Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

Early onset pancreatic cancer-exploring contemporary treatment and outcomes using real-world data.

BACKGROUND: Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. METHODS: A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). RESULTS: Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. CONCLUSIONS: EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.

Current state of radiomic research in pancreatic cancer: focusing on study design and reproducibility of findings.

OBJECTIVES: To critically appraise methodology and reproducibility of published studies on CT radiomics of pancreatic ductal adenocarcinoma (PDAC). METHODS: PRISMA literature search of MEDLINE, PubMed, and Scopus databases was conducted from June to August 2022 relating to CT radiomics human research articles pertaining to PDAC diagnosis, treatment, and/ or prognosis, utilising Image Biomarker Standardisation Initiative-compliant (IBSI) radiomic software. Keyword search included [pancreas OR pancreatic] AND [radiomic OR [quantitative AND imaging] OR [texture AND analysis]]. Analysis included cohort size, CT protocol used, radiomic feature (RF) extraction, segmentation, and selection, software used, outcome correlation, and statistical methodology, with focus on reproducibility. RESULTS: Initial search yielded 1112 articles; however, only 12 articles met all inclusion/exclusion criteria. Cohort sizes ranged from 37 to 352 (median = 106, mean = 155.8). CT slice thickness varied among studies (4 using ≤ 1 mm, 5 using > 1 to 3 mm, 2 using > 3 to 5 mm, 1 not specifying). CT protocol varied (5 using a single portal-venous (pv)-phase, 5 using a pancreas protocol, 1 study using a non-contrast protocol). RF extraction and segmentation were heterogeneous (RF extraction: 5 using pv-phase, 2 using late arterial, 4 using multi-phase, 1 using non-contrast phase; RF selection: 3 pre-selected, 9 software-selected). 2D/3D RF segmentation was diverse (2D in 6, 3D in 4, 2D and 3D in 2 studies). Six different radiomics software were used. Research questions and cohort characteristics varied, ultimately leading to non-comparable outcome results. CONCLUSION: The current twelve published IBSI-compliant PDAC radiomic studies show high variability and often incomplete methodology resulting in low robustness and reproducibility. CLINICAL RELEVANCE STATEMENT: Radiomics research requires IBSI compliance, data harmonisation, and reproducible feature extraction methods for non-invasive imaging biomarker discoveries to be valid. This will ensure a successful clinical implementation and ultimately an improvement of patient outcomes as part of precision and personalised medicine. KEY POINTS: • Current state of radiomics research in pancreatic cancer shows low software compliance to the Image Biomarker Standardisation Initiative (IBSI). • IBSI-compliant radiomics studies in pancreatic cancer are heterogeneous and not comparable, and the majority of study designs showed low reproducibility. • Improved methodology and standardisation of practice in the emerging field of radiomics has the potential of this non-invasive imaging biomarker in the management of pancreatic cancer.

Compliance with Therapeutic Goods Association prescribing information: weekly or second weekly cetuximab for the treatment of metastatic colorectal cancer.

BACKGROUND: Treatment with cetuximab provides a survival benefit for patients with RAS wild-type metastatic colorectal cancer (mCRC). Practice-defining cetuximab studies utilised weekly (q1w) administration. More convenient second weekly (q2w) administration is supported by pharmacokinetic data and a recent meta-analysis, but large head-to-head studies have not been conducted. Therapeutic Goods Association (TGA) prescribing information states cetuximab be administered q1w for all indications. AIM: To assess the real-world use of q1w versus q2w cetuximab schedule and any difference in outcomes. METHODS: We analysed data from a prospective mCRC database at seven Melbourne hospitals from January 2010 to August 2019. Characteristics and outcomes for cetuximab-treated patients were examined, comparing q1w versus q2w schedules. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. RESULTS: Of 214 eligible patients, 103 (48%) received q1w and 111 (52%) received q2w cetuximab. Q2w cetuximab has been used in >70% of patients from 2015. Q2w was more commonly used in public patients (70% vs 13% in private, P < 0.001), in left-sided primary tumours (83% vs 68%, P = 0.025) and in combination with chemotherapy (73% q2w vs 40% q1w, P < 0.001). Q2w treatment was less common in BRAFV600E mutated tumours (4% vs 13%, P = 0.001). PFS was similar across all lines of therapy, including when analyses were limited to a left-sided primary and there was no difference in OS in multivariate analysis. CONCLUSION: This real-world analysis shows q2w cetuximab has become the dominant method of administration, despite TGA guidance. Our outcome data adds to other data supporting the use of q2w cetuximab as the standard option. Consideration could be given to modifying current TGA advice.

