Emerging therapeutic potential of graviola and its constituents in cancers.

Cancer remains a leading cause of death in the USA and around the world. Although the current synthetic inhibitors used in targeted therapies have improved patient prognosis, toxicity and development of resistance to these agents remain a challenge. Plant-derived natural products and their derivatives have historically been used to treat various diseases, including cancer. Several leading chemotherapeutic agents are directly or indirectly based on botanical natural products. Beyond these important drugs, however, a number of crude herbal or botanical preparations have also shown promising utility for cancer and other disorders. One such natural resource is derived from certain plants of the family Annonaceae, which are widely distributed in tropical and subtropical regions. Among the best known of these is Annona muricata, also known as soursop, graviola or guanabana. Extracts from the fruit, bark, seeds, roots and leaves of graviola, along with several other Annonaceous species, have been extensively investigated for anticancer, anti-inflammatory and antioxidant properties. Phytochemical studies have identified the acetogenins, a class of bioactive polyketide-derived constituents, from the extracts of Annonaceous species, and dozens of these compounds are present in different parts of graviola. This review summarizes current literature on the therapeutic potential and molecular mechanism of these constituents from A.muricata against cancer and many non-malignant diseases. Based on available data, there is good evidence that these long-used plants could have both chemopreventive and therapeutic potential. Appropriate attention to safety studies will be important to assess their effectiveness on various diseases caused or promoted by inflammation.

Systematic Review of CT Angiography in Guiding Management in Pediatric Oropharyngeal Trauma.

OBJECTIVES: Pediatric oropharyngeal trauma is common. Although most cases resolve uneventfully, there have been reports of internal carotid artery injury leading to devastating neurovascular sequelae. There is significant controversy regarding the utility of CT angiography (CTA) in children with seemingly minor oropharyngeal trauma. The goal of this study was to appraise changes in diagnosis and treatment based on CTA results. METHODS: A comprehensive search of PubMed, Embase, CINAHL, Scopus, the Cochrane Ear, Nose and Throat Disorders Group Trials Register, and the ClinicalTrials.gov database was performed following PRISMA guidelines. RESULTS: The search yielded 5,078 unique abstracts, of which 8 articles were included. A total of 662 patients were included, with 293 having any CT head/neck imaging, and 255 with CTA. Eleven injuries/abnormalities of the carotid were found on CTAs, comprising edema around the carotid (n = 8), potential intimal tear (n = 1), carotid spasm (n = 1), and carotid compression (n = 1). The pooled proportion of imaging findings on CTA that could lead to changes in clinical management was 0.00 (95% CI 0.00-0.43). Angiography was obtained in 10 patients, in 6 cases due to abnormal CTA. Angiography identified 1 patient with vessel spasm and two patients with carotid intima disruption without thrombus. No patient underwent vascular repair or suffered cerebrovascular injury. CONCLUSION: Imaging with CTA yielded radiological abnormalities in a few instances. These results do not support the routine use of CTA in screening pediatric oropharyngeal trauma when balanced against the risk of radiation, as it rarely resulted in management changes and was not shown to improve outcomes. LEVEL OF EVIDENCE: N/A Laryngoscope, 133:457-466, 2023.

Quality Versus Quantity: Using Scholarly Activity to Assess Otolaryngology Residency Candidates.

Selecting qualified candidates each year for residency positions has become more difficult in recent years, due to the sharp increase in Otolaryngology applicants. Although there are objective measures that can be used to directly compare medical students during the initial screening process, most information in the application is highly subjective and/or variable across institutions. Many programs count the total posters/presentations and publications to gauge scholarship. This measure of quantity may lead to negative bias toward those who have no home program, limited time outside of academics, and/or inadequate resources to engage in volunteer research. Evaluating the quality of research may be superior to quantity. A first-author publication is a viable proxy that demonstrates applicants have developed skills that set them apart from their peers. They likely possess non-clinical, translatable skills including internal motivation, self-regulation, curation of information, and task completion that map closely with qualities that make for excellent residents.

Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring.

Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes. Phosphorylated S6 (p-S6), a downstream effector of EGFR and cyclin D1-CDK4/6 signalling, showed a progressive increase from normal oral tissues to leukoplakia and frank malignancy, and associated with poor outcome of the patients. This increased p-S6 expression was drastically reduced after combination treatment with afatinib and palbociclib in the cell lines and mouse models, suggesting its utiliy as a prognostic marker in HNSCC. Combination treatment also reduced the cell growth and induced cell senescence via increasing reactive oxygen species with concurrent ablation of glycolytic and tricarboxylic acid cycle intermediates. Finally, our findings in sub-cutaneous and genetically engineered mouse model (K14-CreERtam;LSL-KrasG12D/+;Trp53R172H/+) studies showed a significant reduction in the tumor growth and delayed tumor progression after combination treatment. This study collectively demonstrates that dual targeting may be a critical therapeutic strategy in blocking tumor progression via inducing metabolic alteration and warrants clinical evaluation.

Maize DELLA proteins dwarf plant8 and dwarf plant9 as modulators of plant development.

DELLA proteins are nuclear-localized negative regulators of gibberellin signaling found ubiquitously throughout higher plants. Dominant dwarfing mutations of DELLA proteins have been primarily responsible for the dramatic increases in harvest index of the 'green revolution'. Maize contains two genetic loci encoding DELLA proteins, dwarf plant8 (d8) and dwarf plant 9 (d9). The d8 gene and three of its dominant dwarfing alleles have been previously characterized at the molecular level. Almost 20 years after the initial description of the mutant, this investigation represents the first molecular characterization of d9 and its gibberellin-insensitive mutant, D9-1. We have molecularly, subcellularly and phenotypically characterized the gene products of five maize DELLA alleles in transgenic Arabidopsis. In dissecting the molecular differences in D9-1, a critical residue for normal DELLA function has been uncovered, corresponding to E600 of the D9 protein. The gibberellin-insensitive D9-1 was found to produce dwarfing and, notably, earlier flowering in Arabidopsis. Conversely, overexpression of the D9-1 allele delayed flowering in transgenic maize, while overexpression of the d9 allele led to earlier flowering. These results corroborate findings that DELLA proteins are at the crux of many plant developmental pathways and suggest differing mechanisms of flowering time control by DELLAs in maize and Arabidopsis.

Differential mutation spectrum and immune landscape in African Americans versus Whites: A possible determinant to health disparity in head and neck cancer.

African Americans (AA) with Head and Neck Squamous Cell Carcinoma (HNSCC) have a worse disease prognosis than White patients despite adjusting for socio-economic factors, suggesting the potential biological contribution. Therefore, we investigated the genomic and immunological components that drive the differential tumor biology among race. We utilized the cancer genome atlas and cancer digital archive of HNSCC patients (1992-2013) for our study. We found that AA patients with HNSCC had a higher frequency of mutation compared to Whites in the key driver genes-P53, FAT1, CASP8 and HRAS. AA tumors also exhibited lower intratumoral infiltration of effector immune cells (CD8+, γδT, resting memory CD4+ and activated memory CD4+ T cells) with shorter survival than Whites. Unsupervised hierarchical clustering of differentially expressed genes demonstrated distinct gene clusters between AA and White patients with unique signaling pathway enrichments. Connectivity map analysis identified drugs (Neratinib and Selumetinib) that target aberrant PI3K/RAS/MEK signaling and may reduce racial disparity in therapy response.

Sensorineural hearing loss in patients with cystic fibrosis.

OBJECTIVE: To determine the prevalence of sensorineural hearing loss (SNHL) in cystic fibrosis (CF) patients and its relationship to antibiotic use. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care pediatric hospital. SUBJECTS AND METHODS: We reviewed the medical records of CF patients seen in our children's hospital between March 1994 and December 2007. Data collected included patient demographics, audiograms, tympanograms, genotype, and use of potentially ototoxic antibiotics. RESULTS: Seven of 50 (14%) patients had SNHL. Three percent of patients who received 10 courses (P<0.01). No patients who received five or fewer courses of nasal irrigation with aminoglycosides had SNHL versus 23 percent of those who received more than five courses (P<0.05). Nine percent of patients who received five or fewer courses of macrolides had SNHL versus 60 percent of those who received more than five courses (P=0.079). CONCLUSION: CF patients receiving aminoglycosides are at high risk for developing SNHL.

The effect of varus and valgus osteotomies on femoral version.

