Anaplastic thyroid cancer:Improved understanding of what remains a deadly disease.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare, undifferentiated form of thyroid cancer accounting for less that 2 % of thyroid cancers. Here we provide an overview of the contemporary understanding of ATC as well as discussing in detail any pertinent updates in the molecular understanding and treatment of this disease with reference to the 2021 American Thyroid Association (ATA) guidelines. METHODS: A review of the literature regarding the understanding, management and prognosis of ATC was undertaken using both Pubmed and Cochrane databases along with local institutional experience. Studies published in the last 5 years were prioritised for inclusion. RESULTS: Between 80 and 90 % of patients will have disease that has spread beyond the thyroid gland at presentation. Despite the use of aggressive, multimodal, conventional treatment strategies encompassing surgery and chemoradiotherapy, the median overall survival has remained between 3 and 6 months. Our understanding has evolved regarding the key oncogenic mutations involved in the development of ATC. These include BRAF, RAS, PI3K, PTEN, TP53 and TERT mutations. There is growing evidence that novel targeted therapies against these mutations may improve outcomes in this disease which has led to FDA approval of dabrafenib/trametinib combined BRAF/Mek inhibition. CONCLUSIONS: The prognosis of ATC remains dismal. Recent development and approval of targeted therapies offers hope of improved oncologic outcomes with further data eagerly awaited surrounding the impact of these targeted therapies.

The role of surgery for anaplastic thyroid carcinoma in the era of targeted therapeutics: A scoping review.

Background: Questions exist regarding patient selection for surgery in anaplastic thyroid carcinoma (ATC), particularly with the advent of neoadjuvant-targeted therapeutics. The present scoping review sought to evaluate what extent of surgical resection should be performed in ATC. Methods: A scoping review was carried out in accordance with Joanna Briggs Institute and the preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) protocols. Included studies were required to provide clear description of the surgery performed for ATC. Results: The final search identified 6901 articles. Ultimately only 15 articles including 1484 patients met inclusion criteria. A total of 765 patients (51.5%) underwent attempted curative intent surgery. The approach to resection of adjacent tissues varied between studies. Eight studies considered laryngeal ± pharyngeal resection (8/15, 53.3%), eight studies (53.3%) considered tracheal resection and again eight studies (53.3%) considered esophageal resection. More extensive resections increased morbidity without improving overall survival (OS) (<9 months in the 12 studies using a combination of surgery and chemoradiotherapy). In the three studies utilizing targeted therapy in addition to surgery, OS was notably improved while surgical resection following neoadjuvant therapy was less extensive. Conclusions: There is no clear agreement in the literature regarding the limits of surgical resection in locoregionally advanced ATC. A definition of surgically resectable disease will be required to guide surgical decision making in ATC, particularly with the potential to reduce tumor burden using neoadjuvant targeted treatment in suitable patients. Level of evidence: III.

International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System.

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

Pattern of nodal metastasis of cutaneous squamous cell carcinoma involving the temporal bone.

Objective: The objective of this study was to explore the pattern of lymph-node spread of SCCs involving the temporal bone. Methods: We retrospectively reviewed all cutaneous SCCs involving the temporal bone over a 20-year time-period. Forty-one patients were eligible. Results: Mean age was 72.8 years. The diagnosis was cutaneous SCC in all cases.All patients underwent a temporal bone resection, 70.7% had a neck-dissection and 78.0% a parotidectomy.Level 2 was the most common area of neck metastasis, and occurred in 12.2%. The parotid had disease in 34.1%. 51.2% of patients underwent free-flap reconstruction.Mean overall survival of the cohort was 4.2 years. Conclusions: Overall, the rate of cervical nodal metastasis was 22.0% and 13.5% in the occult setting. The parotid was involved in 34.1% and 10.0% in the occult setting. Results from the present study support consideration for performing a parotidectomy at the time of temporal bone resection, while a neck dissection can be performed for adequate staging of the nodal basin. Level of Evidence: 3.

