Does Long-Term Bowel Function Change After Colectomy for Colon Malignancy?

INTRODUCTION: Current understanding of bowel function after colectomy for colon cancer is informed by conflicting data, making preoperative patient counseling difficult. Our previous work demonstrates bowel movement frequency increases by postoperative follow-up, while overall function does not change. Long-term changes are unknown. We aimed to evaluate changes to patient-reported bowel function after colectomy for colon malignancy. METHODS: This is an observational study of patients that underwent colectomy for colon malignancy and completed the Colorectal Functional Outcome (COREFO) questionnaire at preoperative and 30-d postoperative clinic visits. Long-term bowel function was assessed using the same questionnaire via telephone or surveillance clinic visit. Mean domain and Total COREFO scores were compared baseline to long-term using paired t-tests. Quality of life analysis was obtained using the Patient Reported Outcome Measurement Information System-10 Global Health questionnaire for patients who completed this measure at surveillance visits or via telephone. RESULTS: Sixty-six patients met inclusion criteria. Median time between baseline and long-term questionnaire completion was 16 mo (interquartile range 11-30). Stool-related aspects (pain and bleeding with bowel movements, anal skin irritation) improved significantly from baseline to long-term. There were no other differences in any domain or Total COREFO score. Patient Reported Outcome Measurement Information System-10 scores demonstrated quality of life equivalent to the general US population. CONCLUSIONS: Over the long-term, after colectomy for colon cancer, patients report improvements in stool-related aspects (pain and bleeding with bowel movements, anal skin irritation). Evidence-based preoperative patient counseling should include these findings.

Extreme Elevation of Baseline Intraoperative Parathyroid Hormone Measurements: Should Usual Protocols Apply?

INTRODUCTION: Intraoperative parathyroid hormone (IOPTH) monitoring is routinely used to facilitate minimally invasive parathyroidectomy. Many IOPTH protocols exist for predicting biochemical cure. Some patients are found to have extremely high baseline IOPTH levels (defined in this study as >500 pg/mL), which may affect the likelihood of satisfying certain final IOPTH criteria. We aimed to discover whether clinically significant differences exist in patients with extremely high baseline IOPTH and which IOPTH protocols are most appropriately applied to these patients. MATERIALS AND METHODS: This is a retrospective review of 237 patients who underwent parathyroidectomy with IOPTH monitoring for primary hyperparathyroidism (pHPT) from 2016 to 2020. Baseline IOPTH levels, drawn prior to manipulation of parathyroid glands, were grouped into categories labeled "elevated" (>65-500 pg/mL) and "extremely elevated" (>500 pg/mL). Final IOPTH levels were analyzed to determine whether there was a >50% decrease from baseline and whether a normal IOPTH value was achieved. 6-wk postoperative calcium levels were also examined. RESULTS: Of the patients in this cohort, 76% were in the elevated group and 24% in the extremely elevated group. Male sex and higher preoperative PTH levels were correlated with higher baseline IOPTH levels. Patients with extremely elevated baseline IOPTH were less likely to have IOPTH fall into normal range at the conclusion of the case (P = 0.019), and final IOPTH levels were higher (P < 0.001), but the IOPTH was equally likely to decrease >50% from baseline. There was no difference in the mean postoperative calcium levels between the two groups at 6-wk or at longer term follow-up (mean 525 d). CONCLUSIONS: Detection of baseline IOPTH levels >500 pg/mL during parathyroidectomy performed for pHPT is not uncommon. IOPTH in patients with extremely elevated baseline levels were less likely to fall into normal range, but follow-up calcium levels were equal, suggesting that applying more stringent IOPTH criteria for predicting biochemical cure may not be appropriate for this population.

Molecular Profiling of Exceptional Responders to Cancer Therapy.