Use and outcomes of chemotherapy for metastatic pancreatic cancer in Australia.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is highly lethal. Combination chemotherapy regimens improve overall survival (OS). Historically, only one-third of mPDAC patients in Victoria received chemotherapy. AIM: To describe current Australian chemotherapy utilisation and outcomes in patients with mPDAC using the multi-site PURPLE (Pancreatic cancer: Understanding Routine Practice and Lifting End Results) registry. METHODS: PURPLE collects longitudinal data on consecutive patients with pancreatic cancer seen since January 2016. Data were collated for patients with mPDAC from six Victorian sites, and analysed descriptively. RESULTS: Three hundred and sixty-three patients with mPDAC were identified. Median age was 70 years (range 20-94 years). First-line chemotherapy was administered in 195 (54%) patients. Prevalent regimens included gemcitabine-nab-paclitaxel (71%), gemcitabine alone (10%) and FOLFIRINOX (6%). Sixty-two of 195 (32%) patients who received first line treatment have proceeded to second-line chemotherapy. Chemotherapy-treated patients were younger (69 versus 73 years; P < 0.01), with better Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0-1 89 vs 66%; P < 0.01) and lower median Charlson comorbidity index (3 vs 4; P < 0.01) compared with untreated patients. Median OS of the entire cohort from diagnosis of metastases was 5.1 months. Median OS was 9.3 months in the chemotherapy treated patients, and 2.5 months in chemotherapy-untreated patients (P < 0.01). CONCLUSIONS: A substantial proportion of patients with mPDAC still do not receive active treatment, which may in part by explained by age, poor performance status and comorbidity. Gemcitabine-nab-paclitaxel was the preferred first-line chemotherapy regimen. Median OS for treated patients in this cohort was comparable to that of recent published clinical trials.

Cancer clinical trial vs real-world outcomes for standard of care first-line treatment in the advanced disease setting.

Clinical trials have strict eligibility criteria, potentially limiting external validity. However, while often discussed this has seldom been explored, particularly across cancer types and at variable time frames posttrial completion. We examined comprehensive registry data (January 2014 to June 2019) for standard first-line treatments for metastatic colorectal cancer (CRC), advanced pancreatic cancer (PC), metastatic HER2-amplified breast cancer (BC) and castrate-resistant prostate cancer (CaP). Registry patient characteristics and outcomes were compared to the practice-changing trial. Registry patients were older than the matched trial cohort by a median of 2-6 years (all P = <.01) for the CRC, BC and PC cohorts. The proportion of Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 patients was lower for CRC (94.1% vs 99.2%, P = .001) and BC (94.9% vs 99.3%, P = .001). Progression-free survival (PFS) for registry patients was similar to the trial patients or significantly longer (CaP, Hazard Ratio [HR] = 0.65, P = <.001). Overall survival (OS) was also similar or significantly longer (CaP, HR 0.49, P = <.001). In conclusion, despite real-world patients sometimes being older or having inferior PS to trial cohorts, the survival outcomes achieved were consistently equal or superior to those reported for the same treatment in the trial. We suggest that this is potentially due to optimised use of each treatment over time, improved multidisciplinary care and increased postprogression options. We can reassure clinicians and patients that outcomes matching or exceeding those reported in trials are possible. The potential for survival gains over time should routinely be factored into future trial statistical plans.

Prognostic significance of postsurgery circulating tumor DNA in nonmetastatic colorectal cancer: Individual patient pooled analysis of three cohort studies.

Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.

Characteristics and outcomes of participants in colorectal cancer biomarker trials versus a real-world cohort.

