Incidence of pulmonary toxicity in bleomycin-containing regimens for testicular cancer with and without the use of growth factor.

INTRODUCTION: The concurrent use of bleomycin and granulocyte colony-stimulating factors (G-CSFs) has historically been debated as a risk factor for bleomycin-induced pulmonary toxicity in patients with both testicular cancer and Hodgkin's lymphoma. The purpose of this study is to evaluate the incidence of pulmonary toxicity in patients with testicular cancer who were treated with bleomycin and pegfilgrastim concurrently. METHODS: This is a retrospective study that includes male patients over the age of 18 years old diagnosed with testicular cancer who received bleomycin-containing chemotherapy regimens with and without the use of G-CSF agents. RESULTS: There were a total of 33 patients identified as receiving bleomycin, with 30 of those patients having received concurrent G-CSF therapy. Of the patients who received G-CSF therapy, 11 patients (36.6%) experienced pulmonary toxicity leading to discontinuation of bleomycin or changes in chemotherapy regimens altogether. CONCLUSION: There were no major differences in patient demographics or risk factors between those who received G-CSF and developed pulmonary toxicity and those who received G-CSF but did not develop pulmonary toxicity. Further studies are needed in order to fully assess the risk of pulmonary toxicity with this chemotherapy regimen.

A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. METHODS: Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. RESULTS: The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. CONCLUSIONS: In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND Prostate cancer growth is primarily driven by testosterone and 5a-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. MATERIAL AND METHODS This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22-26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. RESULTS Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36-240.46), 13.82 ng/mL (2.91-29.96), and 15.7 ng/mL (3.58-26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was -0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was -0.31 (P=0.54). CONCLUSIONS This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

UNLABELLED: Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. INTRODUCTION: Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. METHODS: To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. RESULTS: +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. CONCLUSIONS: Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

Case-Based Clinical Guidance on Dosing and Management of the Hepatic Artery Infusion Chemotherapy Pump.

Hepatic artery infusion (HAI) delivers localized high-dose floxuridine directly to liver tumors through an implanted pump. While patients are undergoing active treatment, the pump is refilled with chemotherapy alternating with saline every 2 weeks using a specialized noncoring needle. Numerous clinical scenarios influence the dosing of floxuridine, which do not conform to the usual dose modification schema for systemic chemotherapy. This article aims to provide practical clinical management solutions to overcome the common challenges faced by oncologists in the real-world management of HAI pump therapy.

Case report: Enfortumab vedotin induced refractory DKA and multi organ failure - a rare fatal adverse event.

There are very few therapeutic options to treat patients with locally advanced or metastatic Urothelial Cancer (UC). Enfortumab vedotin (EV) was recently approved by the FDA and has become a new therapeutic option for patients previously managed with conventional treatments. Despite its efficacy, EV carries the potential for infrequent yet severe adverse effects. In this report, we present a case of a patient undergoing EV treatment for urothelial carcinoma who developed refractory diabetic ketoacidosis (DKA) unresponsive to escalating insulin doses and necessitating continuous renal replacement therapy. While DKA was resolved, the patient eventually succumbed to progressive maculopapular skin rash, liver failure, and respiratory failure. Additionally, the study delves into a review of cases of EV-induced refractory DKA in the literature, shedding light on the similarities in patient profiles, timelines of adverse effects and the treatment strategies employed to manage the ensuing complications.

Starting a successful hepatic artery infusion pump program: A practical guide.