BACKGROUND: The vast majority of metastatic cancers cannot be cured. Palliative treatment may relieve disease symptoms by stopping or slowing cancer growth and may prolong patients' lives, but almost all patients will inevitably develop disease progression after initial response. However, for reasons that are not fully understood, a very few patients will have extraordinary durable responses to standard anticancer treatments. MATERIALS AND METHODS: We analyzed exceptional responders treated at Fox Chase Cancer Center between September 2009 and November 2017. An exceptional response was defined as a complete response lasting more than 1 year or a partial response or stable disease for more than 2 years. Tumor samples were analyzed using an Ambry Genetics test kit with a 142-gene panel. Messenger RNA expression was evaluated using NanoString's nCounter PanCancer Pathways Panel and Immune Profiling Panel and compared with matched controls for gender, age, and cancer type. RESULTS: Twenty-six exceptional responders with metastatic bladder, kidney, breast, lung, ovarian, uterine, and colon cancers were enrolled. Mutations were identified in 45 genes. The most common mutation was an EPHA5 nonsynonymous mutation detected in 87.5% of patients. Mutations in DNA damage repair pathway genes were also frequent, suggesting increased genome instability. We also found varying expression of 73 genes in the Pathways panel and 85 genes in the Immune Profiling panel, many of them responsible for improvement in tumor recognition and antitumor immune response. CONCLUSIONS: The genomic instability detected in our exceptional responders, plus treatment with DNA damage compounds combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in the patients studied. IMPLICATIONS FOR PRACTICE: With recent advances in the treatment of cancer, there is increased emphasis on the importance of identifying molecular markers to predict treatment outcomes, thereby allowing precision oncology. In this study, it was hypothesized that there is a "specific biologic signature" in the biology of the cancer in long-term survivors that allows sensitivity to systemic therapy and durability of response. Results showed that DNA damage repair pathway alterations, combined with favorable anticancer immunity, may have contributed to exceptional responses. It is very likely that an in-depth examination of outlier responses will become a standard component of drug development in the future.

Does Bowel Function Change After Colectomy for Colon Malignancy?

BACKGROUND: Colon cancer patients often ask how surgery will affect bowel function. Current understanding is informed by conflicting data, making preoperative patient counseling difficult. We aimed to evaluate patient-reported bowel function changes after colectomy for colon malignancy. MATERIAL AND METHODS: This was a retrospective analysis of a prospectively collected institutional database from July 2015 to June 2019. The included patients underwent colectomy for adenocarcinoma of the colon, and completed the Colorectal Functional Outcome (COREFO) questionnaire at preoperative presentation and postoperative followup. Preoperative and postoperative scores were compared using paired t-tests. Multivariable analysis was performed using domains demonstrating statistical significance on bivariate analysis, assessing the factors that were associated with symptomatic bowel function. RESULTS: We identified 117 patients with a mean age of 64 ± 13 y. The median time between preoperative and postoperative questionnaire completion was 52 d (interquartile range 45-70). Bowel movement frequency increased significantly from a mean preoperative score of 9.72 to a mean postoperative score of 14.2 (P = 0.003). There were no significant differences in the remaining four domains of bowel function or global function. Multivariable analysis demonstrated higher likelihood of symptomatic postoperative frequency scores in male patients (OR 3.85, 95% CI 1.44-11.11, P = 0.007) and patients with symptomatic preoperative frequency (OR 5.56, 95% CI 1.62-19.02, P = 0.006). CONCLUSIONS: Patient-reported bowel movement frequency worsens at postoperative follow-up after colectomy for colon cancer, while overall bowel function does not change. Men and patients with preoperative symptomatic frequency have an increased likelihood of reporting symptomatic postoperative frequency. These findings should guide more personalized and evidence-based preoperative patient counseling.

Correction: DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes.

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DNA breakpoint assay reveals a majority of gross duplications occur in tandem reducing VUS classifications in breast cancer predisposition genes.

PURPOSE: Gross duplications are ambiguous in terms of clinical interpretation due to the limitations of the detection methods that cannot infer their context, namely, whether they occur in tandem or are duplicated and inserted elsewhere in the genome. We investigated the proportion of gross duplications occurring in tandem in breast cancer predisposition genes with the intent of informing their classifications. METHODS: The DNA breakpoint assay (DBA) is a custom, paired-end, next-generation sequencing (NGS) method designed to capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2. RESULTS: DBA allowed us to ascertain breakpoints for 44 unique gross duplications from 147 probands. We determined that the duplications occurred in tandem in 114 (78%) carriers from this cohort, while the remainder have unknown tandem status. Among the tandem gross duplications that were eligible for reclassification, 95% of them were upgraded to pathogenic. CONCLUSION: DBA is a novel, high-throughput, NGS-based method that informs the tandem status, and thereby the classification of, gross duplications. This method revealed that most gross duplications in the investigated genes occurred in tandem and resulted in a pathogenic classification, which helps to secure the necessary treatment options for their carriers.

