Sunday, July 6, 2025

Calendar Watch: HRD Testing Today, Webinar, July 15 [Caris]

Confused by HRD testing?  See a webinar, "HRD Testing in Practice," with James Hamrick and Rebecca Arend, hosted by Caris.  It's July 15, 2025, at 2 pm pacific.

Find information and registrtion here:

https://carisls.zoom.us/webinar/register/8817491420887/WN_SYOCF243SLiweIgatZj9gg#/registration

See a Linked In invite also, here.

The invitation reads,

  • Homologous recombination deficiency (HRD) testing is an increasingly important tool in guiding PARP inhibitor therapy for ovarian cancer, but its interpretation remains complex. In this webinar, Dr. Rebecca Arend will present findings from a new large-scale study of over 1,600 real-world ovarian cancer cases, exploring how genomic scar scoring (GSS) and BRCA1/2 mutation status independently and jointly predict survival.
  • The session will also touch on ongoing efforts to harmonize HRD testing methods, highlighting how comprehensive assays may offer improved patient selection. Join us to deepen your understanding of HRD and its evolving role in precision oncology.


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AI CORNER

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I asked Chat GPT for an overview suitable for a new oncology fellow.

Homologous recombination deficiency (HRD) testing is a form of molecular profiling used to identify tumors with impaired ability to repair double-strand DNA breaks through the homologous recombination (HR) repair pathway. This is clinically important because tumors with HRD are particularly sensitive to DNA-damaging agents such as platinum-based chemotherapies and PARP inhibitors. In oncology, HRD testing is most commonly applied in ovarian, breast, prostate, and pancreatic cancers, where it can help guide decisions about using PARP inhibitors like olaparib or niraparib.

The most well-known cause of HRD is a mutation in the BRCA1 or BRCA2 genes. These mutations can be either inherited (germline) or acquired in the tumor (somatic). However, HRD can also result from defects in other genes involved in the homologous recombination pathway, such as RAD51C, RAD51D, and PALB2, or from broader genomic instability that reflects a history of defective repair even if the specific mutation is no longer present.

There are two broad approaches to HRD testing. One type focuses on identifying mutations in specific genes like BRCA1/2, often performed through either blood (germline testing) or tumor tissue (somatic testing). The other type assesses genomic “scars” that indicate underlying HRD, even when no clear mutation is found. These genomic instability assays analyze patterns such as loss of heterozygosity (LOH), telomeric allelic imbalance, and large-scale transitions in the tumor genome. Commercial tests like Myriad’s MyChoice® CDx and Foundation Medicine’s FoundationOne® CDx incorporate such measures to generate an HRD score or LOH score. A high score suggests that the tumor has the characteristic features of HRD and may respond better to therapies that exploit this vulnerability.

In clinical practice, HRD testing is used to identify patients who may benefit from PARP inhibitors beyond just those with BRCA mutations. For example, in ovarian cancer, patients with high HRD scores have shown improved outcomes with maintenance PARP inhibition even if they lack BRCA mutations. However, not all HRD-positive tumors respond to treatment, and some tumors classified as HR-proficient may still benefit. Finally, germline findings in BRCA or other HR pathway genes may have implications for hereditary cancer syndromes, which should prompt genetic counseling and possibly testing of family members.

In short, HRD testing helps oncologists stratify patients based on DNA repair capacity and personalize therapy accordingly, especially in tumors where PARP inhibitors play a key role.

Calendar Watch: European Parliament, July 15, Personalized Medicine & Screening

There will be an event at the European Parliament, Brussels, on July 15, hosted by the European Alliance for Personalized Medicine.  It's about the need for greater use of precision medicine in the EU and in particular, modern molecular cancer screening.

Quoting - The July 15th event at the European Parliament—“Every Second Counts: Modernizing Cancer Screening to Save Lives”, organised by EAPM— comes at a crucial moment. We have the science, technology, and pilots. What’s needed now is the policy will to scale, close the diagnostic equity gap, and build data systems to track who benefits—and who doesn’t.

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See https://euapm.eu/   Find a 3-page agenda in PDF here:

https://drive.google.com/file/d/1fGlOSWw0h868K6YZx1mQCdu52gEisvLn/view




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See also a Linked In article with notes and links here.

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Friday, July 4, 2025

Large-scale Validation of LBX DNA-RNA Tumor Test (Abraham et al.; Caris)

 A few weeks ago, we saw a large-scale validation of transcriptome and genome tumor testing by Yudina et al., Boston Gene.  Blog here.

Now, we have a large-scale validation of RNA-DNA tumor testing from Caris, in Nature Communications as Abraham et al.    Find it here, open access.  The Caris Assure test is plasma-based.   

Validation of an AI-enabled exome/transcriptome liquid biopsy platform for early detection, MRD, disease monitoring, and therapy selection for solid tumors.  Abraham et al.

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I attach the abstract below.

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Effective clinical management of patients with cancer requires highly accurate diagnosis, precise therapy selection, and highly sensitive monitoring of disease burden. Caris Assure is a multifunctional blood-based assay that couples whole exome and whole transcriptome sequencing on plasma and leukocytes with advanced machine learning techniques to satisfy all three clinical testing needs on one platform. 

Caris Assure for therapy selection was CLIA validated using 1,910 samples. 376,197 tissue profiles along with 7,061 paired blood and tissue profiles were used to engineer features for three machine learning models. The MCED model was trained on 1,013 patients and validated on an independent set of 2,675 patients. 

The tissue of origin for MCED model was trained on 1,166 samples and validated using 5-fold cross validation. 

The MRD & Monitoring model was trained on 3,439 patients and validated on two independent sets of 86 patients for MRD and 101 patients for monitoring. 

For early detection, sensitivities for stages I-IV cancers (n = 284, 129, 90, 23 respectively) were 83.1%, 86.0%, 84.4%, and 95.7%, all at 99.6% specificity (n = 2149). The diagnostic first-line procedure for tissue of origin was determined for 8 categories with a top-3 accuracy of 85% for stage I and II cancers. Detection of driver mutations for therapy selection from blood collected within 30 days of matched tumor tissue, demonstrated high concordance (PPA of 93.8%, PPV of 96.8%) using CHIP subtraction. For MRD and recurrence monitoring, the disease-free survival of patients whose cancers were predicted to have an event was significantly shorter than those predicted not to have an event using a tumor naïve approach (HR = 33.4, p < 0.005, HR = 4.39, p = 0.008, respectively). 

The data presented here demonstrate a unified liquid biopsy platform that uses blood-based whole-exome and transcriptome sequencing coupled with artificial intelligence to address the important clinical needs in multi-cancer early detection, monitoring of MRD and recurrent cancers, and precision selection of molecularly targeted therapies.

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AI CORNER
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Summary.

Here is a detailed review of the 2025 Nature Communications paper titled:

"Validation of an AI-enabled exome/transcriptome liquid biopsy platform for early detection, MRD, disease monitoring, and therapy selection for solid tumors"
by Abraham et al. (Caris Life Sciences) — for MD/PhD readers who are experts in genomics and laboratory diagnostics.

Executive Summary

This study presents Caris Assure, an ambitious blood-based platform that integrates whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) of both cell-free DNA/RNA and leukocyte DNA. Coupled with a proprietary multi-omic machine learning algorithm (ABCDai), the assay supports applications in:

  • Multi-cancer early detection (MCED)

  • Tissue-of-origin prediction

  • Minimal residual disease (MRD) detection

  • Recurrence monitoring

  • Therapy selection through blood-based CGP

The authors report impressive analytical and clinical validation across a large and diverse sample set (>370,000 tissue and 7,000 plasma-tissue pairs), making this one of the most expansive liquid biopsy validation studies to date.

Scientific and Technical Strengths

1. Broad Molecular Scope

  • Caris Assure captures WES and WTS data from both cfTNA (cfDNA + cfRNA) and buffy coat DNA, enabling:

    • SNV, indel, CNV, MSI, and fusion detection.