BACKGROUND: The restrictive eligibility criteria of therapy-focused cancer clinical trials can limit the external validity of the results. The characteristics and survival outcomes of patients enrolled in stand-alone biomarker studies have yet to be explored. We examined the characteristics of patients enrolled in a series of biomarker studies in stage II and III colorectal cancer (CRC) and of the broader patient population from which the study cohorts were recruited. MATERIAL AND METHODS: We examined three distinct trial scenarios: a retrospective cohort study (RCS) where archival tissue samples were analyzed, a prospective observational study (POS) where blood samples were collected but patients received standard treatment and a randomized clinical trial (RCT) where biomarker analysis could inform clinical care. Clinical data for each study time period were extracted from a prospective registry. RESULTS: For all CRC patients (n = 4033) in this study, the median age was 70 years and 54% were ECOG 0. For patients in the RCS (n = 450), POS (n = 284) and RCT (n = 230), the median age was 72, 65 and 64 years, with 45%, 74% and 79% being ECOG 0. For the POS and RCT, 33% and 36% of all patients with the relevant disease stage were enrolled over the study recruitment period. Survival outcomes were similar for patients in the RCS and POS. RCT outcome data are not available. CONCLUSION: As for therapy-based trials, enrollment in prospective biomarker studies may be selective, despite relatively broad eligibility criteria. Characteristics and recruitment were similar for POS and RCT patients, indicating study complexity may not necessarily limit patient recruitment. For the prospective biomarker study cohorts examined, the selective recruitment did not significantly impact survival outcomes, suggesting potential for high external validity.

Utilisation of systemic therapy options in routine treatment of metastatic colorectal cancer in Australia.

BACKGROUND: In the treatment of metastatic colorectal cancer (mCRC), exposure to all three active cytotoxic agents, 5-fluorouracil/capecitabine, irinotecan and oxaliplatin, improves overall survival. The addition of biologic agents (bevacizumab and cetuximab/panitumumab) further improves survival. The uptake of available systemic agents for mCRC in routine practice in Australia is poorly described. METHODS: The ACCORD database was interrogated to determine demographics, treatments and outcomes for patients diagnosed with mCRC between 1 January 2011 and 1 January 2016 at six Melbourne centres. RESULTS: About 1130 mCRC patients were identified: median age was 69 years (range 26-105); 61% had synchronous disease. KRAS status was known in 62%, of whom 49% were KRAS wild-type. At the time of analysis, 67% of all patients had commenced systemic treatment, 50% had received two or more lines of therapy and 19% of KRAS wild-type patients had received all five active drugs. Of KRAS-mutated patients, 35% had received all four Pharmaceutical Benefits Scheme-reimbursed active drugs. Patients who had not received chemotherapy included 72 patients who underwent metastasectomy alone. At a median follow up of 34 months, median overall survival was 25 months for all patients and 69 months for those who underwent metastasectomy. CONCLUSION: In this community-based cohort, 33% of patients had not received any systemic therapy for mCRC, and few patients had received all available active systemic agents. As many patients remain alive, these figures will likely increase over time. The overall survival of patients with mCRC in this community-based cohort was 25 months and not dissimilar to that achieved in recent clinical trials.

Emerging biomarkers for immunomodulatory cancer treatment of upper gastrointestinal, pancreatic and hepatic cancers.

Carcinomas of the oesophagus, stomach, pancreas and liver are common and account for a disproportionately high number of cancer deaths. There is a need for new treatment options for patients with advanced disease. Immunomodulatory treatments including immune checkpoint blockade offer a promising new approach, with efficacy shown in other solid tumour types. However, only a small proportion of patients with carcinomas of the oesophagus, stomach, pancreas and liver have responded to single agent checkpoint inhibitors, and there is a need for markers that are predictive of response to guide treatment of individual patients. Predictive markers may include epidemiological factors such as ethnicity, the genomic status of the tumour, circulating markers, expression of immune checkpoint molecules, and other features of the stromal/immune response at the site of the tumour. This review will focus on predictive biomarkers for immune checkpoint blockade in oesophageal, gastric, pancreatic and hepatocellular carcinomas, including the genomic context and immune landscape in which they occur. Pancreatic carcinomas are largely resistant to immune checkpoint inhibition in trials to date, therefore emerging immunomodulatory treatments in this tumour type are also reviewed.

Emerging strategies in the initial management of locally advanced rectal cancer.

The initial management of locally advanced rectal cancer continues to evolve and formulating the ideal treatment plan remains challenging, with a multitude of emerging treatment strategies and either limited or inconsistent data to support these. The main objective of neoadjuvant treatment is to maximize disease control and minimize toxicity and impact on quality of life. Ultimately, the optimal approach needs to be personalized to the individual. In this Review, we discuss the various strategies currently used and being further investigated in the initial treatment of patients presenting with locally advanced rectal cancer. We describe the evidence behind the current standard of care recommendations and emerging new options, as well as potential biomarkers that may assist with further refining treatment selection.