Implementation of a successful hepatic artery infusion pump program requires numerous factors to be in place, and the lack of any of these may lead to program failure. First and foremost, hepatic artery infusion pump programs must have adequate surgical expertise in the complex technical aspects of hepatic artery infusion pump implantation and postoperative management. Most new hepatic artery infusion pump programs are initiated by a surgeon and led in conjunction with a medical oncologist. Medical oncology experience in floxuridine dosing is critical in maximizing the treatment doses and the number of cycles administered while avoiding biliary toxicity. This is facilitated by collaboration with an engaged pharmacy team. To have adequate patient volume for a successful program, internal and external stakeholders must have buy-in, including surgical and medical oncology colleagues unfamiliar with hepatic artery infusion pumps, colorectal surgery, and other referring providers. Programmatic support must be obtained from the hospital, cancer center, and department administration. Day-to-day pump access for chemotherapy and maintenance saline fills must be performed by appropriately trained infusion nurses to avoid complications. Nuclear and diagnostic radiology experience is key to identifying extrahepatic perfusion and hepatic artery infusion pump-specific complications. Additionally, skilled interventional radiologists and gastroenterologists are necessary to identify and treat rare complications rapidly. Finally, given the current rapid expansion of hepatic artery infusion pump programs, new programs must identify engaged mentors to help guide patient selection, navigate the nuanced issues that may arise, and provide advice in the case of complications. Although hepatic artery infusion pump dissemination outside of several major tertiary centers previously had stalled, establishing a successful and active hepatic artery infusion pump is feasible with appropriate training, mentorship, and thoughtful assembly of a dedicated multidisciplinary team.

A Phase I Dose Escalation and Expansion Study of Epidiolex (Cannabidiol) in Patients with Biochemically Recurrent Prostate Cancer.

PURPOSE: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa. EXPERIMENTAL DESIGN: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints. RESULTS: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved). CONCLUSION: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

Case Report: Safety and Efficacy of Enfortumab Vedotin in a Patient With Metastatic Urothelial Carcinoma Undergoing Peritoneal Dialysis.

The clinical management of metastatic urothelial carcinoma has significantly evolved with the emergence of monoclonal antibodies and antibody-drug conjugates (ADCs). Enfortumab vedotin (EV) was granted approval by the FDA in 2021 for patients with locally advanced or metastatic urothelial carcinoma who have received prior immunotherapy and platinum-containing chemotherapy. Little to no data exist for the use of EV in patients with concurrent end-stage renal disease (ESRD) using either hemodialysis or peritoneal dialysis (PD). Here, we present the case of a patient with metastatic urothelial carcinoma on PD who failed multiple lines of treatment but demonstrated an impressive response to EV without significant toxicity. We discuss the possible impact of peritoneal dialysis on the pharmacokinetics of ADCs and the potential for safe administration based on known pharmacokinetic data.

A Case Report of Metastatic Castration-Resistant Prostate Cancer Harboring a PTEN Loss.

The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has dramatically improved over the last decade; however, patients with visceral metastases are still faced with poor outcomes. Phosphatase and tensin homolog (PTEN) loss is observed in 40%-60% of mCRPC patients and is also associated with a poor prognosis. Several PI3K/AKT/mTOR pathway inhibitors have been studied, with disappointing anti-tumor activity. Here, we present a case of a patient with heavily treated mCRPC who had a modest tumor response to concurrent carboplatin, abiraterone acetate/prednisone, and liver-directed radiation therapy. We discuss the potential rationale supporting the use of this combination therapy and its safety in mCRPC. While the underlying basic mechanism of our patient's anti-tumor response remains uncertain, we suggest that further prospective studies are warranted to evaluate whether this combination therapy is effective in this population of patients with pre-treated mCRPC and PTEN loss.

Transgenic over-expression of plasminogen activator inhibitor-1 results in age-dependent and gender-specific increases in bone strength and mineralization.