"Age is just a number"; frailty as a marker of peri-operative risk in head and neck surgery: Systematic review and meta-analysis.

BACKGROUND: Frailty refers to a patient's reduced capacity to withstand stressors due to a reduction in physiologic reserves. We assessed the impact of frailty on outcomes following head and neck surgery. METHODS: We performed a systematic review in accordance with the PRISMA guidelines. Meta-analysis was performed using the Mantel-Haenszel method. RESULTS: Fourteen studies incorporating 182 059 patients were included in qualitative synthesis with 15 953 (8.8%) of patients deemed as frail. Meta-analysis incorporating nine studies demonstrated that frailty is associated with an increased 30 day postoperative morbidity (OR 2.74; 95% CI 1.98-3.80; p < 0.01) and meta-analysis with six studies suggested increased 30-day mortality (OR 2.94; 95% CI 2.62-3.31; p < 0.01). Preliminary meta-analyses between two and five studies suggested that frail patients had reduced overall survival and were more likely to be discharged to a nonhome location or readmitted within 30 days. CONCLUSIONS: Frailty appears to be associated with poor short-term outcomes following head and neck surgery and may improve understanding of an individual patient's peri-operative risk.

Is repeat fine needle aspiration required in thyroid nodules with initial benign cytology? Results from a large Irish series.

BACKGROUND : Fine needle aspiration (FNA) cytology is the preferred method for assessing thyroid nodules for malignancy. Concern remains about the rate of false negative results. The primary aim of this study is to investigate the malignancy rate of thyroid nodules initially classified as benign (Thy 2). METHODS: We retrospectively examined 658 nodules in 653 (429 female) patients between January 2013 to December 2017. All FNA biopsies (FNABs) were performed under ultrasound (US) guidance by a radiologist with expertise in thyroid pathology. Nodules were cytologically classified according to the UK Royal College of Pathologists guidelines. Decisions about further management were made at a regular thyroid multidisciplinary meeting. Follow up of the Thy 2 nodules was determined based on clinical and radiological criteria. RESULTS: The mean age (± SD) was 53.2 (14.6) years. Five hundred out of 658 (76.0%) nodules were classified as Thy 2 (benign) after the first FNAB. Of these thyroid nodules initially classified as benign, 208 (41.6%) underwent repeat FNAB and 9 (1.8%) were surgically removed without repeat FNAB. The remainder were followed up clinically and/or radiologically. Seven (1.4%) of nodules initially classified as Thy 2 were later shown to be or to harbor malignancy after a follow-up of 74.5 (± 19.7) months. Papillary thyroid microcarcinomas were found co-incidentally in two thyroid glands of benign nodules, giving a true prevalence of 5/500 (1.0%). CONCLUSIONS: With a well targeted FNAB, the false negative rate of an initial benign thyroid FNA is very low thus routine second FNAB is not required in patients with a thyroid nodule initially deemed benign. Multidisciplinary input is imperative in informing decision making.

Contemporary management of paragangliomas of the head and neck.

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors typically arising from nonsecretory head and neck parasympathetic ganglia. Historically thought of as aggressive tumors that warranted equally aggressive surgical intervention, evidence has emerged demonstrating that the vast majority of HNPGLs are slow growing and indolent. It is also now recognized that a large proportion of HNPGLs are hereditary with succinate dehydrogenase gene mutations typically implicated. These recent advances have led to significant changes in the way in which clinicians investigate and treat HNPGLs with most now opting for more conservative treatment strategies. However, a proportion of patients present with more aggressive disease and still require nonconservative treatment strategies. Recent studies have sought to determine in which groups of patients the morbidity associated with treatment is justified. We summarize the recent advances in the understanding and management of these tumors and we provide our recommendations regarding the management of HNPGLs.

The impact of switching to mTOR inhibitor-based immunosuppression on long-term non-melanoma skin cancer incidence and renal function in kidney and liver transplant recipients.