BACKGROUND: Although seldom described, varus and valgus osteotomies of the proximal femur can affect femoral version. The magnitude of the effect can be predicted with an understanding of the distinction between femoral version and femoral neck inclination. The purpose of this study was to elucidate this relationship. METHODS: Version, inclination, apparent neck-shaft angle, and true neck-shaft angle were defined and measured in 72 preserved femora. RESULTS: Average values were 19.8+/-11.8 degrees for version versus 14.5+/-10.1 degrees for inclination (P=0.004), giving a mean difference of 27% between version and inclination, with greater discrepancy with increasing neck-shaft angle. There were high correlations between measured inclination and inclination calculated using version and apparent neck-shaft angle (r=0.96) and true neck-shaft angle (r=0.97), validating our formulaic relationship between these variables. CONCLUSIONS: We present and validate the concept of inclination, and its relationship with version and neck-shaft angle. This explains the mechanism for a varus osteotomy decreasing anteversion, and a valgus osteotomy increasing anteversion. CLINICAL RELEVANCE: With an understanding of these concepts, a surgeon can incline the femoral neck axis to achieve a desired amount of version, for any given neck-shaft angle. Without this understanding, precise control of the version and neck-shaft angle is difficult.

Immunometabolic Alterations by HPV Infection: New Dimensions to Head and Neck Cancer Disparity.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with high morbidity and mortality. Racial disparity in HNSCC is observed between African Americans (AAs) and whites, effecting both overall and 5-year survival, with worse prognosis for AAs. In addition to socio-economic status and demographic factors, many epidemiological studies have also identified factors including coexisting human papillomavirus (HPV) infection, primary tumor location, and a variety of somatic mutations that contribute to the prognostic incongruities in HNSCC patients among AAs and whites. Recent research also suggests HPV-induced dysregulation of tumor metabolism and immune microenvironment as the major regulators of HNSCC patient prognosis. Outcomes of several preclinical and clinical studies on targeted therapeutics warrant the need to elucidate the inherent mechanistic and population-based disparities underlying patient responses. This review systematically reports the underlying reasons for inconsistency in disease prognosis and therapy responses among HNSCC patients from different racial populations. The focus of this review is twofold: aside from discussing the causes of racial disparity, we also seek to identify the consequences of such disparity in terms of HPV infection and its associated mutational, metabolic, and immune landscapes. Considering the clinical impact of differential patient outcomes among AA and white populations, understanding the underlying cause of this disparity may pave the way for novel precision therapy for HNSCC.

Use of a preoperative bleeding questionnaire in pediatric patients who undergo adenotonsillectomy.

OBJECTIVE: To determine the efficacy of a preoperative bleeding questionnaire (POBQ) and coagulation screening in predicting hemorrhage associated with adenotonsillectomy. STUDY DESIGN: Retrospective study. SUBJECTS AND METHODS: Between January 1998 and December 2003, 7730 tonsillectomy and adenotonsillectomy patients were administered the POBQ preoperatively. Further coagulation screening was based on POBQ responses. RESULTS: A total of 232 (3.0%) of 7730 had postoperative bleeding; 184 (3.2%) of 5782 patients who had negative questionnaires bled postoperatively compared with 48 (2.5%) of 1948 patients with positive questionnaires (P = 0.126). Of 1948 patients with positive questionnaires, 141 (7.2%) had abnormal preoperative coagulation screens and 9 (6.4%) of 141 bled; of the 1807 (92.8%) with negative coagulation screens, 39 (2.2%) bled (P = 0.005). CONCLUSION: The POBQ is an effective tool for identifying patients who are at potential risk for post-tonsillectomy bleeding. Patients with both a positive POBQ and coagulation screen had a statistically higher likelihood of postoperative bleeding than other patients. The POBQ allowed the identification of individuals with bleeding disorders to be treated before surgery, likely decreasing the risk of bleeding in these patients.

The effect of recovery time and test conditions on viscoelastic measures of tensile damage in cortical bone.