Chemotherapy and biologic use in the routine management of metastatic colorectal cancer in Australia: is clinical practice following the evidence?

BACKGROUND: Emerging evidence on the optimal use of chemotherapy and biologics in patients with metastatic colorectal cancer should impact management in routine care. Recent studies have demonstrated benefits for initial triplet chemotherapy (5-fluorouracil, oxaliplatin and irinotecan, FOLFOXIRI) and for initial treatment with an epidermal growth factor receptor inhibitor (EGFRi) in patients with a RAS wild-type tumour and a left-sided primary tumour. AIM: To explore evolving pattern of metastatic colorectal cancer care over time in Australia. METHODS: We analysed data from the Treatment of Recurrent and Advanced Colorectal Cancer registry. RESULTS: From July 2009 to December 2017, 2552 metastatic colorectal cancer patients were entered into the Treatment of Recurrent and Advanced Colorectal Cancer registry. Of 1585 patients who initially underwent chemotherapy, treatment was with a doublet in 76%. FOLFOXIRI was given to 22 patients (1.4%), mostly young patients and those with potentially resectable disease. Along with first-line chemotherapy, 61% received bevacizumab, while 3.3% received an EGFRi, predominantly over the last 2 years. Within the KRAS wild-type left-sided tumour cohort, EGFRi use increased from 9% in 2015 to 37% in 2017. Across treatment sites, there was a wide variation in the utilisation of FOLFOXIRI and EGFRi therapy; bevacizumab use was more consistent. A clear impact on survival outcomes from these regimens is not evident, potentially due to multiple confounders. CONCLUSION: Doublet chemotherapy + bevacizumab remains the dominant initial strategy, with limited uptake of triplet chemotherapy and of EGFRi. Potential explanations include uncertainty about the significance of post hoc analyses for EGFRi and concerns regarding adverse events for both strategies.

Mismatch repair deficiency assessment by immunohistochemistry: for Lynch syndrome screening and beyond.

While mismatch repair (MMR) deficiency has been studied extensively, the assessment of MMR status in colorectal and other cancers remains highly relevant, particularly in light of recent data demonstrating that MMR deficiency is a strong predictor for treatment benefit with immune checkpoint inhibitors across multiple tumor types. In colorectal cancer, there is a growing consensus in support of routine MMR testing for Lynch syndrome screening, to inform prognosis and adjuvant chemotherapy use in early stage disease, and to predict response to immunotherapy in advanced disease. Here, we provide a review of the Ventana MMR Immunohistochemistry Panel, which was recently approved by the US FDA for use in Lynch syndrome screening.

Exploring the feasibility and utility of exome-scale tumour sequencing in a clinical setting.

BACKGROUND: Technology has progressed from single gene panel to large-scale genomic sequencing. This is raising expectations from clinicians and patients alike. The utility and performance of this technology in a clinical setting needs to be evaluated. AIM: This pilot study investigated the feasibility of using exome-scale sequencing (ESS) to identify molecular drivers within cancers in real-time for Precision Oncology in the clinic. METHODS: Between March 2014 and March 2015, the Victorian Comprehensive Cancer Centre Alliance explored the feasibility and utility of ESS in a pilot study. DNA extracted from the tumour specimens underwent both ESS and targeted 'hotspot' sequencing (TS). Blood was taken for germline analysis. A multi-disciplinary molecular tumour board determined the clinical relevance of identified mutations; in particular, whether they were 'actionable' and/or 'druggable'. RESULTS: Of 23 patients screened, 15 (65%) met the tissue requirements for genomic analysis. TS and ESS were successful in all cases. ESS identified pathogenic somatic variants in 73% (11/15 cases) versus 53% (8/15 cases) using TS. Clinically focused ESS identified 63 variants, consisting of 30 somatic variants (including all 13 identified by TS) and 33 germline variants. Overall, there were 48 unique variants. ESS had a clinical impact in 53% (8/15 cases); 47% (7/15 cases) were referred to the familial cancer clinic, and 'druggable' targets were identified in 53% (8/15 cases). CONCLUSION: ESS of tumour DNA impacted clinical decision-making in 53%, with 20% more pathogenic variants identified through ESS than TS. The identification of germline variants in 47% was an unexpected finding.