False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care.

PURPOSE: There is increasing demand from the public for direct-to-consumer (DTC) genetic tests, and the US Food and Drug Administration limits the type of health-related claims DTC tests can market. Some DTC companies provide raw genotyping data to customers if requested, and these raw data may include variants occurring in genes recommended by the American College of Medical Genetics and Genomics to be reported as incidental/secondary findings. The purpose of this study was to review the outcome of requests for clinical confirmation of DTC results that were received by our laboratory and to analyze variant classification concordance. METHODS: We identified 49 patient samples received for further testing that had previously identified genetic variants reported in DTC raw data. For each case identified, information pertaining to the outcome of clinical confirmation testing as well as classification of the DTC variant was collected and analyzed. RESULTS: Our analyses indicated that 40% of variants in a variety of genes reported in DTC raw data were false positives. In addition, some variants designated with the "increased risk" classification in DTC raw data or by a third-party interpretation service were classified as benign at Ambry Genetics as well as several other clinical laboratories, and are noted to be common variants in publicly available population frequency databases. CONCLUSION: Our results demonstrate the importance of confirming DTC raw data variants in a clinical laboratory that is well versed in both complex variant detection and classification.

Motives and Barriers to Physical Activity Among Older Adults of Different Socioeconomic Status.

This study explored motives and barriers to physical activity (PA) among older adults of differing socioeconomic status (SES) utilizing a self-determination theory and self-efficacy theory framework. Focus groups (n = 4) were conducted with older adults (n = 28) from two SES groups, using thematic analysis to identify motives and barriers. Integrated and identified regulations and, to a lesser extent, intrinsic motives, were evident across SES groups. Verbal persuasion and affective and physiological states emerged as prominent efficacy sources regardless of SES. More barriers were reported by the low SES group, with health conditions, neighborhood safety, and PA guidelines knowledge emerging as most salient. Time emerged as a prominent barrier for the high SES group. Integrated and identified regulations should be fostered in future interventions and policy regardless of SES. Barriers to PA varied across SES groups; thus future interventions and policy should account for such differences.

Management trends in stage I testicular seminoma: Impact of race, insurance status, and treatment facility.

BACKGROUND: The management of stage I testicular seminoma is evolving rapidly. This study examined modern trends in the management of stage I testicular seminoma and the effects of sociodemographic factors on therapy choice. METHODS: Data from the National Cancer Data Base on 34,067 patients with stage I testicular seminoma who were treated between 1998 and 2011 were analyzed. Multivariate logistic regression models were used to assess factors associated with adjuvant management strategies. RESULTS: For patients with stage IA/B testicular seminoma, rates of observation after orchiectomy increased from 23.7% to 54.0%, the receipt of adjuvant chemotherapy increased from 1.5% to 16.0%, and the receipt of radiotherapy decreased from 70.8% to 28.8%. A similar pattern was seen in stage IS testicular seminoma, although these patients were more likely to receive adjuvant radiotherapy/chemotherapy (60.7% vs 44.8% for stage IA/B in 2011, P < .001). For patients with stage IA/B testicular seminoma, observation after orchiectomy was more common in racial minorities (odds ratio [OR] for blacks vs whites, 1.31, P < .001; OR for Hispanics vs whites, 1.39, P < .001) and in the uninsured (OR for uninsured vs privately insured, 1.33, P < .001) and less common at community centers (OR for community centers vs National Cancer Institute-designated cancer centers, 0.80, P = .044). In those with stage IA/B testicular seminoma who received adjuvant radiotherapy/chemotherapy, the receipt of chemotherapy was more common at academic centers and for patients with nonprivate insurance. CONCLUSIONS: Postorchiectomy observation in stage I testicular seminoma has increased significantly in recent years, as has the receipt of chemotherapy, whereas the receipt of radiotherapy has declined, particularly at academic centers. Race, insurance status, and facility type are strongly associated with the choice of adjuvant management.

Reporting ethics committee approval in public administration research.