Stiffness degradation and strength degradation are often measured to monitor and characterize the effects of damage accumulation in bone. Based on evidence that these properties could be affected by not only damage magnitude but also test conditions, the present study investigated the effect of hold condition and recovery time on measures of tensile damage. Machined human femoral cortical bone specimens were subjected to tensile tests consisting of a pre-damage diagnostic loading cycle, a damage loading cycle and post-damage cycle. Controlled variables were recovery time (1, 10, and 100 min) and hold condition (zero load or zero strain) after the damage cycle. Damage measures were calculated as the ratio of each post-damage cycle to the pre-damage value for loading modulus, secant modulus, unloading modulus, stress relaxation and strain (stress) recovery at 1 min post-diagnostic time. The damage cycle caused reductions in all measures, and some measures varied with recovery time and hold condition. Apparent modulus degradation for both hold conditions decreased with recovery time. Stress relaxation was unaffected by recovery time for both hold conditions. Zero-strain hold conditions resulted in lower values for degradation of modulus and change of relaxation. Stress or strain recovery after the damage cycle was evident through 100 min, but 90% of the recovery occurred within 10 min. The results demonstrate that choice of test conditions can influence the apparent magnitude of damage effects. They also indicate that 10 min recovery time was sufficient to stabilize most measures of the damage state.

Pediatric endoscopic dacryocystorhinostomy failures: who and why?

OBJECTIVE: The objectives of this study are to report outcomes of pediatric patients with nasolacrimal duct obstruction (NLDO) who underwent primary endoscopic dacryocystorhinostomy (DCR) and discuss causes of failure. STUDY DESIGN: The authors conducted a retrospective case series. METHODS: Charts of all patients less than 16 years of age who underwent primary endoscopic DCR from 1997 to 2004 were reviewed. Patients were grouped based on the presence or absence of facial anomalies or syndromes and whether the NLDO was congenital or acquired. Success was defined as complete resolution of symptoms, improvement included anatomic patency or partial symptoms, and failure as no improvement or demonstration of patency. RESULTS: Thirty-four patients (43 ducts) aged 11 months to 14 years were identified. There were 17 males and 17 females. Follow up ranged from 2 to 54 months (average, 21 months). Twenty-four patients (29 ducts) had congenital NLDO, seven patients (11 ducts) had congenital syndromes associated with craniofacial abnormalities, and three patients (three ducts) had acquired NLDO. In patients with congenital NLDO without craniofacial abnormalities or syndromes, 22 of 29 eyes (76%) were cured with another three (10%) showing improvement. Only one of 11 (9%) eyes of patients with congenital craniofacial abnormality or syndrome experienced complete resolution and only four of 11 (36%) eyes showed improvement. Of the patients with acquired NLDO, two of three (67%) of the eyes were cured and one (33%) improved. CONCLUSIONS: Endoscopic DCR is safe and effective for most children, although patients with craniofacial abnormalities or syndromes are extremely difficult to cure.

Effectiveness of postoperative follow-up telephone interviews for patients who underwent adenotonsillectomy: a retrospective study.

OBJECTIVE: To evaluate the effectiveness of follow-up telephone interviews and questionnaires after tonsillectomy and adenoidectomy. DESIGN: Cohort study and retrospective review of the outcomes of patients whose follow-ups were conducted by telephone interview. Patients were contacted 2 to 4 weeks after surgery; responses were recorded on a standardized postoperative questionnaire. SETTING: Tertiary pediatric hospital. PATIENTS: A total of 2554 consecutive patients who had undergone tonsillectomy, adenoidectomy, or both procedures and completed a follow-up telephone interview during the period of January 8, 2000, to September 23, 2004. MAIN OUTCOME MEASURES: Time to return to normal diet and activities, postoperative complications, pain management, postoperative visits, and caregiver's evaluation of the follow-up telephone survey. RESULTS: A total of 2554 patient outcomes were reviewed. The mean patient age was 5.9 years. Follow-up contact occurred a mean of 24.1 days after surgery. Of the surgical procedures performed, there were 1957 adenotonsillectomies, 235 adenoidectomies, and 362 tonsillectomies. At the time of follow-up, 2.7% of the patients had undergone an additional surgical procedure to treat postoperative bleeding, 96.9% had resumed eating a normal diet, and 96.2% had resumed normal activities. Bleeding from the nose or mouth was reported to have occurred at some point during the recovery period in 12.8%. On a pain scale of 1 to 10, a mean pain peak of 6.7 was reported. For most patients, pain was highest on the second day after surgery. The percentage of patients who had temporary voice change was 62.7%, and 15.4% had a follow-up clinic visit. Regarding caregivers, 99.5% reported being given instructions for postoperative care, and 98.8% reported that they felt well prepared to care for their child at home. There were no adverse events reported from surgical intervention. CONCLUSIONS: Compared with our previous experience with scheduled postsurgical clinic follow-ups, telephone interviews and standardized postoperative questionnaires pose no additional risk to patients. Considerable cost reduction and patient convenience were realized with a reduction of patient visits.

