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Timothy M Pawlik

Publications and source records attributed to Timothy M Pawlik.

At least 19 recordsLinked to original sources
PubMed2026

Genetic Ancestry and Colorectal Cancer in the All of Us Dataset.

IMPORTANCE: Genetic ancestry may complement biological, behavioral, and clinical factors in understanding colorectal cancer (CRC) disparities; yet, ancestry-informed analyses in CRC remain limited. OBJECTIVE: To characterize associations of genetic ancestry with CRC burden, age at diagnosis, and age-specific risk, and to develop a multiethnic CRC risk-prediction model. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used All of Us data from July 1986 to October 2023, with follow-up through last visit or death (median [IQR], 133.1 [57.1-186.5] months); analyses were conducted from February to June 2026. All of Us is a US research cohort with linked electronic health record (EHR) and short-read whole-genome sequencing (srWGS) data. All of Us Research Program participants with srWGS and linked EHR data were included, except those with hereditary polyposis or Lynch syndrome. EXPOSURES: Genetically inferred ancestry categories and principal components. MAIN OUTCOMES AND MEASURES: Any CRC was the primary outcome. Associations were evaluated using Fisher exact tests, cumulative incidence functions with Gray tests, cause-specific and Fine-Gray subdistribution hazard models, and pooled multivariable logistic regression. Prediction models used penalized least absolute shrinkage and selection operator and extreme gradient boosting (XGBoost). RESULTS: Among 316 624 participants (median [IQR] age, 56.3 [40.2-68.2] years; 172 327 [54.4%] of European ancestry; 191 705 female [61.2%]; 121 585 male [38.8%]), 2914 (0.9%) developed CRC. European ancestry was associated with higher odds of CRC vs all other ancestries combined (odds ratio, 1.50; 95% CI, 1.39-1.62). The median age at CRC diagnosis was older in European (63.4 [53.9-71.2] years) than in American admixed-Latino, African, East Asian, and Other ancestry groups. In cause-specific hazard models on the attained-age scale, American admixed-Latino (hazard ratio, 1.30; 95% CI, 1.14-1.47) and East Asian (hazard ratio, 1.43; 95% CI, 1.06-1.94) ancestry had higher age-specific CRC hazard than European ancestry, with consistent findings on the subdistribution scale accounting for competing death. The multiethnic XGBoost model performed best (receiver operating characteristic area under the curve, 0.898; 95% CI, 0.882-0.912; precision-recall area under the curve, 0.338; 95% CI, 0.296-0.379) and was well calibrated. CONCLUSIONS AND RELEVANCE: In this cohort study, genetic ancestry was associated with meaningful differences in CRC burden and age-specific risk. These findings suggest that a multiethnic XGBoost model may complement CRC screening as a risk-enrichment tool.

Aged↗
PubMed2025

Comprehensive assessment of genomic heterogeneity, coalterations, and outcomes of patients with colorectal cancer: An AACR GENIE project analysis.

INTRODUCTION: Colorectal cancer remains a leading cause of cancer mortality in the United States and can be characterized by racial and sex-based disparities. The objective of the current study was to characterize the genomic heterogeneity of colorectal cancer among diverse demographic groups, assess coalteration patterns and their impact on long-term outcomes among patients with colorectal cancer. METHODS: Data from the American Association for Cancer Research GENIE registry were analyzed to assess genomic alterations in colorectal cancer. The cohort included 20,542 samples from 19,542 patients, stratified by race or ethnicity, sex, and age of onset (<50 years for early-onset colorectal cancer). Genomic alterations and coalterations among the 48 most prevalent loci were evaluated for any association with overall survival in an external Memorial Sloan Kettering Cancer Center cohort. RESULTS: Among 19,542 patients, KRAS mutations were more prevalent among Black patients (57.1%) compared with White (41.8%) and Asian (43.4%) patients (P < .001), whereas TP53 alterations were more frequent among Asian (75.6%) than White (69.9%) or Black (71.9%) patients (P < .001). Coalterations with KRAS were associated with improved survival over KRAS alteration alone, a pattern less-frequently observed among Black patients. Sex-based differences were also observed, with BRAF mutations more prevalent among females (14.6% vs 9.7%; P < .001) and TP53 mutations more common among males (73% vs 70.5%;P = .009). Although KRAS alterations tended to co-occur with alterations in ATM, ARID1A, CREBBP, FAT1, KMT2B, and KMT2D genes among patients with "early onset" colorectal cancer (all p & q < 0.05), alterations of these gene pairs were mutually exclusive among individuals with late onset colorectal cancer. CONCLUSION: Genomic alterations and coalteration patterns varied relative to race/ethnicity, sex, and age at disease onset. Differences in genomic alteration patterns of colorectal cancer somatic tumor cells are an important consideration to help address disparities among different demographic groups.