    • CHIP subtraction from buffy coat to reduce false positives.

    • Integrated transcriptomic features.

  • Custom hybrid capture targets 720 cancer-relevant genes deeply, plus >20,000 genes at lower coverage.

  • Uses NovaSeq 6000 for high-throughput sequencing, with sophisticated extraction chemistry and bioinformatics to handle both DNA and RNA.

2. Multi-pillar Machine Learning Architecture (ABCDai)

  • Caris engineers nine molecular "pillars":

    • Canonical genomic features: Mutationome, Copyome, Fusionome, Transcriptome.

    • Liquid biopsy-specific features: Fragmentome, Motifome, Positionome (NU & TF), Entropyome.

  • Uses XGBoost-based gradient-boosted decision trees and a pan-omic feature selection strategy.

  • These features capture not only somatic mutation burden but also nucleosomal positioning, transcriptional start-site fragment patterns, and motif entropy—some of the most cutting-edge concepts in cfDNA biology.

Key Validation Results

A. Therapy Selection (CGP)

  • PPA of 93.8%, PPV of 96.8% vs. matched tumor tissue in metastatic cancer (blood drawn within 30 days).

  • CHIP subtraction shown to be critical: >50% of patients had CHIP-associated mutations in genes like KRAS, ATM, CHEK2.

B. Multi-Cancer Early Detection (ABCDai-MCED)

  • Stage I–IV sensitivity: 83.1% (I), 86.0% (II), 84.4% (III), 95.7% (IV) at 99.6% specificity.

  • Demonstrated superior sensitivity vs. GRAIL's MCED test in early-stage gastric, uterus, kidney, breast, and prostate cancers.

C. Diagnostic Pathway Prediction (ABCDai-GPS)

  • Trained on 660 early-stage cancer patients and 506 normals.

  • Top-3 accuracy of 85% for selecting the optimal diagnostic imaging/test modality (e.g., mammogram, colonoscopy, PSA).

D. MRD Detection and Monitoring (ABCDai-M&M)

  • Tumor-naïve approach—no need for baseline tumor sequencing.

  • MRD cohort: HR = 33.4 (p < 0.005); 89% sensitivity, 98% NPV, 76% specificity.

  • Monitoring cohort: HR = 4.39 (p = 0.008); 45% sensitivity, 92.6% NPV, 83% specificity.

  • Average lead time vs. imaging = 261 days.

Innovative Concepts and Contributions

  1. CHIP-aware Plasma Genotyping
    This is arguably one of the most carefully designed CHIP filtering pipelines in a commercial setting—essential for improving cfDNA test specificity and avoiding false treatment signals.

  2. Use of Plasma Transcriptome Data (cfRNA)
    While rare in the liquid biopsy space due to RNA degradation, Caris shows that plasma WTS can yield meaningful transcriptomic features for detection and classification.

  3. Panomic Feature Integration
    The authors unify expression (WTS), nucleosome positioning, motif analysis, and fragmentomic signatures into one robust AI platform—an integrative approach unmatched in commercial assays today.

  4. Tumor-Naïve MRD
    This circumvents logistical burdens (tumor tissue access, turnaround time), potentially enabling broader adoption.

Limitations and Open Questions

  • Sample sizes for certain cancer subtypes and stages are small, which limits granularity for rare cancers.

  • The model's reliance on proprietary features and non-public algorithmic code raises reproducibility questions, even though code is available upon legal request.

  • RNA-based liquid biopsy features remain biologically compelling but technically vulnerable to variation—though Caris reports RNA extraction optimization, real-world performance remains to be seen.

  • For MRD, comparative head-to-head studies vs. tumor-informed methods (e.g., Signatera) are pending, though the paper states these are planned.

Clinical Implications for Lab Directors and Genomics Experts

  • Caris Assure represents a paradigm shift toward a single-platform solution across early detection, CGP, and MRD—challenging the market silo of GRAIL, Guardant, Natera, and Foundation.

  • The platform may allow laboratories to consolidate test ordering, logistics, and reporting, streamlining decision-making and reducing redundancies.

  • The tumor-naïve MRD approach could reduce turnaround time and tissue acquisition burden, making it attractive to community oncology settings.

  • CLIA validation and >1,900 samples tested across assays indicate high readiness for clinical adoption—though CMS and MolDx coverage pathways remain a key unknown.

Conclusion

Abraham et al. present a landmark study validating Caris Assure, a unified exome + transcriptome liquid biopsy platform empowered by sophisticated AI. The assay’s breadth, sensitivity, specificity, and clinical versatility are notable. While prospective studies will be essential for regulatory acceptance and clinical guidelines integration, this work clearly positions Caris Assure among the most advanced multi-purpose liquid biopsy systems currently in development or clinical use.

Let me know if you'd like a slide deck summary, side-by-side product comparison (e.g., with GRAIL or Natera), or Medicare coverage pathway assessment.


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Here is an AI_generated reimbursement assessment.   

THIS IS PROVIDED FOR CURIOUSITY ONLY AND SHOULD NOT BE TAKEN LITERALLY.


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Here is a Medicare coverage pathway assessment for the Caris Assure liquid biopsy platform, tailored for genomics experts and lab directors evaluating strategy under CMS and MolDx frameworks:

🔍 Medicare Coverage Pathway Assessment for Caris Assure

I. Summary of Caris Assure’s Clinical Functions

Caris Assure is a multifunctional WES/WTS blood-based assay that supports:

  1. Therapy selection in metastatic disease (via CGP from cfDNA/RNA)

  2. Multi-cancer early detection (MCED)

  3. Tumor-naïve MRD detection and recurrence monitoring

  4. Tissue-of-origin prediction (diagnostic aid)

Each of these clinical use cases faces separate coverage hurdles under Medicare, with different lead MACs, LCDs, and regulatory precedent.

II. Coverage Pathways by Clinical Use Case

1. Therapy Selection via Plasma CGP

Goal: Coverage under the existing MolDx LCDs for blood-based comprehensive genomic profiling (e.g., LCD L37810 or successor policies).

  • ✅ Pathway Exists: Caris can pursue coverage through Palmetto/MolDx under the existing cfDNA CGP policies, which require:

    • Validated detection of guideline-relevant biomarkers (e.g., EGFR, ALK, BRAF).

    • Concordance data vs. tissue (which Caris reports: PPA 93.8%, PPV 96.8%).

    • CHIP correction is a favorable feature, mitigating false positives.

  • 🔍 Considerations:

    • Must publish or submit clinical utility data showing treatment decisions changed and improved outcomes.

    • MolDx prefers inclusion in NCCN guidelines or demonstration that the test identifies FDA-approved therapy indications.

2. MRD Detection (Tumor-Naïve)

Goal: Coverage for MRD surveillance following curative-intent treatment (e.g., in stage II/III colorectal, breast, or lung cancers).

  • ⚠️ Pathway Exists but Challenging: MolDx’s existing LCD for MRD (L38779) supports coverage of tumor-informed platforms like Signatera or RaDaR, especially in colorectal cancer.

  • ❗ Caris Assure uses a tumor-naïve approach, which:

    • Bypasses logistical delays of tumor sequencing (a strength).

    • But lacks direct precedent in current LCD language.

  • ✅ Supportive Evidence in Paper:

    • HR = 33.4 for MRD recurrence, with 98% NPV.

    • Concordance with events and lead time advantage (+261 days).

  • 🧩 Coverage Path:

    • Submit dossier for LCD expansion or reconsideration via MolDx.

    • Support inclusion in CIRCULATE-US–type trials or joint publications.

    • Engage clinical KOLs in oncology to advocate for tumor-naïve MRD as an efficient alternative.