Examining the impact of regular aspirin use and PIK3CA mutations on survival in stage 2 colon cancer.

BACKGROUND/AIM: Data suggest aspirin improves survival in colorectal cancer (CRC) harbouring PIK3CA mutations. The impact of aspirin is thought predominantly to be through an anti-inflammatory effect. The aim of this study is to explore the effect of aspirin use on survival in a real-world cohort of stage 2 colon cancer (CC) patients. METHODS: A prospective CRC database identified patients diagnosed with stage 2 CC between 2000 and 2011. PIK3CA mutation status was determined by next generation sequencing. Neutrophil-lymphocyte ratio greater than 5 at diagnosis represented systemic inflammation. Chart review was used to record regular aspirin use at diagnosis. Clinico-pathological features and survival data were available. Survival analyses used the Cox proportional hazards method. RESULTS: Of 488 patients with stage 2 CC, 95 patients were aspirin users and 70 patients had PIK3CA mutations. Aspirin users were more likely to be older (median: 76.4 years vs 68.3 years, P < 0.001), to be less fit (American Society of Anaesthetists Score 3-4: 58% vs 31%, P < 0.001) and to have systemic inflammation (neutrophil-lymphocyte ratio > 5: 39% vs 27%, P = 0.027). Regular aspirin use did not significantly improve recurrence-free survival. In the PIK3CA mutated group, there was a trend towards improved recurrence-free survival (hazard ratio: 0.45, P = 0.42). CONCLUSIONS: Our study did not demonstrate a significant survival advantage from aspirin use in stage 2 PIK3CA mutated CC. The 'real-world' nature of our cohort and the subsequent uncontrolled differences in age and fitness in aspirin users are likely to have contributed to this result. Defining the true impact of aspirin in CRC requires prospective randomised clinical trials.

Urinary Sodium and Potassium Excretion and CKD Progression.

CKD is a major risk factor for ESRD, cardiovascular disease, and premature death. Whether dietary sodium and potassium intake affect CKD progression remains unclear. We prospectively studied the association of urinary sodium and potassium excretion with CKD progression and all-cause mortality among 3939 patients with CKD in the Chronic Renal Insufficiency Cohort Study. Urinary sodium and potassium excretion were measured using three 24-hour urine specimens, and CKD progression was defined as incident ESRD or halving of eGFR. During follow-up, 939 CKD progression events and 540 deaths occurred. Compared with the lowest quartile of urinary sodium excretion (<116.8 mmol/24 h), hazard ratios (95% confidence intervals) for the highest quartile of urinary sodium excretion (≥194.6 mmol/24 h) were 1.54 (1.23 to 1.92) for CKD progression, 1.45 (1.08 to 1.95) for all-cause mortality, and 1.43 (1.18 to 1.73) for the composite outcome of CKD progression and all-cause mortality after adjusting for multiple covariates, including baseline eGFR. Additionally, compared with the lowest quartile of urinary potassium excretion (<39.4 mmol/24 h), hazard ratios for the highest quartile of urinary potassium excretion (≥67.1 mmol/24 h) were 1.59 (1.25 to 2.03) for CKD progression, 0.98 (0.71 to 1.35) for all-cause mortality, and 1.42 (1.15 to 1.74) for the composite outcome. These data indicate that high urinary sodium and potassium excretion are associated with increased risk of CKD progression. Clinical trials are warranted to test the effect of sodium and potassium reduction on CKD progression.

BRAF Inhibition in BRAFV600E-Positive Anaplastic Thyroid Carcinoma.

The efficacy of targeted monotherapy for BRAF(V600E)-positive anaplastic thyroid carcinomas (ATC) is not established. We report 2 cases of BRAF(V600E)-positive ATC treated with a BRAF inhibitor. A 49-year-old woman with a T4bN1bM0 ATC manifested symptomatic metastatic disease 8 weeks after radical chemoradiotherapy. Within 1 month of BRAF inhibitor monotherapy, a complete symptomatic response was observed, with FDG-PET scan confirming metabolic and radiologic response. Treatment was terminated after 3 months because of disease progression. The patient died 11 months after primary diagnosis. A 67-year-old man received first-line BRAF inhibitor for a T4aN1bM0 ATC. Within 10 days of treatment his pain had stabilized and his tumor had clinically halved in size. Stable disease was achieved for 11 weeks but the patient died 11 months after diagnosis because of disease progression. BRAF inhibitor monotherapy in ATC may obtain clinical benefit of short duration. Upfront combination therapy should be investigated in this patient subgroup.