While public administration research is thriving because of increased attention to social scientific rigor, lingering problems of methods and ethics remain. This article investigates the reporting of ethics approval within public administration publications. Beginning with an overview of ethics requirements regarding research with human participants, I turn to an examination of human participants protections for public administration research. Next, I present the findings of my analysis of articles published in the top five public administration journals over the period from 2000 to 2012, noting the incidences of ethics approval reporting as well as funding reporting. In explicating the importance of ethics reporting for public administration research, as it relates to replication, reputation, and vulnerable populations, I conclude with recommendations for increasing ethics approval reporting in public administration research.

The Effectiveness and Perceptions of Three Moderate Intensity Walking Cadence Aids and their Effects on Affective States: A Mixed Methods Study.

Substantial health benefits can be derived from walking at a moderate intensity cadence. To help regulate this cadence, three distinct aids exist 1) self-perception; 2) cadence prescription; 3) auditory cues. This study aimed to compare the effectiveness and explore perceptions of these aids to promote moderate intensity walking and effects on affective states, thereby addressing an important research gap. Individualised moderate relative intensity waking cadence was determined for participants (n = 23, Mage = 26.35, SD = 10.11). A convergent mixed-methods design was employed. A within-persons repeated measures design was used to explore the effectiveness of three aids (general guidelines, cadence prescription, and music) on promoting moderate intensity physical activity and positive affective states. Perceptions of these aids were elicited through qualitative interviews and thematic content analysis. Main effects for condition on relative physical activity intensity (η2 = .72) and positive affect (η2 = .25) were observed. Music evoked significantly higher relative physical activity intensity than other conditions (p values < .01), and higher positive affect compared to the general guidelines condition (p = .038). A significantly greater proportion of participants achieved moderate relative intensity physical activity during the music compared to general guidelines condition (p = .03). Congruently, qualitative findings suggested that participants predominantly perceived music as most effective for promoting a moderate intensity cadence and positive affect. However, individual variability existed in ability to utilise this aid. Implications of the findings for practitioners seeking to promote a moderate intensity cadence and positive affect during walking are discussed.

Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer.

BACKGROUND: Recent studies have suggested differing toxicity patterns for patients with prostate cancer who receive treatment with 3-dimensional conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), or proton beam therapy (PBT). METHODS: The authors reviewed patient-reported outcomes data collected prospectively using validated instruments that assessed bowel and urinary quality of life (QOL) for patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153) or PBT (n = 95). Clinically meaningful differences in mean QOL scores were defined as those exceeding half the standard deviation of the baseline mean value. Changes from baseline were compared within groups at the first post-treatment follow-up (2-3 months from the start of treatment) and at 12 months and 24 months. RESULTS: At the first post-treatment follow-up, patients who received 3DCRT and IMRT, but not those who received PBT, reported a clinically meaningful decrement in bowel QOL. At 12 months and 24 months, all 3 cohorts reported clinically meaningful decrements in bowel QOL. Patients who received IMRT reported clinically meaningful decrements in the domains of urinary irritation/obstruction and incontinence at the first post-treatment follow-up. At 12 months, patients who received PBT, but not those who received IMRT or 3DCRT, reported a clinically meaningful decrement in the urinary irritation/obstruction domain. At 24 months, none of the 3 cohorts reported clinically meaningful changes in urinary QOL. CONCLUSIONS: Patients who received 3DCRT, IMRT, or PBT reported distinct patterns of treatment-related QOL. Although the timing of toxicity varied between the cohorts, patients reported similar modest QOL decrements in the bowel domain and minimal QOL decrements in the urinary domains at 24 months. Prospective randomized trials are needed to further examine these differences.

Recent advances and the emerging role for chemoradiation in nonmuscle invasive bladder cancer.

PURPOSE OF REVIEW: The management of nonmuscle invasive bladder cancer (NMIBC) recurrent after bacillus Calmette-Guérin therapy is complex and further complicated by high numbers of patients who are not candidates for cystectomy. This article reviews data supporting the use of chemoradiation in NMIBC and discusses emerging biomarkers of treatment response. RECENT FINDINGS: Radiotherapy, especially when combined with chemotherapy, has shown great promise for treating bladder cancer. Recent studies have identified that many patients with bladder cancer do not receive potentially curative therapies. Many such patients are elderly or infirm and represent an unmet need for curative therapeutic alternatives to radical cystectomy. Although radiotherapy alone does not appear superior to intravesical therapy in NMIBC, at least one series with long-term follow-up has shown excellent results in patients treated with radiation and concurrent chemotherapy. A clinical trial investigating the role for chemoradiation in T1 disease that has recurred is underway. Biomarkers able to predict radiotherapy response may allow for personalized therapy in the near future. SUMMARY: Chemoradiation is an emerging treatment option for selected patients with NMIBC. Prospective validation of currently identified biomarkers is needed along with further research to identify which patients may benefit the most from such therapy.