3. Recurrence Monitoring (Longitudinal Surveillance)

  • ⚠️ Limited Pathway: Medicare rarely covers indefinite recurrence monitoring unless tied to:

    • Specific disease states with expected recurrence (e.g., high-risk colorectal cancer).

    • Actionable downstream changes in management.

  • 📈 Caris data supports clinical utility (HR = 4.39, p = 0.008), but:

    • Needs longer-term outcomes and real-world treatment change documentation.

    • Could be packaged as a "surveillance bundle" with MRD under the same policy.

4. Multi-Cancer Early Detection (MCED)

Goal: Screening use in asymptomatic patients or high-risk cohorts.

  • ⛔ No Current Pathway for MCED Screening Under Medicare

    • USPSTF has not endorsed any MCED test.

    • Statutory CMS rules prohibit coverage of screening tests without USPSTF A/B rating under SSA §1861(ddd).

    • No existing LCD or NCD provides a pathway unless under Coverage with Evidence Development (CED).

  • 🧠 Options for Caris:

    • Collaborate with NCI or CMS on a prospective MCED study under CED.

    • Pursue inclusion in programs like PREVENTABLE or PATHFINDER-style cohorts.

    • Pilot diagnostic aid framing, e.g., "rule-in" for symptomatic patients with nonspecific findings.

III. Regulatory and Reimbursement Milestones Required

Use Case Coverage Pathway Caris Status Next Steps
CGP – Therapy MolDx LCD (L37810) Strong Submit concordance + clinical utility
MRD – Tumor-Naïve LCD (L38779 – CRC) Moderate Reconsideration with tumor-naïve data
Recurrence Monitoring Not clearly defined Weak/Exploratory Package with MRD evidence
MCED – Screening Not eligible for FFS Medicare None Consider CED or commercial plans

IV. Coverage Strategy Recommendations

  1. Near-Term Focus:

    • Submit for MolDx coverage of CGP and MRD (target colorectal and breast first).

    • Emphasize tumor-naïve efficiencies, especially in community settings lacking FFPE access.

  2. Mid-Term Focus:

    • Develop comparative trials vs. tumor-informed platforms.

    • Build real-world data registry aligned with CMS's "totality of evidence" approach.

  3. Long-Term Vision:

    • Seek commercial insurer partnerships for MCED pilots.

    • Join NIH or CMS-sponsored MCED umbrella projects for eventual CED petition.

V. Conclusion

Caris Assure has a robust technical foundation and meets multiple high-priority clinical needs. Its CGP and MRD use cases are ready for Medicare engagement, while MCED requires long-term strategic planning aligned with USPSTF and CMS evidence frameworks. A sequenced approach—starting with CGP and MRD under MolDx and building toward broader utility—is the optimal path to widespread reimbursement.

Let me know if you'd like a PowerPoint version, payer value proposition sheet, or LCD comparison grid next.


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ALSO FOR YOUR CURIOUSITY ONLY, HERE IS AN AI GENERATED "OP ED"

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Editorial Commentary: Toward a Unified Liquid Biopsy Platform for Cancer Care
By the Editors of Nature Communications

The study by Abraham et al., published in this issue of Nature Communications, introduces an ambitious and technically impressive liquid biopsy platform—Caris Assure—that brings together whole exome and transcriptome sequencing with a sophisticated machine learning framework (ABCDai) to address a broad range of clinical applications in oncology. From early cancer detection to therapy selection and recurrence monitoring, this single blood-based assay aspires to support the full continuum of precision cancer care.

That ambition alone warrants attention. But what sets this work apart—and makes it timely—is the integration of multi-omic liquid biopsy signals with machine learning at population scale. The authors trained and validated their models on over 376,000 tumor samples and 7,000 matched plasma-tissue pairs, a sample size unmatched by most published studies in the field.

Bringing Breadth and Depth to Liquid Biopsy

Caris Assure is more than another cfDNA panel. The assay combines:

  • High-depth WES and WTS on cfDNA and cfRNA,

  • Matched buffy coat sequencing for CHIP subtraction,

  • A machine learning platform built from nine separate molecular “pillars,” including novel fragmentomic and epigenomic surrogates.

This results in a panomic diagnostic signal—one that appears to outperform existing commercial benchmarks in early-stage cancer sensitivity, particularly in breast, gastric, and prostate cancer. The authors report >83% sensitivity for stage I cancers at 99.6% specificity, addressing the Achilles’ heel of many MCED platforms: early-stage detection with acceptable false positive rates.

The same architecture powers a tumor-naïve MRD tool that stratifies relapse risk with hazard ratios as high as HR = 33.4, enabling long lead times over conventional imaging and offering a compelling alternative to tumor-informed strategies.

From Concept to Clinic: Strengths and Challenges

From an editorial perspective, the paper’s strengths lie in its scope, rigor, and transparency:

  • The authors provide detailed methodological appendices, including feature engineering approaches and validation cohorts.

  • CHIP subtraction is treated not as an afterthought, but as a core analytic safeguard.

  • The test is already CLIA validated, enhancing translational relevance.

However, challenges remain. While the use of cfRNA is innovative, its reliability in real-world clinical workflows—where pre-analytical variables abound—will require further study. Likewise, while the multi-feature machine learning model shows superior performance, its interpretability and reproducibility in external settings are open questions. Readers should note that the algorithms are currently proprietary and available only upon request.

Moreover, multi-cancer early detection (MCED) remains a regulatory frontier. Without U.S. Preventive Services Task Force endorsement, MCED applications face barriers to clinical reimbursement. This means that Caris Assure’s path to widespread adoption may rest more securely—at least initially—on its use in therapy selection and MRD surveillance, particularly where tumor access is limited or tissue-based testing is infeasible.

A Platform for the Future

What this paper ultimately represents is a strategic vision for oncology diagnostics: a unified, scalable, blood-based testing system that can inform clinical decisions across the cancer care pathway. Whether the clinical community is ready for a single test that screens, stratifies, and guides treatment remains to be seen—but Caris Assure provides the technological groundwork for such a paradigm.

As liquid biopsy platforms evolve, studies like this one remind us that assay versatility, biological signal integration, and clinical scalability will be the benchmarks of next-generation precision medicine.

We commend the authors for their bold and comprehensive work and look forward to future data—particularly from prospective trials—that may define how such technologies change the standard of care.

—The Editors
Nature Communications

Thursday, July 3, 2025

AMA Publishes New PLA Codes (July 1, 2025)

 AMA publishes a running update of new active PLA codes.  This is the update published July 1, 2025, for codes considered in 2Q2025.

Note that AMA provides an evergreen link and it will change quarter to quarter.  

https://www.ama-assn.org/system/files/cpt-pla-codes-long.pdf

There are 25 new codes 0575U-0599U, so we're on the brink of having 600 PLA codes.

Where Did "SLIDE" Codes Go?

On April 14, 2025, AMA released the submitter's text for all PLA codes enrolled for consideration in April/May.  This list included two codes about "slides:"

  • Oncology (lung), augmentative algorithmic analysis, digitized hematoxylin and eosin stained slides from lung cancer formalin fixed paraffin embedded tumor tissue, whole slide imaging of histologic features for seven molecular biomarkers, including pathogenic or likely pathogenic alterations in ALK, BRAF, EGFR, ERBB2, MET, RET, ROS1, reported as increased or decreased probability for each biomarker
  • Oncology (endometrial), augmentative algorithmic analysis, digitized hematoxylin and eosin stained slides from endometrial cancer formalin fixed paraffin embedded tumor tissue, whole slide imaging of histologic features for five molecular biomarkers, including MSI-High status and presence of pathogenic or likely pathogenic alterations in CTNNB1, POLE, PTEN, TP53, reported as increased or decreased probability for each biomarker 

However, on the July 1 final codes release, there are no codes containing the word "slide."  Possibly the Fall 2025 AMA code book, for 2026, will contain clarification of policy for slide-based PLA codes.  