The plasminogen activation system (PAS) and its principal inhibitor, plasminogen activator inhibitor-1 (PAI-1), are recognized modulators of matrix. In addition, the PAS has previously been implicated in the regulation of bone homeostasis. Our objective was to study the influence of active PAI-1 on geometric, biomechanical, and mineral characteristics of bone using transgenic mice that over-express a variant of human PAI-1 that exhibits enhanced functional stability. Femora were isolated from male and female, wildtype (WT) and transgenic (PAI-1.stab) mice at 16 and 32 weeks of age (n=10). Femora were imaged via DEXA for BMD and muCT for cortical mid-slice geometry. Torsional testing was employed for biomechanical properties. Mineral composition was analyzed via instrumental neutron activation analysis. Female femora were further analyzed for trabecular bone histomorphometry (n=11). Whole animal DEXA scans were performed on PAI-1.stab females and additional transgenic lines in which the functional domains of the PAI-1 protein were specifically disrupted. Thirty-two week female PAI-1.stab femora exhibited decreased mid-slice diameters and reduced polar moment of area compared to WT, while maintaining similar cortical bone width. Greater biomechanical strength and stiffness were demonstrated by 32 week PAI-1.stab female femora in addition to a 52% increase in BMD. PAI-1.stab trabecular bone architecture was comparable to WT. Osteoid area was decreased in PAI-1.stab mice while mineral apposition rate increased by 78% over WT. Transgenic mice expressing a reactive-site mutant form of PAI-1 showed an increase in BMD similar to PAI-1.stab, whereas transgenic mice expressing a PAI-1 with reduced affinity for vitronectin were comparable to WT. Over-expression of PAI-1 resulted in increased mineralization and biomechanical properties of mouse femora in an age-dependent and gender-specific manner. Changes in mineral preceded increases in strength/stiffness and deterred normal cross-sectional expansion of cortical bone in females. Trabecular bone was not altered in PAI-1.stab mice whereas MAR increased significantly, further supporting mineral changes as the underlying factor in strength differences. The primary influence of PAI-1 occurred during a period of basal bone remodeling, attributing a role for this system in remodeling as opposed to development. Comparison of transgenic lines indicates that PAI-1's influence on bone is dependent on its ability to bind vitronectin, and not on its proteolytic activity. The impact of PAI-1 on mouse femora supports a regulatory role of the plasminogen activation system in bone homeostasis, potentially elucidating novel targets for the treatment of bone disease.

Isolation and characterization of an autonomously replicating sequence from Ustilago maydis.

DNA fragments that function as autonomously replicating sequences (ARSs) have been isolated from Ustilago maydis. When inserted into an integrative transforming vector, the fragments increased the frequency of U. maydis transformation several-thousandfold. ARS-containing plasmids were transmitted in U. maydis as extrachromosomal elements through replication. They were maintained at a level of about 25 copies per cell but were mitotically unstable. One ARS characterized in detail, which we called UARS1, was localized to a 1.7-kilobase fragment. UARS1 contained a cluster of active sequences. This element could be reduced further into three separate subfragments, each of which retained ARS activity. The smallest one was 383 base pairs (bp) long. Although not active itself in yeast, this small fragment contained seven 8-bp direct repeats, two contiguous 30-bp direct repeats, and five 11-bp units in both orientations with sequences similar but not identical to the consensus sequence found to be crucial for ARS activity in Saccharomyces cerevisiae.

Differential expression of the myocyte enhancer factor 2 family of transcription factors in development: the cardiac factor BBF-1 is an early marker for cardiogenesis.

In the present study, we have used single chicken blastoderms of defined early developmental stages, beginning with the prestreak stage, stage 1 (V. Hamburger and H. L. Hamilton, J. Morphol. 88:49-92, 1951), to analyze the onset of cardiac myogenesis by monitoring the appearance of selected cardiac muscle tissue-specific gene transcripts and the functional expression of the myocyte enhancer factor 2 (MEF-2) proteins. Using gene-specific oligonucleotide primers in reverse transcriptase PCR assay, we have demonstrated that the cardiac myosin light-chain 2 (MLC2) and alpha-actin gene transcripts appear as early as stage 5, i.e., immediately after the cardiogenic fate assignment at stage 4. Consistent with this observation is the developmental expression pattern of DNA-binding activity of BBF-1, a cardiac muscle-specific member of the MEF-2 protein family, which also begins at stage 5 prior to MEF-2. Differential expression of DNA-binding complexes is also observed with another AT-rich DNA sequence (CArG box) as probe, but the binding pattern with the ubiquitous TATA-binding proteins remains unchanged during the same developmental period. Thus, the cardiogenic commitment and differentiation of the precardiac mesoderm, as exemplified by the appearance of cardiac MEF-2, MLC2, and alpha-actin gene products, occur earlier than previously thought and appear to be closely linked. The onset of skeletal myogenic program follows that of the cardiogenic program with the appearance of skeletal MLC2 at stage 8. We also observed that mRNA for the MEF-2 family of proteins appears as early as stage 2 and that for CMD-1, the chicken counterpart of MyoD, appears at stage 5. The temporal separation of activation of cardiac and skeletal MLC2 genes, which appears immediately after the respective fate assignments, and those of cardiac MEF-2 and CMD-1, which occur before, are consistent with the established appearance of the myogenic programs and with the acquisition pattern of the two tissue-specific morphological characteristics in the early embryo. The preferential appearance of BBF-1 activity in precardiac moesderm, relative to that of MEF-2, indicates that these two protein factors are distinct members of the MEF-2 family and provides a compelling argument in support of the potential role of BBF-1 as a regulator of the cardiogenic cell lineage determination, while cardiac MEF-2 might be involved in maintenance of the cardiac differentiative state.