Background: Solid organ transplantation is associated with increased risk of non-melanoma skin cancer. Studies with short follow up times have suggested a reduced occurrence of these cancers in recipients treated with mammalian target of rapamycin inhibitors as maintenance immunosuppression. We aimed to describe the occurrence of skin cancers in renal and liver transplant recipients switched from calcineurin inhibitor to sirolimus-based regimes.Methods: We performed a retrospective study of sirolimus conversion within the Irish national kidney and liver transplant programs. These data were linked with the National Cancer Registry Ireland to determine the incidence of NMSC among these recipients. The incidence rate ratio (IRR) for post versus pre-conversion NMSC rates are referred in this study as an effect size with [95% confidence interval].Results: Of 4,536 kidney transplants and 574 liver transplants functioning on the 1 January 1994 or transplanted between 1 January 1994 and 01 January 1994 and 01 January 2015, 85 kidney and 88 liver transplant recipients were transitioned to sirolimus-based immunosuppression. In renal transplants, the rate of NMSC was 131 per 1000 patient years pre-switch to sirolimus, and 68 per 1000 patient years post switch, with adjusted effect size of 0.48 [0.31 - 0.74] (p = .001) following the switch. For liver transplant recipients, the rate of NMSC was 64 per 1,000 patient years pre-switch and 30 per 1,000 patient years post switch, with an adjusted effect size of 0.49 [0.22 - 1.09] (p .081). Kidney transplant recipients were followed up for a median 3.4 years. Liver transplants were followed for a median 6.6 years.Conclusions: In this study, the conversion of maintenance immunosuppression from calcineurin inhibitors to mTOR inhibitors for clinical indications did appear to reduce the incidence of NMSC in kidney and liver transplant recipients.

Cancer survival in kidney transplant recipients in Ireland.

BACKGROUND: Transplantation is a well-known risk factor for malignancy. However, outcomes of cancer in transplant recipients compared with non-transplant recipients are less well studied. We aim to study the survival in kidney transplant recipients who develop cancer and compare this with cancer outcomes in the general population. METHODS: We linked data from the National Cancer Registry Ireland with the National Kidney Transplant Database. The period of observation was from 1 January 1994 until 31 December 2014. Transplant recipients were considered at risk from the time of diagnosing cancer. We administratively censored data at 10 years post-cancer diagnosis. Survival was compared with all patients in the general population that had a recorded diagnosis of cancer. RESULTS: There were 907 renal transplant recipients and 426679 individuals in the general population diagnosed with cancer between 1 January 1994 and 31 December 2014. In those with non-melanoma skin cancer, the hazard ratio (HR) for 10-year, all-cause mortality [HR = 3.06, 95% confidence interval (CI) 2.66-3.52] and cancer-specific mortality (HR = 3.91, 95% CI 2.57-5.96) was significantly higher among transplant recipients than the general population. Patients who developed non-Hodgkin lymphoma (HR = 2.89, 95% CI 1.96-4.25) and prostate cancer (HR = 4.32, 95% CI 2.39-7.82) had increased all-cause but not cancer-specific mortality. Colorectal, lung, breast and renal cell cancer did not show an increased risk of death in transplant recipients. CONCLUSION: Cancer-attributable mortality is higher in kidney transplant recipients with non-melanoma skin cancer compared with non-transplant patients. The American Joint Committee on Cancer staging should reflect the increased hazard of death in these immunosuppressed patients.

'Good cancer gone bad': a narrative review of HPV oropharyngeal cancer and potential poor outcomes.