Existing slide-based codes include 0108U, 0220U, 0261U, 0295U, 0376U, 0414U, 0418U, 0512U, 0513U.  513U was created July 1, 2024, and effective since October 1, 2024.  All the codes 376U-513U are $706 at CMS.

Duplicate PLA's Are Allowed

One of the oldest codes is 0035U, prion protein, shaking assay, from the National Prion Disease Pathology Surveillance Center.   AMA has issued a duplicate code as 0584U, which is the same descriptor for a test run at the Mayo CSF laboratory and called RT-QUIC Prion.  Duplicate codes (from different labs) get an odd symbol which looks like two parenthesis placed back-to-back.   See the odd symbol to the left of the black dot below.


Nerd Note - normally, the quarterly new PLA codes are a surprise.  But the July 1 ones are never a surprise, because they were finalized about May 10 and were already included and released in the agenda of the June 2025 public comment meeting for pricing new codes at CMS.


MolDx Finalized LCD July 3: Non-NGS Tests for BCR-ABL Negative Neoplasms

 MolDx finalizes a draft LCD offered last year; the final LCD is in comment period July 3-August 16, 2025.

MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms.  L39919 (Palmetto, Final).

Note that this is to complement another LCD, "NGS LDTs for Myloid Malignancies," L38047.

I've clipped the full MolDx rules of coverage below.  Ahead of that, I clip a Chat GPT simplification.  You can use the simplification as an entry point for your reading, but only use the Full LCD Rules verbatim, for actual cases and claims.

I haven't done a redline comparing draft to final, but from the Comments article A60223 there are selective acknowledgements of corrections madein the final.  There were, however, quite a few comments.  Find A60223 here.   Find an AI discussion of A60223, below, after the cut/paste LCD sections.

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Simplified Version - Chat GPT - For Curiousity Only.  See Full Intricate MolDx Rules at Bottom.

Here's a concise AI summary of the Medicare MolDx coverage criteria for non-NGS molecular testing of BCR-ABL-negative myeloproliferative neoplasms (MPNs) from the LCD:

Coverage Summary: Simplified, Non-Official: Non-NGS Molecular Testing for Suspected BCR-ABL-Negative MPNs

Covered MPNs:
Classical MPNs (PV, ET, PMF) and select non-classical types (e.g., CNL, CEL-NOS).
Myelodysplastic/Myeloproliferative neoplasms are excluded.

General Requirements (All Must Be Met):

  1. Patient is being evaluated for BCR-ABL-negative MPN per WHO or ICC criteria.

  2. BCR-ABL testing must precede molecular testing (except in PV suspicion).

  3. Test methods (e.g., qPCR, ddPCR) must detect mutations with high sensitivity (VAF ≤1% for JAK2; ≤3% for CALR/MPL).

  4. For single-gene tests, a reflexive stepwise approach is required and must stop once a diagnosis is reached:

    • Step 1: BCR-ABL

    • Step 2: JAK2 V617F

    • Step 3: If JAK2 V617F-negative or <1% VAF:

      • JAK2 exon 12 (if PV suspected)

      • CALR and MPL (if ET/PMF suspected)

  5. For multiplex PCR panels, must include genes needed for accurate diagnosis of the suspected MPN:

    • Always include JAK2 (V617F and exon 12), CALR, MPL.

    • For CNL: CSF3R required (after excluding classical MPNs).

    • If blast-phase PMF is suspected: test must include AML-associated genes, likely requiring NGS (see LCD L38047).

  6. If initial non-NGS testing is negative (including low VAF results), NGS panel may be used to detect additional, non-duplicative mutations (per guidelines).

Analytical & Clinical Standards:
7. All analytes must have published peer-reviewed evidence of clinical validity.
8. Test must be used in a population and setting consistent with its validated intended use.
9. Test must pass technical assessment (TA) confirming AV, CV, and CU.
10. Tests similar to existing covered ones must show equal or superior performance.
11. Covered for diagnosis only, not for monitoring or MRD.

Note:
NGS-based testing for MPNs is not covered under this LCD. It must meet criteria outlined in LCD L38047.

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FULL OFFICIAL MOLDX RULES FOLLOW NOW:

MolDx writes, and I quote,

This policy provides limited coverage for multi-gene non-next generation sequencing (NGS) panel testing and limited coverage for single-gene testing for the diagnostic workup of patients with suspected BCR-ABL negative myeloproliferative neoplasms (MPNs).

Classical BCR-ABL negative MPNs include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), and non-classical BCR-ABL negative MPNs include Chronic Neutrophilic Leukemia (CNL) and Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL, NOS), among other rare entities.

Myelodysplastic/Myeloproliferative neoplasms are considered a separate class outside the scope of this LCD.

Testing myeloid and suspected neoplasms by NGS is covered by a separate LCD, MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies (L38047).

ALL of the following criteria must be met:

1. The patient is being evaluated for a BCR-ABL-negative MPN according to national or international consensus diagnostic criteria (i.e., World Health Organization (WHO); International Consensus Classification (ICC)).

2. Testing follows the assessment of BCR-ABL (this is required unless the patient is only suspected of having PV).

3. The test is comprised of one or more highly sensitive single- or multi- gene assays (i.e., quantitative polymerase chain reaction [PCR], digital droplet PCR [ddPCR]) that can accurately detect a minimum variant allele frequency (VAF) of ≤1% for JAK2 (and 1-3% for CALR and MPL when they are included in the testing).

4. If testing is performed using single gene tests, a sequential and reflexive approach is expected. Once a positive result is obtained and the appropriate diagnosis is established, further testing should stop unless required for subsequent management of the patient or as further described below.

  • When testing for the classical BCR-ABL-negative MPNs (PV, ET, or PMF) using single gene tests, reflex testing to the next gene will be considered reasonable and necessary according to the following sequence of tests for known driver mutations:
  • BCR-ABL negative test results, progress to ii.
  • Note: For the rare patient with high clinical suspicion of PV despite a positive BCR-ABL result, testing for a mutation in JAK2 mutation may still be performed.
  • JAK2 V617F negative test results (this includes JAK2 V617F positive at <1% VAF), progress to iii or iv.
  • JAK2, exon 12 (required when PV is suspected)
  • Calreticulin (CALR) and Thrombopoietin Receptor (MPL) driver mutations (required when ET or PMF is suspected)
  • Note: testing for CALR/MPL does NOT require a negative JAK2 exon 12, just a negative JAK2 V617F result.

5. If testing is performed using a panel (i.e., multiplex PCR) the panel must include at least the minimum necessary genes and gene alterations that would be reasonably expected by the test to achieve a diagnosis according to national or international consensus guidelines, given the specific MPN subtype suspected. For example:

  • Molecular testing for mutations in JAK2 (including V617F and exon 12), CALR and MPL genes is considered medically necessary for the identification of the classical MPNs.
  • However, if the accelerated/blast phase of PMF is suspected at diagnosis, molecular testing should also include acute myeloid leukemia (AML)- associated mutations and would likely require the performance of a NGS panel; in this case, a panel that does not include the AML-associated mutations does not meet the minimum necessary gene requirements.
  • Additional MPN-associated genes must also be included as appropriate for the identification of other non-classical BCR-ABL-negative MPNs. For example, when CNL is suspected, testing for the colony stimulating factor 3 receptor (CSF3R) is required. Note also that testing for CNL requires the exclusion of the classical BCR-ABL-negative MPNs.

6. Patients with high suspicion of a BCR-ABL negative MPN who test negative by a non-NGS test for mutations in JAK2 (including the detection of JAK2 V617F at a VAF <1%), CALR, MPL and/or CSF3R may have a subsequent NGS panel performed for additional relevant mutations, as outlined in national or international consensus guidelines. The additional testing by NGS must comprise non-duplicative genetic alterations.

7. Clinical validity (CV) of analytes measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population.

8. The test is being used (a) in a patient who is part of the population in which the test was analytically validated and (b) according to the intended use of the test.