Cell cycle control as a promising target in melanoma.

PURPOSE OF REVIEW: This review highlights recent clinical developments in the therapeutic targeting of cell cycle control in melanoma with cyclin-dependent kinase inhibitors, checkpoint kinases, MDM2, MDM4 and p53 inhibitors. RECENT FINDINGS: The high prevalence of activating genetic aberrations along the p16 INK4A:cyclinD-CDK4/6:RB pathway in melanoma and increasing evidence that alterations in this pathway are linked to melanomagenesis, make targeting the p16 INK4A:cyclinD-CDK4/6:RB pathway in melanoma logical and highly attractive. The presence of elevated CDK4 activity appears to correlate with greater CDK4/6 inhibitor therapeutic activity, whereas the loss of RB1 has been linked to CDK inhibitor resistance. Other novel compounds targeting cell cycle control via reactivating wild-type p53 and checkpoint kinases are also currently under investigation in melanoma. SUMMARY: Cell cycle control is a promising target in the management of melanoma with early data reporting therapeutic benefit with cyclin-dependent kinase inhibitors, MDM2, and p53 reactivation compounds. Many of these drugs have entered phase I and II clinical trial development. Preliminary data from these studies are discussed in this review along with future treatment strategies for maximizing treatment outcomes in advanced melanoma. VIDEO ABSTRACT: http://links.lww.com/COON/A12.

Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease.

BACKGROUND: We studied the association of inflammatory biomarkers including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) with chronic kidney disease (CKD). METHODS: We conducted a case-control study among 201 CKD patients and 201 community-based controls in the greater New Orleans area. CKD was defined as estimated-glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or albuminuria ≥30 mg/24-h. Serum CRP, TNF-α, and IL-6 were measured using standard methods. Multivariable regression models were used to examine associations between the inflammatory biomarkers and CKD adjusting for important CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin. RESULTS: The multivariable-adjusted medians (interquartile-range) were 2.91 (1.47, 5.24) mg/L in patients with CKD vs. 1.91 (0.99, 3.79) mg/L in controls without CKD (p = 0.39 for group difference) for CRP; 1.86 (1.51, 2.63) pg/mL vs. 1.26 (1.01, 1.98) pg/mL (p < 0.0001) for TNF-α; and 2.53 (1.49, 4.42) pg/mL vs. 1.39 (0.95, 2.15) pg/mL (p = 0.04) for IL-6, respectively. Compared to the lowest tertile, the highest tertile of TNF-α (OR 7.1, 95% CI 3.2 to 15.5) and IL-6 (OR 2.5, 95% CI 1.1 to 5.5) were significantly associated with higher odds of CKD in multivariable-adjusted models. Additionally, higher TNF-α and IL-6 were independently and significantly associated with lower eGFR and higher albuminuria. CONCLUSIONS: Our data suggest that TNF-α and IL-6, but not CRP, are associated with the prevalence and severity of CKD, independent from established CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.

Evolution of Liquid Biopsies for Detecting Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by late diagnosis and poor prognosis. Despite advancements, current diagnostic and prognostic strategies remain limited. Liquid biopsy techniques, including circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), circulating tumour exosomes, and proteomics, offer potential solutions to improve PDAC diagnosis, prognostication, and management. A systematic search of Ovid MEDLINE identified studies published between 2019 and 2024, focusing on liquid biopsy biomarkers for PDAC. A total of 49 articles were included. ctDNA research shows some promise in diagnosing and prognosticating PDAC, especially through detecting mutant KRAS in minimal residual disease assays. CTC analyses had low sensitivity for early-stage PDAC and inconsistent prognostic results across subpopulations. Exosomal studies revealed diverse biomarkers with some diagnostic and prognostic potential. Proteomics, although relatively novel, has demonstrated superior accuracy in PDAC diagnosis, including early detection, and notable prognostic capacity. Proteomics combined with CA19-9 analysis has shown the most promising results to date. An update on multi-cancer early detection testing, given its significance for population screening, is also briefly discussed. Liquid biopsy techniques offer promising avenues for improving PDAC diagnosis, prognostication, and management. In particular, proteomics shows considerable potential, yet further research is needed to validate existing findings and comprehensively explore the proteome using an unbiased approach.