PURPOSE: Oropharyngeal cancer (OPC) remains a significant health burden and about 15-30% of these have been attributed to the human papillomavirus (HPV). Human papillomavirus-related oropharyngeal cancer (HPV OPC) includes tumours which are detected to be p16INK4A positive or have the HPV DNA detected by in situ hybridisation or polymerase chain reaction. HPV OPC is generally believed to have a relatively good prognosis. More recently, there is a recognised pattern of atypical spread in a highly aggressive subset of HPV OPC. These are HPV OPCs which develop distant metastasis or recurrence. This review raises awareness of this subset of HPV OPC and factors associated with poor outcomes. METHODS: A review of the literature available on HPV OPC was carried out. Studies were sourced from PubMed with searching of relevant headings and sub-headings and cross-referencing. RESULTS: Factors associated with highly aggressive HPV OPC include nodal stage and nodal morphology, alcohol and tobacco use, age and biological characteristics. Treatment options in cases of disease recurrence include salvage resection radiotherapy and/or chemotherapy and management options vary depending on the nature of recurrence and initial treatment. Recent updates in HPV OPC staging have made staging and treatment of tumours more accurate. CONCLUSION: While HPV OPC overall carries a relatively good prognosis, it is important for clinicians to be aware of potentially highly aggressive cases of HPV OPC and to be aware of factors that should prompt close monitoring.

Safety Recommendations for Evaluation and Surgery of the Head and Neck During the COVID-19 Pandemic.

Importance: The rapidly expanding novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has challenged the medical community to an unprecedented degree. Physicians and health care workers are at added risk of exposure and infection during the course of patient care. Because of the rapid spread of this disease through respiratory droplets, health care workers who come in close contact with the upper aerodigestive tract during diagnostic and therapeutic procedures, such as otolaryngologists-head and neck surgeons, are particularly at risk. A set of safety recommendations was created based on a review of the literature and communications with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic. Observations: A high number of health care workers were infected during the first phase of the pandemic in the city of Wuhan, China. Subsequently, by adopting strict safety precautions, other regions were able to achieve high levels of safety for health care workers without jeopardizing the care of patients. The most common procedures related to the examination and treatment of upper aerodigestive tract diseases were reviewed. Each category was reviewed based on the potential risk imposed to health care workers. Specific recommendations were made based on the literature, when available, or consensus best practices. Specific safety recommendations were made for performing tracheostomy in patients with COVID-19. Conclusions and Relevance: Preserving a highly skilled health care workforce is a top priority for any community and health care system. Based on the experience of health care systems in Asia and Europe, by following strict safety guidelines, the risk of exposure and infection of health care workers could be greatly reduced while providing high levels of care. The provided recommendations, which may evolve over time, could be used as broad guidance for all health care workers who are involved in the care of patients with COVID-19.

Strengthening the case for gender-neutral and the nonavalent HPV vaccine.

PURPOSE: The purpose of this review is to highlight the benefits of gender-neutral and the nonavalent human papillomavirus vaccination. Human papillomavirus infection is the most commonly sexually transmitted disease and is known to cause several types of cancers, including cervical, vulvar, vaginal, penile, oropharyngeal, anal, and rectal. 5% of cancers every year are attributable to human papillomavirus infection, with cervical cancer the most common and oropharyngeal cancer estimated to surpass the incidence of cervical cancer by 2020. METHODS: PubMed and MEDLINE were searched using the following search terms: [(human papillomavirus OR HPV) AND (vaccine OR vaccination)] AND [(gardasil OR gardasil9 OR cervarix OR quadrivalent OR nonavalent OR ninevalent) OR (gender neutral OR male)]. RESULTS: There are currently three different types of human papillomavirus vaccinations and range in cover from four to nine different strains known to cause human disease. Most countries currently only supply vaccination to females; however, recent data point towards both a personal benefit as well as a cost-effective population-based benefit with gender-neutral vaccination. Data from female vaccination only have shown the vaccine to be effective in preventing premalignant cervical lesions, and are believed to have the same effect for other human papillomavirus cancers. Male vaccination not only provides personal benefit but also has a "herd effect" for females by preventing the propagation of the virus. CONCLUSION: Gender-neutral vaccination provides significant cost-effective benefits for preventing human papillomavirus-related diseases, and this effect is further enhanced by the use of the nonavalent vaccine.

Development and external validation of a risk-prediction model to predict 5-year overall survival in advanced larynx cancer.