Humans↗
PubMed2006

Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases.

PURPOSE: Chemotherapy before resection of hepatic colorectal metastases (CRM) may cause hepatic injury and affect postoperative outcome. PATIENTS AND METHODS: Four hundred six patients underwent hepatic resection of CRM between 1992 and 2005. Pathologic review of the nontumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal injury. The effect of chemotherapy and liver injury on perioperative outcome was analyzed. RESULTS: One hundred fifty-eight patients (38.9%) received no preoperative chemotherapy, whereas 248 patients (61.1%) did. The median duration of chemotherapy was 16 weeks (range, 2 to 70 weeks). Chemotherapy consisted of fluoropyrimidine-based regimens (fluorouracil [FU] alone, 15.5%; irinotecan plus FU, 23.1%; and oxaliplatin plus FU, 19.5%) and other therapy (3.0%). On pathologic analysis, 36 patients (8.9%) had steatosis, 34 (8.4%) had steatohepatitis, and 22 (5.4%) had sinusoidal dilation. Oxaliplatin was associated with sinusoidal dilation compared with no chemotherapy (18.9% v 1.9%, respectively; P < .001; odds ratio [OR] = 8.3; 95% CI, 2.9 to 23.6). In contrast, irinotecan was associated with steatohepatitis compared with no chemotherapy (20.2% v 4.4%, respectively; P < .001; OR = 5.4; 95% CI, 2.2 to 13.5). Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (14.7% v 1.6%, respectively; P = .001; OR = 10.5; 95% CI, 2.0 to 36.4). CONCLUSION: Steatohepatitis is associated with an increased 90-day mortality after hepatic surgery. In patients with hepatic CRM, the chemotherapy regimen should be carefully considered because the risk of hepatotoxicity is significant.

Adolescent↗
PubMed2006

Proteomic analysis of nipple aspirate fluid from women with early-stage breast cancer using isotope-coded affinity tags and tandem mass spectrometry reveals differential expression of vitamin D binding protein.

BACKGROUND: Isotope-coded affinity tag (ICAT) tandem mass spectrometry (MS) allows for qualitative and quantitative analysis of paired protein samples. We sought to determine whether ICAT technology could quantify and identify differential expression of tumor-specific proteins in nipple aspirate fluid (NAF) from the tumor-bearing and contralateral disease-free breasts of patients with unilateral early-stage breast cancer. METHODS: Paired NAF samples from 18 women with stage I or II unilateral invasive breast carcinoma and 4 healthy volunteers were analyzed using ICAT labeling, sodium dodecyl sulfate-polyacrylamide gel (SDS-PAGE), liquid chromatography, and MS. Proteins were identified by sequence database analysis. Western blot analysis of NAF from an independent sample set from 12 women (8 with early-stage breast cancer and 4 healthy volunteers) was also performed. RESULTS: 353 peptides were identified from tandem mass spectra and matched to peptide sequences in the National Center for Biotechnology Information database. Equal numbers of peptides were up- versus down-regulated. Alpha2HS-glycoprotein [Heavy:Light (H:L) ratio 0.63] was underexpressed in NAF from tumor-bearing breasts, while lipophilin B (H:L ratio 1.42), beta-globin (H:L ratio 1.98), hemopexin (H:L ratio 1.73), and vitamin D-binding protein precursor (H:L ratio 1.82) were overexpressed. Western blot analysis of pooled samples of NAF from healthy volunteers versus NAF from women with breast cancer confirmed the overexpression of vitamin D-binding protein in tumor-bearing breasts. CONCLUSION: ICAT tandem MS was able to identify and quantify differences in specific protein expression between NAF samples from tumor-bearing and disease-free breasts. Proteomic screening techniques using ICAT and NAF may be used to find markers for diagnosis of breast cancer.

Biomarkers, Tumor↗
PubMed2006

Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease.