9. The test satisfactorily completes a technical assessment (TA) that will evaluate and confirm that analytical validity (AV), clinical validity (CV), and clinical utility (CU) have been demonstrated.

10. Tests utilizing a similar methodology or evaluating a similar molecular analyte to a test for which there is a generally accepted testing standard or for which existing coverage exists must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the intended-use population.

11. Testing is performed for diagnosis and not as a test of cure or for monitoring minimal residual disease (MRD).

NOTE: Testing by NGS falls outside the scope of this LCD but must fulfill the criteria outlined in LCD L38047, MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies.

[End full MolDx rules]

####

####

And you've been waiting for - an AI summary of the Q&A document.

###

Here is a focused summary of the MolDx revisions made in response to public comments on LCD A60223:

✅ MolDx Revisions to LCD A60223 [AI]

  1. JAK2 Variant Allele Frequency (VAF) Threshold Updated

    • Revised minimum sensitivity requirement from “<1%” to “≤1%” for JAK2 testing, acknowledging the standard practice and literature support.

  2. Clarified Allowance for Simultaneous Testing

    • Confirmed that simultaneous testing (e.g., JAK2 V617F and exon 12, or JAK2/CALR/MPL) is permitted and not restricted to reflex-only workflows.

  3. Revised Reflex Testing Language (Criterion #4)

    • Clarified that further testing may proceed if required for patient management, not only until initial diagnosis is established.

  4. Updated Terminology for Myelofibrosis

    • Replaced "PMF" with “MF” to reflect NCCN's broader category (including primary and secondary MF).

  5. Corrected Misattributed NCCN Citations

    • Removed one citation incorrectly attributed to NCCN and re-attributed it to its original sources (Arber et al., Thiele et al.).

  6. Added Clarifications for High-Risk Patients

    • Clarified high-risk definitions for PV and ET in alignment with current NCCN guidelines.

  7. Updated Guideline References

    • Cited the most recent NCCN Guidelines (Version 1.2025) and deleted outdated Table 1, instead referring to NCCN and other authoritative sources.

These revisions reflect MolDx's responsiveness to clinical practice realities, stakeholder feedback, and evolving guidelines.

###

###

Here's a concise summary of the MolDx response to public comments on the draft LCD A60223 for non-NGS testing of BCR-ABL-negative myeloproliferative neoplasms (MPNs):

🔍 Main Stakeholder Concerns & MolDx Responses A60223

1. JAK2 Sensitivity Threshold (<1% VAF)

  • Concern (AMP, CAP, Labcorp): Requiring detection below 1% variant allele frequency (VAF) for JAK2 is unrealistic and unsupported. Most labs validate to a 1% VAF.

  • Response: MolDx revised the policy to accept a VAF of ≤1% for JAK2, aligning with the International Consensus Classification (ICC) and alleviating lab concerns.

2. Reflex Testing Requirements

  • Concern (Labcorp, NCCN): Mandating sequential (reflexive) single-gene testing delays diagnosis. Simultaneous testing (e.g., JAK2 V617F + exon 12) is often faster and more efficient.

  • Response: MolDx clarified that simultaneous testing is allowed, especially when clinically appropriate (e.g., high suspicion of PV), and that PCR testing is usually fast.

3. Use of Prognostic Panels (e.g., NGS) After Diagnosis

  • Concern (NCCN): Once diagnosis is confirmed, guidelines recommend further molecular testing for prognostication. Current LCD wording would prevent this.

  • Response: MolDx clarified that further testing is covered if it informs subsequent patient management, not just for prognosis alone. Criterion #4 was revised accordingly.

4. Guideline Alignment & Citation Accuracy

  • Concern (NCCN): Requested updates for:

    • Language (e.g., use “MF” instead of “PMF”)

    • VAF interpretation clarity

    • Up-to-date guideline references (Version 1.2025)

  • Response: MolDx accepted all suggestions, updating citations, removing outdated Table 1, and clarifying terminology and source attributions.

5. Supportive Comment

  • Concern (Independent Commenter): Expressed general support for the policy and the importance of accurate molecular testing in MPN diagnosis.

  • Response: Thanked the commenter and acknowledged their support.

✅ Key Policy Clarifications & Changes

  • JAK2 VAF threshold updated to ≤1%

  • Simultaneous testing (e.g., JAK2 + CALR/MPL) is allowed where appropriate

  • Further testing post-diagnosis is covered if clinically actionable

  • NCCN language and citations updated for accuracy and alignment

This summary should assist labs and clinicians in understanding the intent and flexibility of the LCD, as well as reassure stakeholders that practical clinical realities and guideline alignment were taken into account in finalizing the policy.

Journal Club: Huybrechts & Henandez-Diaz: "Calling It a Targeted Trial Doesn't Make it One." [Simulating RCTs]

 Here's an interesting article from JAMA Psychiatry:

Estimating Treatment Effects From Observational Data—Calling It a Target Trial Does Not Make It One     Krista F. Huybrechts, MS, PhD1,2; Sonia Hernández-Díaz, MD, DrPH2

Find it here.  It might come with an access version here.

  • See also NEJM, Hubbard 2024, on "target trial emulation." - here.  
  • And, Hernan, the target trial framework, causal inference from observational data, Ann Intern Med 2025 here. (My blog re Hernan here.)
  • There's also Wilson, Real World Data - Trials to Practice, Lancet 2024 here.  
  • And Wang, Emulating RCTs with Databases, JAMA 2023, here.  (Op Ed, Sheldrick, here.)
    • Wang has already been cited 241 times.  

Find an AI summary of HUYBRECHTS below.

Find an integrated AI discussion of all five or six papers as a sidebar - here.

###

"Calling It a Target Trial Doesn’t Make It One" — Huybrechts & Hernández-Díaz (JAMA Psychiatry, 2025)

This editorial underscores that simply labeling an observational study as a "target trial emulation" does not ensure its rigor.  [Ha!]

The authors explain how true target trial emulation requires careful alignment of key elements: eligibility, treatment assignment, and the start of follow-up ("time zero")—just as in a randomized controlled trial (RCT).

They warn of immortal time bias, a design flaw common in real-world data studies, where periods in which outcomes cannot occur are improperly handled, leading to inflated treatment benefits. For instance, including prevalent users of a drug (rather than new users) can bias results, as only survivors remain in the sample. [patients who tolerate the drug, for example]

Target trial emulation is a valuable framework, but only when fully applied: researchers must explicitly define the hypothetical trial’s protocol and transparently map each component using real-world data. 

Otherwise, the label becomes a veneer over flawed methods. The takeaway: design trumps terminology, and emulation demands rigorous planning—not just a rhetorical nod to RCTs.


Wednesday, July 2, 2025

RFK Jr on Tucker Carlson: An AI-Generated Summary

 On June 30, 2025, the channel TuckerCarlson.com published a one hour video interview with Secretary of Health RFK Jr.   Watch the full interview here:

https://tuckercarlson.com/tucker-show-rfk-jr-2025

It got relatively brief coverage, eg A review at Gizmodo is here.  MedCityNews on RFK & pharma marketing here.   For readers that want to study RFK's full range of opinions and thinking, I found a full corrected transcript here.  

Below, I attach a Chat GPT "neutral article" about the full-length interview, based on an auto-transcript.  
>>AI pull-quotes may not be exact.    

##

AI CORNER Chat GPT 4o

###

Here is a detailed, neutral news article summarizing the July 1, 2025, interview between Secretary of Health and Human Services Robert F. Kennedy Jr. and Tucker Carlson, along with a sidebar listing 10 notable takeaways.