OBJECTIVES/HYPOTHESIS: TNM-classification inadequately estimates patient-specific overall survival (OS). We aimed to improve this by developing a risk-prediction model for patients with advanced larynx cancer. STUDY DESIGN: Cohort study. METHODS: We developed a risk prediction model to estimate the 5-year OS rate based on a cohort of 3,442 patients with T3T4N0N+M0 larynx cancer. The model was internally validated using bootstrapping samples and externally validated on patient data from five external centers (n = 770). The main outcome was performance of the model as tested by discrimination, calibration, and the ability to distinguish risk groups based on tertiles from the derivation dataset. The model performance was compared to a model based on T and N classification only. RESULTS: We included age, gender, T and N classification, and subsite as prognostic variables in the standard model. After external validation, the standard model had a significantly better fit than a model based on T and N classification alone (C statistic, 0.59 vs. 0.55, P < .001). The model was able to distinguish well among three risk groups based on tertiles of the risk score. Adding treatment modality to the model did not decrease the predictive power. As a post hoc analysis, we tested the added value of comorbidity as scored by American Society of Anesthesiologists score in a subsample, which increased the C statistic to 0.68. CONCLUSIONS: A risk prediction model for patients with advanced larynx cancer, consisting of readily available clinical variables, gives more accurate estimations of the estimated 5-year survival rate when compared to a model based on T and N classification alone. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:1140-1145, 2018.

Anaplastic thyroid carcinoma: Failure of conventional therapy but hope of targeted therapy.

BACKGROUND: Anaplastic thyroid cancer has a median survival between 1.2 and 10 months. The purpose of our study was to evaluate the outcomes of patients with anaplastic thyroid cancer in Ireland. METHODS: We carried out a retrospective analysis of the Irish National Cancer Database for patients with anaplastic thyroid cancer between 2000 and 2010. RESULTS: Of a total of 64 patients (40 women, 24 men), the median age was 69 years, and 29.7% of the patients had distant metastases. The overall median survival was 2.3 months and the 1, 2, and 5-year survival was 12.5%, 6.25%, and 4.69%, respectively. On univariate analysis age, sex, metastases at diagnosis, and multimodality treatment were statistically significant indicators of prognosis, and metastases at diagnosis remained statistically significant on multivariate analysis. CONCLUSION: These results correlate with the American Thyroid Association (ATA) guidelines, in which, when possible, multimodality therapy offers a survival advantage to a select group of patients. Novel therapies may offer the greatest hope for these patients. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1122-E1129, 2016.

Treatment-related toxicities in older adults with head and neck cancer: A population-based analysis.

BACKGROUND: Despite advantages in terms of cancer control and organ preservation, the benefits of chemotherapy and radiation therapy (CTRT) may be offset by potentially severe treatment-related toxicities, particularly in older patients. The objectives of this study were to assess the types and frequencies of toxicities in older adults with locally or regionally advanced head and neck squamous cell carcinoma (HNSCC) who were receiving either primary CTRT or radiation therapy (RT) alone. METHODS: With Surveillance, Epidemiology, and End Results cancer registry data linked with Medicare claims, patients who were 66 years old or older with locally advanced HNSCC, were diagnosed from 2001 to 2009, and received CTRT or RT alone were identified. Differences in the frequency of toxicity-related hospital admissions and emergency room visits as well as feeding tube use were examined, and controlling for demographic and disease characteristics, this study estimated the impact of chemotherapy on the likelihood of toxicity. RESULTS: Among patients who received CTRT (n = 1502), 62% had a treatment-related toxicity, whereas 46% of patients who received RT alone (n = 775) did. When the study controlled for demographic and disease characteristics, CTRT patients were twice as likely to experience an acute toxicity in comparison with their RT-only peers. Fifty-five percent of CTRT patients had a feeding tube placed during or after treatment, whereas 28% of the RT-only group did. CONCLUSIONS: In this population-based cohort of older adults with HNSCC, the rates of acute toxicities and feeding tube use in patients receiving CTRT were considerable. It is possible that for certain older patients, the potential benefit of adding chemotherapy to RT does not outweigh the harms of this combined-modality therapy.