Comparison of vestibular and abducens internuclear projections to the medial rectus subdivision of the oculomotor nucleus in the monkey.

Comparisons were made of projections from the vestibular nuclei (VN) and abducens internuclear neurons (AIN) to cell group A of the medial rectus subdivision (MRS) of the oculomotor nuclear complex. Cell group A, the major component of the MRS, receives projections only from the ipsilateral VN and the contralateral AIN. Neither ipsilateral vestibular projections to cell group A, arising from the medial vestibular nucleus, nor projections from MVN to the opposite abducens nucleus, match the massive projection of AIN to the MRS.

Distribution of primary vestibular fibers in the brainstem and cerebellum of the monkey.

Attempts were made to determine the central projections of ganglion cells innervating individual semicircular ducts in the monkey by implanting or injecting tritiated amino acids (leucine and/or proline), or horseradish peroxidase (HRP), selectively into a single ampulla. Central transport via the vestibular ganglion in animals receiving isotope implants or injections fell into three categories: (1) transport from ganglion cells innervating all receptive elements of the labyrinth, (2) transport from ganglion cells innervating the three semicircular ducts, and (3) transport from cells of the inferior vestibular ganglion innervating the posterior semicircular duct. Transneuronal transport of isotope was observed in secondary vestibular fibers in animals where proline was used and survival exceeded 12 days. Transneuronal labeling of secondary auditory fibers was independent on the [3H]amino acid used, and occurred with survivals of 10 or more days. HRP implanted into the ampulla of the lateral semicircular duct in several animals produced retrograde transport to efferent vestibular and cochlear neurons, but did not result in transganglionic labeling of primary vestibular or auditory fibers. Primary vestibular fibers terminate throughout the superior (SVN) and medial vestibular nuclei (MVN). Within SVN, terminals are most pronounced in its central large-celled portion, but extend into peripheral parts of the nucleus, except for a small medial area near its junction with the oral pole of MVN. Primary projections to MVN are homogenously distributed throughout the nucleus excepting a small circular area of sparse terminals along its ventral margin. Primary vestibular afferents terminate mainly in rostral and caudal portions of the inferior vestibular nucleus (IVN), but do not reach cell group 'f'. Projections to the lateral vestibular nucleus (LVN) are restricted to its ventral part. Primary projections to the accessory vestibular nuclei reach the interstitial nucleus of the vestibular nerve (NIVN) and cell group 'y'. Fibers project beyond the vestibular nuclei (VN) to terminate ipsilaterally in the accessory cuneate nucleus (ACN), the subtrigeminal lateral reticular nucleus (SLRN), and well-defined portions of the reticular formation (RF). Projections to SVN and MVN are derived primarily from ganglion cells innervating the semicircular ducts, while projections to caudal IVN, cell group 'y' and ACN are related mainly to macular portions of the vestibular ganglion. NIVN receives both macular and duct afferents.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent and efferent connections of the medial, inferior and lateral vestibular nuclei in the cat and monkey.

