absence of TCR- or pre-TCR-derived signals can promote an aberrant pathway of T cell differentiation and highlight the importance of finely regulated physiologic expression of CD28 and B7 in maintaining integrity of the "beta" checkpoint for pre-TCR/TCR-dependent thymic differentiation.

Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8+ T cell tumorigenesis.

Tumorigenesis in rodents, as well as in humans, has been shown to be a multistep process, with each step reflecting an altered gene product or gene regulatory process leading to autonomy of cell growth. Initial genetic mutations are often associated with dysfunctional growth regulation, as is demonstrated in several transgenic mouse models. These changes are often followed by alterations in tumor suppressor gene function, allowing unchecked cell cycle progression and, by genomic instability, additional genetic mutations responsible for tumor metastasis. Here we show that reduced transforming growth factor-beta signaling in T lymphocytes leads to a rapid expansion of a CD8+ memory T-cell population and a subsequent transformation to leukemia/lymphoma as shown by multiple criteria, including peripheral blood cell counts histology, T-cell receptor monoclonality, and host transferability. Furthermore, spectral karyotype analysis of the tumors shows that the tumors have various chromosomal aberrations. These results suggest that reduced transforming growth factor-beta signaling acts as a primary carcinogenic event, allowing uncontrolled proliferation with consequent accumulation of genetic defects and leukemic transformation.

A dose effect of IL-7 on thymocyte development.

To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced alphabeta T-cell development. In contrast, in the highest overexpressing founder line, TgB, alphabeta T-cell development was disturbed with a block at the earliest intrathymic precursor stage. This was due to decreased progenitor proliferation as assessed by Ki-67 staining and in vivo bromodeoxyuridine (BrdU) incorporation. Bcl-2 was up-regulated in T-cell-committed progenitors in all Tg lines, and accounted for greater numbers of double positive (DP), CD4 single positive (SP), and CD8SP thymocytes in TgA mice where, in contrast to TgB mice, thymocyte progenitor proliferation was normal. Mixed marrow chimeras using TgB(+) and congenic mice as donors, and experiments using anti-IL-7 monoclonal antibody (MAb) in vivo, confirmed the role of IL-7 protein in the observed TgB phenotype. In conclusion, at low Tg overexpression, IL-7 enhanced alphabeta T-cell development by increasing thymocyte progenitor survival, while at high overexpression IL-7 reduces their proliferation, inducing a dramatic block in DP production. These results show for the first time in vivo a dose effect of IL-7 on alphabeta T-cell development and have implications for IL-7 in the clinical setting.