Proton beam radiation therapy for prostate cancer-is the hype (and the cost) justified?

Although in use for over 40 years, proton beam therapy for prostate cancer has only recently come under public scrutiny, due to its increased cost compared to other forms of treatment. While the last decade has seen a rapid accumulation of evidence to suggest that proton beam therapy is both safe and effective in this disease site, a rigorous comparison to other radiotherapy techniques has not yet been completed. In this review, we provide an in-depth look at the evidence both supporting and questioning proton beam therapy's future role in the treatment of prostate cancer, with emphasis on its history, physical properties, comparative clinical and cost effectiveness, advances in its delivery and future promise.

Research integrity in greater China: surveying regulations, perceptions and knowledge of research integrity from a Hong Kong perspective.

In their 2010 article 'Research Integrity in China: Problems and Prospects', Zeng and Resnik challenge others to engage in empirical research on research integrity in China. Here we respond to that call in three ways: first, we provide updates to their analysis of regulations and allegations of scientific misconduct; second, we report on two surveys conducted in Hong Kong that provide empirical backing to describe ways in which problems and prospects that Zeng and Resnik identify are being explored; and third, we continue the discussion started by Zeng and Resnik, pointing to ways in which China's high-profile participation in international academic research presents concerns about research integrity. According to our research, based upon searches of both English and Chinese language literature and policies, and two surveys conducted in Hong Kong, academic faculty and research post-graduate students in Hong Kong are aware of and have a positive attitude towards responsible conduct of research. Although Hong Kong is but one small part of China, we present this research as a response to concerns Zeng and Resnik introduce and as a call for a continued conversation.

Effective alcohol policies are associated with reduced consumption among demographic groups who drink heavily.

BACKGROUND: Alcohol policies stand out among other noncommunicable disease-relevant policies for the lack of uptake. Composite indicators have been developed to measure the effects of alcohol control policy. We investigated whether drinking patterns among demographic groups from general population samples of drinkers from diverse countries are associated with alcohol control policy as measured by the International Alcohol Control (IAC) Policy Index. METHODS: Representative samples of adult drinkers from 10 countries (five high-income and five middle-income) were surveyed about alcohol consumption, using beverage and location-specific questions. MEASUREMENTS: The IAC Policy Index was analyzed with frequency, typical occasion quantity, and volume consumed. Analyses used mixed models that included interactions between country IAC Policy Index score and age group, gender, and education level. FINDINGS: Each increase in IAC policy index score (reflecting more effective alcohol policy) was associated with a 13.9% decrease in drinking frequency (p = 0.006) and a 16.5% decrease in volume (p = 0.001). With each increase in IAC Policy Index score, both genders decreased for all three measures, but men less so than women. Women decreased their typical occasion quantity by 1.2% (p = 0.006), frequency by 3.1% (p < 0.001), and total volume by 4.2% (p < 0.001) compared to men. Low and mid-education groups decreased their typical occasion quantity by 2.6% (p < 0.001) and 1.6% (p = 0.001), respectively, compared to high education, while for drinking frequency the low education group increased by 7.0% (p < 0.001). There was an overall effect of age (F = 19.27, p < 0.0001), with 18-19 and 20-24-year-olds showing the largest decreases in typical occasion quantity with increasing IAC policy index score. CONCLUSIONS: The IAC Policy Index, reflecting four effective policies, was associated with volume and frequency of drinking across 10 diverse countries. Each increase in the IAC Policy Index was associated with lower typical quantities consumed among groups reporting heavy drinking: young adults and less well-educated. There is value in implementing such alcohol policies and a need to accelerate their uptake globally.

Pharmacologic downregulation of c-FLIP(L) restores juxtacrine death receptor-mediated apoptosis in cancer cells in a peritoneal carcinomatosis model.