BACKGROUND: Resection of melanoma metastatic to the liver remains controversial. We evaluated the efficacy of hepatic resection in patients with metastatic ocular and cutaneous melanoma and assessed factors that could affect survival after resection. METHODS: Forty patients with hepatic melanoma metastasis underwent resection at four major hepatobiliary centers. Clinicopathologic factors were evaluated with regard to recurrence and survival by using chi(2) and log-rank tests. RESULTS: The primary tumor was ocular in 16 patients and cutaneous in 24. The median disease-free interval from the time of primary tumor treatment to hepatic metastasis was the same for both groups (ocular, 62.9 months; cutaneous, 63.1 months; P = .94). Most patients underwent either an extended hepatic resection (37.5%) or hemihepatectomy (22.5%). Twenty-six patients (65%) received perioperative systemic therapy. Thirty (75.0%) of 40 patients developed tumor recurrence. The median time to recurrence after hepatic resection was 8.3 months (ocular, 8.8 months; cutaneous, 4.7 months; P = .3). Patients with primary ocular melanoma were more likely to experience recurrence within the liver (53.3% vs. 17.4%; P = .015), whereas patients with a cutaneous primary tumor more often developed extrahepatic involvement. The 5-year survival rate for patients with a primary ocular melanoma was 20.5%, whereas there were no 5-year survivors for patients with cutaneous melanoma (P = .03). CONCLUSIONS: Patterns of recurrence and prognosis after resection of hepatic melanoma metastasis differ depending on whether the primary melanoma is ocular or cutaneous. Resection should be performed as part of a multidisciplinary approach, because recurrence is common.

Adult↗
PubMed2006

Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma.

BACKGROUND: The reported data on surgery plus radiotherapy for retroperitoneal soft tissue sarcomas (RPS) have been mostly from retrospective studies. We evaluated the long-term outcome of patients with operable RPS who were treated with protocol-based preoperative radiotherapy followed by complete surgical resection. METHODS: Data from two prospective trials that included preoperative radiotherapy and surgery for patients with radiographically resectable RPS were combined to define long-term relapse rates and survival. RESULTS: Seventy-two patients with intermediate- or high-grade RPS were treated with preoperative radiotherapy (median dose, 45 Gy; range, 18.0-50.4 Gy). Fifty-four patients (75%) had primary RPS, whereas 18 (25%) had recurrent disease. The median tumor size was 15.5 cm. Sixty-four patients completed the planned preoperative radiotherapy; 57 (89%) underwent laparotomy with curative intent, and 54 (95%) had a macroscopically complete (R0 or R1) resection. With a median follow-up of 40.3 months, 28 patients (52%) who received preoperative radiotherapy and underwent a macroscopically complete resection had recurrences. For the 54 patients who underwent R0 or R1 resection after preoperative radiotherapy, the 5-year local recurrence-free, disease-free, and overall survival rates were 60%, 46%, and 61%, respectively. The median overall survival has not been reached (>60 months). CONCLUSIONS: Patients with intermediate- or high-grade RPS treated with preoperative radiotherapy plus complete resection had a median survival >60 months. This compares favorably to historical data for similar patients treated with surgery alone.

Adult↗
PubMed2006

Assessment of the role of sentinel lymph node biopsy for primary cutaneous desmoplastic melanoma.

BACKGROUND: The role of sentinel lymph node biopsy (SLNB) in the treatment of desmoplastic melanoma (DM) remains undefined. The purpose of this study was to evaluate the use of SLNB for DM. METHODS: In all, 1850 patients with cutaneous melanoma underwent wide local excision and SLNB. Patients with DM were identified and stratified as 'pure' DM or 'mixed' DM (i.e., DM associated with at least one other common histologic subtype). RESULTS: Of the 1850 patients, 65 (3.5%) had DM. Of these, 46 (70.8%) had pure DM and 19 (29.2%) had mixed DM. Patients with pure DM had a median tumor thickness of 3.5 mm and 6.5% were ulcerated. Compared with patients with pure DM, patients with either mixed DM or non-DM (n = 1785) had thinner primary tumors (median, 1.7 mm and 1.5 mm, respectively, each P < 0.001 vs. pure DM) that were more likely to be ulcerated (27.7% and 21.3%, respectively, each P < 0.05 vs. pure DM). Although the incidence of a positive SLN was similar in patients with mixed DM (15.8%) and non-DM (17.5%), patients with pure DM were less likely to have a positive SLN (2.2%) (each P < 0.01 vs. non-DM and mixed DM). At a median follow-up of 2.9 years, no patient with pure DM had recurred. CONCLUSIONS: Despite having thicker primary tumors, patients with pure DM have a lower incidence of positive SLNs compared with patients with non-DM. Whereas the treatment approach for patients with mixed DM should be similar to that of other melanoma patients, patients with pure DM are unlikely to have metastatic disease in regional lymph nodes and SLNB may not be warranted.