Evaluation of machining methods for trabecular metal implants in a rabbit intramedullary osseointegration model.

Implant success is dependent in part on the interaction of the implant with the surrounding tissues. Porous tantalum implants (Trabecular Metal, TM) have been shown to have excellent osseointegration. Machining this material to complex shapes with close tolerances is difficult because of its open structure and the ductile nature of metallic tantalum. Conventional machining results in occlusion of most of the surface porosity by the smearing of soft metal. This study compared TM samples finished by three processing techniques: conventional machining, electrical discharge machining, and nonmachined, "as-prepared." The TM samples were studied in a rabbit distal femoral intramedullary osseointegration model and in cell culture. We assessed the effects of these machining methods at 4, 8, and 12 weeks after implant placement. The finishing technique had a profound effect on the physical presentation of the implant interface: conventional machining reduced surface porosity to 30% compared to bulk porosities in the 70% range. Bone ongrowth was similar in all groups, while bone ingrowth was significantly greater in the nonmachined samples. The resulting mechanical properties of the bone implant-interface were similar in all three groups, with only interface stiffness and interface shear modulus being significantly higher in the machined samples.

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells.

The dismal prognosis of locally advanced and metastatic squamous cell carcinoma of the head and neck (HNSCC) is primarily due to the development of resistance to chemoradiation therapy (CRT). Deregulation of Epidermal Growth Factor Receptor (EGFR) signaling is involved in HNSCC pathogenesis by regulating cell survival, cancer stem cells (CSCs), and resistance to CRT. Here we investigated the radiosensitizing activity of the pan-EGFR inhibitor afatinib in HNSCC in vitro and in vivo. Our results showed strong antiproliferative effects of afatinib in HNSCC SCC1 and SCC10B cells, compared to immortalized normal oral epithelial cells MOE1a and MOE1b. Comparative analysis revealed stronger antitumor effects with afatinib than observed with erlotinib. Furthermore, afatinib enhanced in vitro radiosensitivity of SCC1 and SCC10B cells by inducing mesenchymal to epithelial transition, G1 cell cycle arrest, and the attenuating ionizing radiation (IR)-induced activation of DNA double strand break repair (DSB) ATM/ATR/CHK2/BRCA1 pathway. Our studies also revealed the effect of afatinib on tumor sphere- and colony-forming capabilities of cancer stem cells (CSCs), and decreased IR-induced CSC population in SCC1 and SCC10B cells. Furthermore, we observed that a combination of afatinib with IR significantly reduced SCC1 xenograft tumors (median weight of 168.25 ± 20.85 mg; p = 0.05) compared to afatinib (280.07 ± 20.54 mg) or IR alone (324.91 ± 28.08 mg). Immunohistochemical analysis of SCC1 tumor xenografts demonstrated downregulation of the expression of IR-induced pEGFR1, ALDH1 and upregulation of phosphorylated γH2AX by afatinib. Overall, afatinib reduces tumorigenicity and radiosensitizes HNSCC cells. It holds promise for future clinical development as a novel radiosensitizer by improving CSC eradication.

The effect of three-dimensional shape optimization on the probabilistic response of a cemented femoral hip prosthesis.

Probabilistic analyses allow the effect of uncertainty in system parameters on predicted model performance measures to be determined. Furthermore, using performance functions to describe a failure event, the probability of failure can be quantified. The effect of three-dimensional prosthesis shape optimization on the probabilistic response and failure probability of a cemented hip prosthesis system is investigated. Random variables include joint and muscle loading, cortical and cancellous bone and PMMA bone cement elastic properties, and strength parameters describing failure of the bone cement and the prosthesis-bone cement interface. Several performance functions describing the bone cement and prosthesis-cement interface are used to compute the probability of failure. When evaluated deterministically, most performance functions indicated a safe design, with the exception of interface tensile failure. However, when evaluated probabilistically, finite probabilities of failure were computed, some significant. The most likely mode of failure before shape optimization was prosthesis-bone cement interface tensile failure with a predicted probability of failure of 97.9%. Deterministic prosthesis shape optimization reduced the probability of failure for all performance functions and reduced prosthesis-bone cement interface tensile failure by 31.7%. Probability sensitivity factors indicate that the uncertainty in the joint loading, cement strength, and implant-cement interface strength have the greatest effect on the computed probability of failure. Implant shape optimization results in a more robust implant design that is less sensitive to uncertainties in joint loading, which cannot be easily controlled, and more sensitive to cement and interface properties, which are easier to modify.