RFK Jr. Lays Out Health Reform Vision
in Interview with Tucker Carlson


WASHINGTON, DC – July 1, 2025 [AI]  — In a sweeping one-hour interview with Tucker Carlson, Secretary of Health and Human Services Robert F. Kennedy Jr. detailed his plans to reform the U.S. public health system, calling for greater transparency in vaccine science, pharmaceutical marketing, and the structure of scientific oversight. Speaking candidly on topics ranging from autism research to AI in regulatory agencies, Kennedy sought to position himself as both a reformer and a disrupter.

During the conversation, Kennedy repeatedly emphasized his intention to overhaul what he described as a system plagued by “perverse incentives.” He accused longstanding health bureaucracies and media institutions of suppressing data and failing to conduct meaningful scientific studies, particularly on vaccine safety and pharmaceutical outcomes.

“We’re going to give people gold-standard science,” Kennedy said. “We’re going to publish our protocols in advance… and we’re going to require replication of every study, which never happens at NIH now.”

Autism Studies Revisited

Kennedy confirmed that his department has launched a major effort to revisit the possible connections between vaccines and rising autism rates—a long-debated topic that played a key role in his early estrangement from the Democratic Party. He criticized past CDC studies as inadequate and announced the release of federal databases to independent scientists for transparent reanalysis. He expects initial findings by September and broader conclusions within six months.

Vaccine Advisory Shake-up

Among the more dramatic administrative moves since assuming office, Kennedy confirmed the firing of members of the CDC’s Advisory Committee on Immunization Practices (ACIP), citing undisclosed financial conflicts and lack of placebo-based safety trials in prior vaccine approvals.

“We fired that board because it was just an instrument. It was a sock puppet for the industry that it was supposed to regulate,” Kennedy said.

Pharmaceutical Advertising and Trust

Kennedy reiterated his concerns over direct-to-consumer pharmaceutical advertising, calling it misleading and distorted by financial entanglements. While legal precedent limits how much HHS can restrict such ads, he suggested that HHS is examining rule changes to mandate greater transparency in how risks and benefits are portrayed.

He claimed media outlets were financially dependent on pharmaceutical advertising, referencing former Fox News CEO Roger Ailes as having privately admitted that any coverage critical of vaccines was effectively prohibited due to advertising revenue concerns.

Use of Artificial Intelligence in Health Policy [See "AI Appendix" below]

A forward-looking section of the interview centered on Kennedy’s commitment to AI as a transformative tool for regulatory science. He said HHS is recruiting top-tier engineers to apply AI across drug evaluation, fraud detection at CMS, and outcome studies across vast national datasets.

“We have the potential now to use AI in ways that are going to revolutionize medicine,” he said.

Legal and Ethical Legacies

When asked about vaccine injury liability, Kennedy discussed potential reforms to the National Vaccine Injury Compensation Program, originally enacted in 1986 to shield vaccine manufacturers from civil lawsuits. He indicated that efforts are underway to reopen access for individuals with claims related to COVID-19 vaccines, particularly those who fell outside of the narrow statute of limitations.

On the controversial topic of Anthony Fauci’s legacy and possible gain-of-function research ties to the Wuhan lab, Kennedy called for a “truth commission” akin to those held in post-conflict societies. He also voiced support for the full declassification of JFK, RFK, and MLK assassination documents.

Cross-Party Alliances and Trump Collaboration

Throughout the interview, Kennedy described his collaboration with the Trump administration in warm terms. He praised cabinet members like Pam Bondi and Marco Rubio, noting ideological differences in the past but emphasizing current policy alignment. He also emphasized President Trump’s role in “restoring hope” and credited him with reshaping not only the Republican Party but also driving policy reactions among Democrats.

AI Sidebar:
10 Noteworthy Takeaways from the RFK Jr.–Tucker Carlson Interview

  1. Autism-Vaccine Study Reboot: RFK Jr. has launched a full-spectrum analysis using CMS and VSD data, aiming to resolve questions about vaccine safety and neurodevelopmental outcomes.

  2. AI Across HHS: Artificial Intelligence is being deployed not only to streamline drug approvals (reducing reliance on animal models) but also to track national health outcomes in real time.

  3. ACIP Overhaul: Kennedy fired the entire vaccine advisory panel due to long-standing financial conflicts of interest and absence of placebo-controlled safety trials.

  4. DTCA Restrictions in the Works: HHS is considering policy changes to limit or restructure pharmaceutical advertising, especially those deemed misleading in imagery or emotional appeal.

  5. Public Access to Raw Data: For the first time, researchers worldwide will get access to HHS-controlled vaccine and outcomes databases under open grant programs.

  6. Malinformation as Censorship Tool: Kennedy described how factual but inconvenient information about vaccines was allegedly reclassified by federal agencies as "malinformation" to justify its suppression.

  7. Revamp of Vaccine Injury Compensation: Efforts are underway to expand the federal vaccine injury program, including extending the statute of limitations and introducing transparency reforms.

  8. COVID Vaccine as a Clinical Trial: A new version of the COVID-19 vaccine is being offered under a clinical trial framework, with required follow-up to collect real-world safety data.

  9. Fauci and the Wuhan Lab: Kennedy stated that Fauci-funded scientists gave Chinese researchers techniques to obscure viral engineering, questioning the public health rationale.

  10. Empathy in Trump’s Cabinet: Kennedy praised Trump for assembling a “deep and thoughtful” cabinet and spoke positively of Trump’s empathy, particularly in discussions about war and public health.

Author’s Note: This article aims to provide a factual overview of the interview for stakeholders in public health policy, research, and regulation. Statements and viewpoints expressed during the interview are presented without editorial endorsement and may be subject to future policy or legal developments.

[END CHAT GPT]

 AI APPENDIX from TRANSCRIPT - RFK's AI Paragraphs

We’re going to absolutely change VAERS [adverse event AE data] and we’re going to make it, we’re going to create either within VAERS or supplementary to VAERS, a system that actually works. And you know that right now even that system is antiquated because we have access to AI.

And one of the, you know, we are creating here at HHS an AI revolution. We’ve been able to attract the top people from Silicon Valley. People have walked away from billion dollar businesses and they don’t want prestige, they don’t want position, they don’t want power, they want to change, they want to make the system work.

And we’re, we’re going to, we are at the cutting edge of AI. We’re implementing it in all of our departments at FDA where we’re accelerating drug approvals so that you don’t need to use primates or even animal models. You can, you know, you can do the drug approvals very, very quickly with AI.

And we’re also implementing a CMS to detect waste, abuse and fraud, which is, it’s extraordinary at that. But we’re also going to use it at CDC and throughout our system to look at the megadata that we have and be able to make really good decisions about interventions.

For example, if you look at the population as a whole and say, okay, we’re using three different diabetes drugs with five different statin drugs or all these SSRIs and others. You can then look drug by drug and you can tell on the population whether it’s working or not and which one is giving you the best bang for the buck. Which one has the most side effects. We have a potential now to use AI in ways that are going to revolutionize medicine.

Monday, June 30, 2025

Brief Blog: Billing for G0452 (Molecular Pathology Interpretation) in 2023

CMS recently released Part B billing records for doctors and laboratories, for CY2023 (here).

I pulled the records for G0452, Molecular Pathology Interpretation (about $50).

##

Medicare Part B paid for 152,659 services of G0452,  for a total of $7.2M dollars allowed.

The top-billing provider was a laboratory in Arizona (not starting with C), with 12,234 services or 8% of the total.

Of the top-20 billing entities, 2 were registered as clinical laboratories.  Of the other 18, 5 had MD-PhD degrees and the rest MD.   Most of the MDs were facility-based (e.g. in a pathology service or department or practice that is hospital-based).

19 providers billed for >1000 cases of G0452.  Of 680 total providers, the top 20 had 32% of G0452 revenue.  Click to enlarge.

Click to enlarge



Friday, June 27, 2025

The Supreme Court Birthright Decision - Would It Have Changed a Single Texas Judge "Tossing Out" FDA LDT Regulation?