Female↗
PubMed2006

Solitary colorectal liver metastasis: resection determines outcome.

BACKGROUND: Hepatic resection (HR) and radiofrequency ablation (RFA) have been proposed as equivalent treatments for colorectal liver metastasis. HYPOTHESIS: Recurrence patterns after HR and RFA for solitary liver metastasis are similar. DESIGN: Analysis of a prospective database at a tertiary care center with systematic review of follow-up imaging in all of the patients. PATIENTS AND METHODS: Patients with solitary liver metastasis as the first site of metastasis treated for cure by HR or RFA were studied (patients received no prior liver-directed therapy). Prognostic factors, recurrence patterns, and survival rates were analyzed. RESULTS: Of the 180 patients who were studied, 150 underwent HR and 30 underwent RFA. Radiofrequency ablation was used when resection would leave an inadequate liver remnant (20 patients) or comorbidity precluded safe HR (10 patients). Tumor size and treatment determined recurrence and survival. The local recurrence (LR) rate was markedly lower after HR (5%) than after RFA (37%) (P<.001). Treatment by HR was associated with longer 5-year survival rates than RFA, including LR-free (92% vs 60%, respectively; P<.001), disease-free (50% vs 0%, respectively; P = .001), and overall (71% vs 27%, respectively; P<.001) survival rates. In the subset with tumors 3 cm or larger (n = 79), LR occurred more frequently following RFA (31%) than after HR (3%) (P = .001), with a 5-year LR-free survival rate of 66% after RFA vs 97% after HR (P<.001). Patients with small tumors experienced longer 5-year overall survival rates after HR (72%) as compared with RFA (18%) (P = .006). CONCLUSIONS: The survival rate following HR of solitary colorectal liver metastasis exceeds 70% at 5 years. Radiofrequency ablation for solitary metastasis is associated with a markedly higher LR rate and shorter recurrence-free and overall survival rates compared with HR, even when small lesions (< or = 3 cm) are considered. Every method should be considered to achieve resection of solitary colorectal liver metastasis, including referral to a specialty center, extended hepatectomy, and chemotherapy.

Adult↗
PubMed2006

Results of a single-center experience with resection and ablation for sarcoma metastatic to the liver.

HYPOTHESIS: A subset of patients with sarcoma liver metastasis may benefit from hepatic resection and/or ablation. DESIGN: Retrospective review of prospectively collected cancer center database records. PATIENTS AND METHODS: Sixty-six patients who underwent hepatic resection and/or open radiofrequency ablation of metastatic sarcoma between July 1, 1996, and April 30, 2005, were identified from the database. Clinicopathologic, operative, recurrence, and long-term survival data were analyzed. RESULTS: The primary sarcoma site was the abdomen or retroperitoneum (n = 22), stomach (n = 18), small or large bowel (n = 17), pelvis (n = 4), uterus (n = 3), or other (n = 2). Tumor pathologic types included gastrointestinal stromal tumor (n = 36), leiomyosarcoma (n = 18), and sarcoma not otherwise classified (n = 12). Thirty-five patients underwent resection, 18 underwent resection plus radiofrequency ablation, and 13 underwent radiofrequency ablation only. With a median follow-up of 35.8 months, 44 patients (66.7%) had recurrence (intrahepatic only, n = 16; extrahepatic only, n = 11; both, n = 17). Treatment with radiofrequency ablation (either alone or combined with resection) (P = .002) and lack of adjuvant chemotherapy (P = .01) predicted shorter disease-free survival. The 1-, 3-, and 5-year overall survival rates were 91.2%, 65.4%, and 27.1%, respectively. Patients with gastrointestinal stromal tumor who were treated with adjuvant imatinib mesylate had the longest median survival (not reached) (P = .003). CONCLUSIONS: Long-term survival can be achieved following surgical treatment of sarcoma liver metastasis, especially in patients with gastrointestinal stromal tumor. Patients with sarcoma liver metastasis should be evaluated by a multidisciplinary team, as recurrence is common and adjuvant therapy may prolong survival.

Adult↗
PubMed2006

Subtotal hepatectomy following neoadjuvant chemotherapy for a previously unresectable hepatocellular carcinoma.