A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing.

INTRODUCTION: Mutation testing for the MEN1 gene is a useful method to diagnose and predict individuals who either have or will develop multiple endocrine neoplasia type 1 (MEN 1). Clinical selection criteria to identify patients who should be tested are needed, as mutation analysis is costly and time consuming. This study is a report of an Australian national mutation testing service for the MEN1 gene from referred patients with classical MEN 1 and various MEN 1-like conditions. RESULTS: All 55 MEN1 mutation positive patients had a family history of hyperparathyroidism, had hyperparathyroidism with one other MEN1 related tumour, or had hyperparathyroidism with multiglandular hyperplasia at a young age. We found 42 separate mutations and six recurring mutations from unrelated families, and evidence for a founder effect in five families with the same mutation. DISCUSSION: Our results indicate that mutations in genes other than MEN1 may cause familial isolated hyperparathyroidism and familial isolated pituitary tumours. CONCLUSIONS: We therefore suggest that routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services. We do not recommend routine sequencing of the promoter region between nucleotides 1234 and 1758 (Genbank accession no. U93237) as we could not detect any sequence variations within this region in any familial or sporadic cases of MEN1 related conditions lacking a MEN1 mutation. We also suggest that testing be considered for patients <30 years old with sporadic hyperparathyroidism and multigland hyperplasia.

Passive smoke exposure as a risk factor for airway complications during outpatient pediatric procedures.

OBJECTIVE: Determine if passive smoke exposure (PSE) increases airway complications during outpatient mask anesthesia procedures in children. METHODS: A prospective cohort of children who underwent surgical procedures under mask anesthesia was studied with the American Thoracic Society children's questionnaire on environmental and respiratory factors. Double-blinded outcomes with respect to adverse airway events were recorded both intraoperatively and in the recovery room for patients with and without passive smoke exposure. Multivariate comparisons assessing the likelihood of these airway complications were conducted between the PSE and nonexposed groups. RESULTS: Of 405 children, 168 (41.5%) had PSE. The incidence of airway complications during anesthesia or postanesthetic recovery was higher for all outcome measures for PSE children (all P

Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p.

Pheochromocytomas are tumors of the adrenal medulla originating in the chromaffin cells derived from the neural crest. Ten % of these tumors are associated with the familial cancer syndromes multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and rarely, neurofibromatosis type 1, in which germ-line mutations have been identified in RET, VHL, and NF1, respectively. In both the sporadic and familial form of pheochromocytoma, allelic loss at 1p, 3p, 17p, and 22q has been reported, yet the molecular pathogenesis of these tumors is largely unknown. Allelic loss at chromosome 1p has also been reported in other endocrine tumors, such as medullary thyroid cancer and tumors of the parathyroid gland, as well as in tumors of neural crest origin including neuroblastoma and malignant melanoma. In this study, we performed fine structure mapping of deletions at chromosome 1p in familial and sporadic pheochromocytomas to identify discrete regions likely housing tumor suppressor genes involved in the development of these tumors. Ten microsatellite markers spanning a region of approximately 70 cM (1pter to 1p34.3) were used to screen 20 pheochromocytomas from 19 unrelated patients for loss of heterozygosity (LOH). LOH was detected at five or more loci in 8 of 13 (61%) sporadic samples and at five or more loci in four of five (80%) tumor samples from patients with multiple endocrine neoplasia type 2. No LOH at 1p was detected in pheochromocytomas from two VHL patients. Analysis of the combined sporadic and familial tumor data suggested three possible regions of common somatic loss, designated as PC1 (D1S243 to D1S244), PC2 (D1S228 to D1S507), and PC3 (D1S507 toward the centromere). We propose that chromosome 1p may be the site of at least three putative tumor suppressor loci involved in the tumorigenesis of pheochromocytomas. At least one of these loci, PC2 spanning an interval of <3.8 cM, is likely to have a broader role in the development of endocrine malignancies.