 On June 27, 2025, the Supreme Court issued a ruling that (for now) prevents single federal district courts from issuing national junctions.  The test case was a birthright citizenship case.

But in March 2025, a Texas judge "threw out" an FDA regulation about LDTs, saying the regulation was outside the FDA's legal scope for medical devices, and void.

Here's the $60,000 question - 

What if the March 2025 Texas FDA decision had come after today - after today's limitation on national injunctions.   Would it be different?  I am not an attorney, and this is for entertainment only, but here is what Chat GPT says.   

Chat GPT read both the March FDA case and the Birthright case, Trump v Casa.

##

AI CORNER

##

Yes, the FDA lab-developed test (LDT) Texas ruling would likely be impacted or at least called into question by the new June 27, 2025 Trump v. CASA decision on universal injunctions—though the outcome wouldn't necessarily reverse the substance of the FDA ruling.

Here’s how they intersect:

✅ Texas Ruling on LDT Regulation (March 31, 2025)

  • The Texas federal court vacated the FDA’s 2024 LDT final rule nationally, ruling that FDA exceeded its statutory authority under the FDCA.

  • The judge concluded that LDTs are services, not “devices,” and are comprehensively regulated under CLIA, not FDA.

  • The ruling applied nationwide, not just to the plaintiffs. The judge explicitly dicussed & justified nationwide relief, likely referencing precedents like Texas v. United States and 5th Circuit reasoning allowing broader relief in APA cases.

⚖️ SCOTUS Birthright Citizenship Decision (June 27, 2025)

  • In Trump v. CASA, the Supreme Court rejected universal (nationwide) injunctions unless necessary to give “complete relief” to the named plaintiffs.

  • Barrett, writing for the Court, held that injunctions should be party-specific, as traditional equity never allowed nationwide remedies.

  • The Court vacated nationwide injunctions against a Trump executive order and instructed lower courts to limit relief to actual plaintiffs.

🔁 Implications for the FDA LDT Ruling

  • The LDT ruling vacated the FDA rule under the APA (Administrative Procedure Act), not just enjoined it.

  • But the APA has its own framework: courts “shall… set aside” unlawful agency rules (5 U.S.C. § 706(2)). Courts have debated whether that means facial invalidation or plaintiff-specific relief.

  • Trump v. CASA leans heavily against sweeping remedies, so litigants or the DOJ could now argue that the LDT ruling should be narrowed to apply only to the plaintiffs in the case, not all labs nationwide.

  • However, the Texas judge in the LDT case seemed to anticipate this debate and explicitly justified nationwide vacatur, which some appellate courts (e.g., D.C. Circuit) still permit in APA cases.

🔍 Bottom Line

  • Yes, the SCOTUS CASA decision could prompt the FDA or DOJ to seek modification or narrowing of the Texas LDT ruling—especially if it moves to appeal.

  • Whether that would alter the outcome or enforcement effect depends on whether the 5th Circuit (which covers Texas) embraces CASA’s limits strictly, or defers to APA precedents supporting broad vacatur.

  • Strategically, it introduces new risks to relying on the LDT ruling as a shield for non-party labs, and the FDA could continue enforcing the rule against others not named in the case—unless and until enjoined again.

Let me know if you'd like a one-paragraph advisory version for client communications.

##

"Natioanl Injunctions" in Trump/CASA.  "National Vacatur" in FDA LDT.   ???

##

Yes, the distinction between injunction and vacatur matters a great deal in this context—especially in light of the Trump v. CASA ruling.

🔹 Injunction vs. Vacatur: What’s the Difference?

  • An injunction tells the government not to enforce a rule or policy—typically against the plaintiffs.

  • A vacatur (under the APA, 5 U.S.C. § 706(2)) nullifies the agency’s rule entirely—treating it as legally void if found unlawful.

⚖️ How Trump v. CASA Changes the Terrain

In Trump v. CASA, the Supreme Court held that universal injunctions—i.e., barring enforcement against non-parties—exceed the equitable authority of federal courts. That decision was about injunctions, not vacatur.

But this doesn’t automatically apply to vacatur under the APA, which has been interpreted differently across the circuits:

  • The D.C. Circuit and some others treat vacatur as automatic and nationwide when a rule is invalidated.

  • The 5th Circuit (where the Texas LDT case sits) has been more skeptical and may now lean toward party-specific relief, especially post-CASA.

🧩 Why the Distinction Matters

  • If the Texas ruling had only enjoined FDA from enforcing the LDT rule against the plaintiffs, CASA would clearly limit its scope.

  • But because the Texas court vacated the rule under the APA, it arguably treated the FDA rule as void across the board—a different legal act.

However, post-CASA, FDA or DOJ could argue that vacatur is functionally no different from a universal injunction, and that courts must now narrow even APA vacatur to apply only where needed for plaintiff relief.

🟨 Conclusion

The fact that the Texas LDT ruling used vacatur rather than injunction gives it a stronger claim to nationwide effect—but that ground is now legally unsettled after Trump v. CASA. The FDA may test this distinction in appeals or enforcement discretion. For labs not party to the case, relying solely on the Texas vacatur is now riskier than before.


##

I'd add, the FDA regulation is still on the books, so, for example, could the FDA try imposing the FDa regulation, exactly as it is, against a lab in Ohio, or Minnesota, next week?   When the lab protests, FDA could say the Texas decision applied only to Texas, in light of the Birthright case.  (Only a hypothetical).

##

Again, this is an AI opinion and for entertainment only.

##

AI:

In light of the Supreme Court’s June 27, 2025 decision in Trump v. CASA, which sharply limited the use of nationwide injunctions, the March 2025 Texas court decision vacating FDA’s LDT rule may no longer be securely applicable to all labs nationwide. While the Texas ruling explicitly set aside the FDA rule under the APA, Trump v. CASA calls into question the legitimacy of such broad relief unless strictly necessary to protect the named plaintiffs. As a result, FDA or DOJ may now argue that the Texas court’s ruling should apply only to the specific plaintiffs in the case, leaving other labs potentially subject to enforcement unless they obtain their own relief. This development introduces uncertainty regarding the scope of protection the Texas ruling provides and may warrant a cautious review of compliance and legal exposure for non-party labs.

Supreme Court Preserves ACA Preventive Requirements for Private Plans; Rejects Challenge to USPSTF

 The Affordable Care Act of 2010 requires private insurance to cover preventive benefits endorsed by the USPTF.   The legitimacy of the USPSTF to set such requirements was challenged, and the challenge "won" in district court and federal appeals court.   However, the USPSTF authorities were preserved on June 27 2025, in a 6-3 decision.   Thomas, Gorsuch, and Alito dissented.

Find coverage at NYT here.  Genomeweb here.  AJMC here.  NPR here.  Reuters here. MedCityNews here. USAToday here.  JAMA here.  "The Supreme Court ruled that ... the HHS secretary could modify, or even overturn, recommendations made by the Task Force."

Find the actual decision here, Braidwell case.  The case is 86 pages, with the dissent beginning on page 49.  The main point is whether the USPSTF members are inferior officers subject to management, or, if not, are they indeed "principal" officers who should require Senate confirmation.

Separate topic - How the administration funds, staffs, or controls USPSTF is "TBD."

###

AI CORNER

###

Summary for Health Policy Experts and Legal Audiences:

In Kennedy v. Braidwood Management, Inc., the Supreme Court ruled (6–3) that members of the U.S. Preventive Services Task Force (USPSTF) are inferior officers under the Appointments Clause and thus lawfully appointed by the Secretary of HHS, rather than requiring presidential nomination and Senate confirmation.

The case centered on the ACA’s provision mandating that health insurers cover preventive services graded “A” or “B” by the USPSTF at no cost to patients. The plaintiffs, including Braidwood Management, objected to covering certain services and argued that USPSTF members were principal officers—with legally binding power but no clear supervision—rendering their appointments unconstitutional.