An awareness of variant hepatic vascular anatomy provides vital information in the preoperative evaluation of patients with hepatocellular carcinoma. The authors present a patient with unresectable hepatocellular carcinoma who responded to combination systemic and regional chemotherapy. Because of the presence of an enlarged inferior right hepatic vein, the patient subsequently underwent successful subtotal hepatectomy with resection of all three main hepatic veins. This case illustrates that the combination of innovative neoadjuvant chemotherapy and well-planned surgical approaches may benefit a small number of patients previously deemed unresectable.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases.

Some investigators have suggested that wedge resection (WR) confers a higher incidence of positive margins and an inferior survival compared with anatomic resection (AR) of colorectal liver metastases (CLM). We sought to investigate the margin status, pattern of recurrence, and overall survival of patients with CLM treated with WR or AR. We identified 253 consecutive patients, in a multi-institutional database from 1991 to 2004, who underwent either WR or AR. WR was defined as a nonanatomic resection of the CLM, and AR was defined as single or multiple resections of one or two contiguous Couinaud segments. Clinicopathologic factors were analyzed with regard to pattern of recurrence and survival. One hundred six WRs were performed in 72 patients and 194 ARs in 181 patients. There was no difference in the rate of positive surgical margin (8.3%), overall recurrence rates, or patterns of recurrence between patients treated with WR vs. AR. Patients who had a positive surgical resection margin were more likely to recur at the surgical margin regardless of whether they underwent WR or AR. The median survival was 76.6 months for WR and 80.8 months for AR, with 5-year actuarial survival rates of 61% and 60%, respectively. AR is not superior to WR in terms of tumor clearance, pattern of recurrence, or survival. WR should remain an integral component of the surgical treatment of CLM.

Adult↗
PubMed2006

Debunking dogma: surgery for four or more colorectal liver metastases is justified.

Treatment of four or more colorectal liver metastases (CRLMs) is controversial and remains a relative contraindication to surgery at some institutions. We sought to assess the outcome of patients with four or more CRLMs treated with surgery. Patients (159) with four or more CRLMs were treated surgically at a single institution. The median number of treated lesions was 5 (range, 4-14). The majority of patients received neoadjuvant chemotherapy (89.9%). Forty-six (29.0%) patients underwent resection only, 12 (7.5%) underwent radiofrequency ablation (RFA) only, and 101 (63.5%) underwent resection plus RFA. The 5-year actuarial disease-free and overall survival rates were 21.5% and 50.9%, respectively. Patients who underwent RFA as part of their surgical procedure (hazard ratio [HR] = 1.81, P = 0.03) and those with a positive surgical resection margin (HR = 1.52, P = 0.01) were more likely to have a shorter time to recurrence. Patients who did not have a reduction in tumor size following neoadjuvant chemotherapy had a higher likelihood of death following surgical treatment (HR = 2.53, P = 0.01). Patients with four or more CRLMs should be considered for aggressive surgical treatment, including liver resection with or without RFA, in order to improve the chance of long-term survival. Certain clinicopathologic factors, including lack of response to neoadjuvant chemotherapy, were associated with a worse prognosis.

Adult↗
PubMed2005

Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy.

BACKGROUND: In-transit recurrence is a unique and uncommon pattern of treatment failure in patients with melanoma. Little information exists concerning the incidence, predictors, and natural history of in-transit disease since the introduction of sentinel lymph node biopsy (SLNB). METHODS: Between 1991 and 2001, 1395 patients with primary melanoma underwent SLNB. Univariate and multivariate logistic regression analyses were performed to examine the association among known clinicopathologic factors, in-transit recurrence, and distant metastatic failure after the development of in-transit disease. RESULTS: With a median follow-up of 3.9 years, 241 patients (17.3%) experienced disease recurrence, including 91 (6.6%) who developed in-transit recurrence. Independent predictors of in-transit recurrence included age >50 years, a lower extremity location of the primary tumor, Breslow depth, ulceration, and sentinel lymph node (SLN) status. Of the 69 patients who presented with in-transit disease as the sole site of first recurrence, 39 developed distant disease. By univariate analysis, predictors of distant failure among patients with in-transit disease included SLN status, largest metastatic focus in the SLN >2.5 mm2, subcutaneous location of in-transit disease, in-transit tumor size > or = 2 cm, and a disease-free interval before in-transit recurrence of <12 months. In-transit tumor size remained a significant predictor of distant metastasis by multivariate analysis (odds ratio, 9.69). CONCLUSIONS: The overall incidence of in-transit metastases in patients undergoing SLNB is low and does not seem to have increased since the introduction of the SLNB technique. In-transit recurrence, as well as subsequent distant metastatic failure, can be predicted on the basis of adverse tumor factors and SLN status.

Adolescent↗