Metastasis occurs when circulating cancer cells implant in normal secondary tissues. Paradoxically, many cancer cells express death receptors while many normal tissues express the cognate death receptor ligands, suggesting that cancer cells possess mechanisms to inhibit death receptor signaling. Pharmacological restoration of juxtacrine-mediated death receptor signaling could prevent cancer cells from implanting in normal tissues such as the peritoneum. The results showed that BAY 11-7085 significantly inhibited peritoneal carcinomatosis in mice following the introduction of colon and pancreatic cancer cell lines into the intra-abdominal cavity. Treatment with BAY 11-7085 restored juxtacrine death receptor signaling during the adhesion of the cancer cells to mesothelial cells, which line the peritoneum. BAY 11-7085 rapidly inhibited c-FLIP(L) expression in colon and pancreatic cancer cell lines during adhesion to mesothelial cells. Pancreatic cancer cells sorted for high c-FLIP(L) expression formed peritoneal implants much more readily than cells with low c-FLIP(L) expression, and RNAi inhibition of c-FLIP(L) in colon cancer cells dramatically reduced peritoneal implantation. This is a novel demonstration that the restoration of death receptor-mediated apoptotic signaling in cancer cells through the pharmacological inhibition of c-FLIP(L) can inhibit tumor implantation in a clinically relevant model of peritoneal carcinomatosis, a fatal disease. Pharmacological inhibitors of FLIP hold promise as a way to curtail cancer cell colonization of secondary tissues.

Factors influencing survival in patients undergoing palliative bypass for pancreatic adenocarcinoma.

PURPOSE: The purpose of this study is to identify factors predictive of early mortality following palliative bypass in patients with previously unsuspected advanced pancreatic adenocarcinoma to provide a basis for the selection of appropriate therapies. METHODS: All patients with pancreatic adenocarcinoma who underwent a bypass procedure at our institution between 9/30/1994 and 1/31/2006 were reviewed. Patients with peri-operative mortality were excluded from the analysis. Univariate analysis was performed on peri-operative data to identify factors associated with early mortality (death within 6 months of surgery). Patients having multiple risk factors were assigned an overall prognostic score based on the sum of these factors. RESULTS: Of the 397 patients with pancreatic adenocarcinoma analyzed, four factors were found to predict early mortality following palliative bypass: Presence of distant metastatic disease (HR 2.59, P < 0.0001), poor tumor differentiation (HR 1.71, P = 0.009), severe pre-operative nausea and vomiting (HR 1.48, P = 0.013), and lack of previous placement of a biliary stent (HR 1.36, P = 0.048). Patients with a prognostic score of 0 were significantly more likely to survive past 6 months than patients with a prognostic score of 1 (HR 2.71, P < 0.0001), 2 (HR 3.70, P < 0.0001), or ≥3 (HR 5.63, P < 0.0001). CONCLUSIONS: In a cohort of patients undergoing a palliative bypass procedure, specific peri-operative factors can be used to identify patients who are at risk of early mortality. These factors may be helpful in selecting appropriate interventions for this group of patients.

Serial changes in liquid biopsy-derived variant allele frequency predict immune checkpoint inhibitor responsiveness in the pan-cancer setting.

Major immunotherapy challenges include a limited number of predictive biomarkers and the unusual imaging features post-therapy, such as pseudo-progression, which denote immune infiltrate-mediated tumor enlargement. Such phenomena confound clinical decision-making, since the cancer may eventually regress, and the patient should stay on treatment. We prospectively evaluated serial, blood-derived cell-free DNA (cfDNA) (baseline and 2-3 weeks post-immune checkpoint inhibitors [ICIs]) for variant allele frequency (VAF) and blood tumor mutation burden (bTMB) changes (next-generation sequencing) (N = 84 evaluable patients, diverse cancers). Low vs. high cfDNA-derived average adjusted ΔVAF (calculated by a machine-learning model) was an independent predictor of higher clinical benefit rate (stable disease ≥6 months/complete/partial response) (69.2% vs. 22.5%), and longer median progression-free (10.1 vs. 2.25 months) and overall survival (not reached vs. 6.1 months) (all P < .001, multivariate). bTMB changes did not correlate with outcomes. Therefore, early dynamic changes in cfDNA-derived VAF were a powerful predictor of pan-cancer immunotherapy outcomes.