Attempts were made to determine the afferent and efferent connections of the medial (MVN), inferior (IVN) and lateral (LVN) vestibular nuclei (VN) in the cat and monkey using retrograde and anterograde axoplasmic transport technics. Injections of HRP and [3H]amino acids were made selectively into MVN, IVN and LVN and into: (1) MVN and IVN, (2) LVN and IVN and (3) all 4 VN. Contralateral afferents to MVN arise from (1) the nuclei prepositus (NPP) and intercalatus (NIC), (2) all parts of MVN and cell group 'y' and (3) parts of the superior vestibular nucleus (SVN), IVN and the fastigial nucleus (FN). Ipsilateral projections to MVN arise from: (1) a central band of the flocculus and the nodulus and uvula, (2) the interstitial nucleus of Cajal (INC), and (3) visceral nuclei of the oculomotor nuclear complex (OMC). Efferent projections of MVN are to: (1) the ipsilateral supraspinal nucleus (SSN), and (2) the contralateral central cervical nucleus (CCN), MVN, SVN, cell group 'y', the rostroventral region of LVN, the trochlear nucleus (TN) and the INC. Projections to the abducens nuclei (AN) and the OMC are bilateral. Some ascending fibers in the cat cross within the OMC. In the monkey fibers from MVN end in a central band of the ipsilateral flocculus. Afferents to IVN arise ipsilaterally from SVN, the nodulus, the uvula and the anterior lobe vermis. Contralateral afferents arise from: (1) parts of CCN, MVN, SVN, IVN and cell group 'y' and (2) the central third of the FN. IVN receives bilateral projections from the perihypoglossal nuclei (PH) and the visceral nuclei of the OMC. Efferents from IVN project: (1) ipsilaterally to nucleus beta of the inferior olive, (2) contralaterally to parts of MVN, SVN and cell group 'y' and (3) bilaterally to the paramedian reticular nuclei. No commissural fibers interconnect cell groups 'f' and 'x'. Ascending fibers from IVN terminate contralaterally in the TN and the OMC. In the monkey fibers from IVN terminate in the ipsilateral nodulus, uvula and anterior lobe vermis; no fibers project to FN in either the cat or the monkey. Afferents to the LVN arise primarily from the ipsilateral anterior lobe vermis and bilaterally from rostral parts of the FN. No commissural fibers interconnect the LVN. Projections of the LVN are primarily to spinal cord via the vestibulospinal tract (VST); collaterals of the VST terminate in the lateral reticular nucleus (LRN). Ascending uncrossed projections from LVN in the cat terminate in the medial rectus subdivision of the OMC.(ABSTRACT TRUNCATED AT 400 WORDS)

Connections of the subthalamic nucleus in the monkey.

Attempts were made to determine the afferent and efferent connections of the subthalamic nucleus (STN) in the monkey using retrograde and anterograde axoplasmic transport technics. Following HRP injections limited to the STN, label was transported to arrays of cells adjacent, and parallel, to the lateral medullary lamina in the rostral two thirds of the lateral pallidal segment (LPS). Only sparse label was transported to cells of the pedunculopontine nucleus (PPN) and the locus ceruleus (LC). No enzyme was transported across the midline, or to the striatum, medial pallidal segment (MPS), thalamus, substantia nigra (SN) or dorsal nucleus of the raphe (DNR). HRP injected into portions of both the STN and SN produced retrograde transport of the enzyme to cells in parallel arrays in the LPS related rostrocaudally to the injection site. Additional enzyme transport was seen in cells of the striatum, the DNR and the PPN. Only a few isolated cells were labeled in the sensorimotor cortex. Efferent connections of the STN were studied in monkeys in which [3H]amino acids were injected hydraulically or iontophoretically into the STN. Isotope traced in serial autoradiographs was distributed to: (1) both segments of the globus pallidus (GP) in arrays parallel to the medullary laminae, and (2) the pars reticulata of SN (SNpr). The greatest number of terminals was found in the MPS. Fibers from the rostral part of the STN descended along the dorsal border of the SN and projected ventrally to terminations in the SNpr. No isotope was transported across the midline, or to the striatum, thalamus, DNR or PPN. Isotope injected into both the STN and SN produced similar transport to the GP and transport via nigral efferent fibers to: (1) portions of the striatum, (2) specific thalamic nuclei (VAmc, VLm, DMpl), (3) deep and middle gray layers of the superior colliculus and (4) PPN. Control studies indicated that [3H]amino acids injected only into the SN were transported to PPN. HRP injected into PPN produced profuse retrograde transport in cells of the MPS and SNpr and distinct label in a few cells of the zona incerta and STN. These data suggest that the STN receives its major subcortical input from cell of the LPS arranged in arrays which have a rostrocaudal organization. No cells of the MPS or SN project to the STN. The output of the STN is to both segments of the GP and SNpr. Major subcortical projections to PPN arise from the MPS and SNpr, but afferents also arise from other sources. The major projection of PPN is to SN.