Treatment complications and survival in advanced laryngeal cancer: a population-based analysis.

OBJECTIVES/HYPOTHESIS: Primary curative treatment of advanced laryngeal cancer may include surgery or chemoradiation, although recommendations vary and both are associated with complications. We evaluated predictors and trends in the use of these modalities and compared rates of complications and overall survival in a population-based cohort of older adults. STUDY DESIGN: Retrospective population-based cohort study. METHODS: Using Surveillance Epidemiology and End Results (SEER) cancer registry data linked with Medicare claims, we identified patients over 65 with advanced laryngeal cancer diagnosed 1999 to 2007 who had total laryngectomy (TL) or chemoradiation (CTRT) within 6 months following diagnosis. We identified complications and estimated the impact of treatment on overall survival, using propensity score methods. RESULTS: The proportion of patients receiving TL declined from 74% in 1999 to 26% in 2007 (P < 0.0001). Almost 20% of the CTRT patients had a tracheostomy following treatment, and 57% had a feeding tube. TL was associated with an 18% lower risk of death, adjusting for patient and disease characteristics. The benefit of TL was greatest in patients with the highest propensity to receive surgery. CONCLUSION: TL remains an important treatment option in well selected older patients. However, treatment selection is complex; and factors such as functional status, patient preference, surgeon expertise, and post-treatment support services should play a role in treatment decisions. LEVEL OF EVIDENCE: 2b. Laryngoscope, 124:2707-2713, 2014.

Kimura disease: diagnostic challenges and clinical management.

Kimura disease is a rare inflammatory lesion of the head and neck region, usually seen in young Asian men. Patients usually present with a painless mass involving a major salivary gland with lymphadenopathy. Current studies suggest an immunologic mechanism for the pathogenesis of this disease entity. Histopathologically, this tumor is composed of vascular proliferation and lymphoid infiltrate rich in eosinophils. The immunohistochemical findings are usually nonspecific but might help in eliminating malignancies. The role of fine needle aspiration (FNA) and biopsy procedure appears to be limited in making the histologic diagnosis of Kimura disease. The natural history of the disease, however, appears to be indolent, without any malignant transformation reported, although recurrence can be frequent. Here, we describe 2 cases of Kimura disease with differing presentations, diagnostic difficulties, and their clinical management. The difficulties encountered in establishing an accurate preoperative diagnosis and the complexity of surgical management highlight the need for an index of suspicion for this clinical entity while mandating appropriate surgical management to minimize operative morbidity and reduce the risk of recurrence.

In utero DNA damage from environmental pollution is associated with somatic gene mutation in newborns.

Transplacental exposure to carcinogenic air pollutants from the combustion of fossil fuels is a growing health concern, given evidence of the heightened susceptibility of the fetus. These mutagenic/carcinogenic pollutants include aromatic compounds such as polycyclic aromatic hydrocarbons that bind to DNA, forming chemical-DNA adducts. We have investigated the genotoxic effects of transplacental exposure in humans by analyzing aromatic-DNA adducts and the frequency of gene mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in umbilical cord and maternal blood samples. Here we show, in a cross-sectional study of 67 mothers and 64 newborns from the Krakow Region of Poland, that aromatic-DNA adducts measured by (32)P-postlabeling are positively associated with HPRT mutant frequency in the newborns (beta = 0.56, P = 0.03) after controlling for exposure to tobacco smoke, diet, and socioeconomic status. In contrast to the fetus, HPRT mutations and DNA adducts do not reflect similar exposure periods in the mother, and the maternal biomarkers were not correlated. Adducts were higher in the newborn than the mother, indicating differential susceptibility of the fetus to DNA damage; but HPRT mutation frequency was 4-fold lower, consistent with the long lifetime of the biomarker. These results provide the first demonstration of a molecular link between somatic mutation in the newborn and transplacental exposure to common air pollutants, a finding that is relevant to cancer risk assessment.