Lower Court Victories for Braidwood:

  • Both the district court and the Fifth Circuit agreed with Braidwood, finding that USPSTF members were not meaningfully supervised and thus principal officers, improperly appointed under Article II.

Supreme Court Reversal:

  • Justice Kavanaugh, writing for the majority, reversed the Fifth Circuit. The Court held that Task Force members are inferior officers because:

    • They are removable at will by the Secretary of HHS.

    • The Secretary has statutory authority to review and block recommendations before they take legal effect (under ACA provisions like 42 U.S.C. §300gg-13(b) and §202).

    • Their authority is non-final without the Secretary’s approval—thus preserving executive chain-of-command accountability as required by Edmond v. United States.

Key Legal Finding:
The majority reasoned that “independent” in the statute (42 U.S.C. §299b–4(a)(6)) does not imply for-cause removal or insulation from review. Instead, “independent” refers to freedom from external stakeholder influence, such as hospitals or academic affiliations.

Dissenting Opinion (Thomas, joined by Alito and Gorsuch):

  • The dissent strongly objected to the majority’s interpretation, arguing that the USPSTF holds binding policymaking authority without genuine oversight.

  • It rejected the idea that mere removal or post-hoc review powers constitute “supervision” under Article II.

  • The dissent warned that this decision blurs the distinction between principal and inferior officers and invites future constitutional abuse by allowing politically consequential decisions to be made by officials not confirmed by the Senate.

Policy Implications:

  • The decision preserves the ACA’s preventive services mandate infrastructure, avoiding immediate disruption to insurance coverage requirements.

  • It sets a clearer boundary for what constitutes sufficient executive supervision to qualify federal officers as “inferior” under the Constitution.

  • It may limit future constitutional challenges to similar advisory or expert panels—so long as a cabinet-level officer retains power to remove members and review their output before legal force attaches.

Bottom Line:
Despite initial wins in the district and appeals courts, Braidwood’s challenge to the USPSTF structure ultimately failed at SCOTUS. The Court reaffirmed a broad view of executive supervision sufficient to satisfy the Appointments Clause—while the dissent viewed this as a dangerous dilution of constitutional safeguards.




##
We read it's "remanded for further proceedings."  ???

“Remand for further proceedings” is a common legal phrase, and yes, it’s important—but not dramatic.

In this context, the Supreme Court reversed the lower courts’ rulings (which had struck down the USPSTF appointments) and sent the case back (“remanded”) to the lower courts to apply the Supreme Court’s new decision and handle any remaining issues.

Here's what it means:

  • "Reversed": The Supreme Court disagreed with the Fifth Circuit and district court, ruling that Task Force members are not principal officers.

  • "Remanded": The case goes back to the lower court to clean up the details, implement the ruling, and resolve any leftover matters (e.g., how exactly the injunctions are lifted or narrowed).

Is it important?

Yes, but mostly procedural now:

  • It confirms that Braidwood doesn’t win on the Appointments Clause claim.

  • But the remand allows the lower court to finalize what this means for the actual injunction and the parties (for example, what remains under the Religious Freedom Restoration Act claim, which was not appealed and still stands in part).

In short: The big question is settled, but the paperwork’s not done.

Thursday, June 26, 2025

Brief Blog: Cancer Inpatients, Cancer Outpatients: Both Have High Antibiotic Resistance Risks

June 26, 2025, Eckardt publishes in Forbes an article about the high prevalence and mortality risks of antimicrobial resistance (AMR) in cancer patients - both inpatients and outpatients.  

As an experiment, here is an AI-created essay about the Forbes article and Gupta 2024, Gupta 2025.

###

Gupta 2024, cancer inpatients.  Gupta 2025, cancer outpatients.

Forbes news article, Eckardt June 26.

###

AI Corner

###

A growing body of evidence now confirms that patients with cancer—both hospitalized and ambulatory—face significantly elevated rates of antimicrobial-resistant (AMR) infections, with incidence and odds ratios for key pathogens often exceeding 1.5 to 2.0 compared to non-cancer populations.

These findings underscore the immunologic vulnerability of oncology patients and the compounding risks posed by chemotherapy, mucositis, and indwelling devices. But the implications for clinical microbiology and molecular diagnostics go beyond recognition of risk. Laboratories must now operationalize cancer-specific strategies for AMR surveillance, prioritize rapid diagnostics that can guide empiric therapy within hours rather than days, and collaborate with oncology and stewardship teams to recalibrate local antibiograms and testing workflows for high-risk populations. 

The data support not only enhanced testing frequency and faster turnaround, but also selective deployment of molecular resistance panels or metagenomic tools where culture-based methods are too slow or insensitive to support timely cancer care.

###

Here is a concise, expert-level blog summary of the recent studies on antimicrobial resistance (AMR) in cancer patients by Gupta et al. (2024–2025), plus the Forbes news article, aimed at a genomics and microbiology-savvy audience:

A New Front in the War on Cancer: 
Antimicrobial Resistance (AMR) in Oncology Care

Summary of Two Landmark Studies from the Cancer AMR Consortium (Gupta et al., 2024–2025)

The Cancer AMR Consortium—a collaboration involving Becton Dickinson, the AMR Action Fund, and UICC—has published a trilogy of studies that comprehensively characterize the burden of antimicrobial resistance in cancer patients, both hospitalized and ambulatory. The results highlight a silent but rapidly escalating threat to cancer care delivery, underscoring urgent needs in diagnostics, surveillance, and infection control.

1. Inpatient Setting: Multicenter Analysis Across 168 U.S. Hospitals

Published in Cancer Medicine (2024)

This study evaluated over 4.6 million hospital admissions, including ~297,000 admissions of cancer patients. Key findings:

  • AMR rates were 1.5–2x higher in hospitalized cancer patients vs non-cancer patients for multiple resistant pathogens:

    • VRE: IRR 1.95

    • ESBL-producing Enterobacterales: IRR 1.48

    • Carbapenem-nonsusceptible Enterobacterales: IRR 1.46

    • MDR P. aeruginosa: IRR 1.31

  • AMR isolate proportions (non-susceptibility % of isolates) were significantly higher in cancer patients for VRE and ESBLs, even after adjusting for hospital size, urban/rural status, and teaching affiliation.

  • The authors emphasize that routine oncology care practices—central lines, chemotherapy-induced mucositis, immunosuppression—are strong vectors for AMR exposure, warranting targeted prevention and stewardship strategies.

2. Outpatient Setting: Multicenter Cohort in 198 Clinics

Published in The Lancet Oncology (2025)

Expanding the lens to ambulatory oncology, this large-scale study analyzed 1.65 million outpatient pathogen isolates, 3.2% of which were from cancer patients.

  • AMR odds were significantly elevated in cancer patients across all major organism groups:

    • P. aeruginosa (carbapenem non-susceptibility): OR 1.22

    • Enterobacterales:

      • Fluoroquinolone resistance: OR 1.44

      • Carbapenem resistance: OR 1.89

      • MDR phenotype: OR 2.03

      • ESBL+: OR 1.96

    • S. aureus (MRSA): OR 1.20

    • Enterococcus (VRE): OR 2.20

  • Relative AMR burden (IRR) was up to 3-fold higher in outpatients with cancer, especially for VRE and carbapenem-resistant pathogens.

The outpatient data demonstrate that AMR risk is not confined to the inpatient setting, and routine surveillance, empiric therapy guidelines, and antibiotic stewardship must be recalibrated in the cancer clinic context.

3. Editorial and Policy Context: Forbes Perspective (Eckhardt, June 2025)

Forbes contextualized these findings with urgency: infections are now the second leading cause of death in cancer patients, frequently from resistant organisms. The article criticizes oncology's institutional blindness to AMR: “Patients may die of an infection, but the death is still logged as 'cancer.'”

The piece underscores:

  • The lack of rapid diagnostics: culture-based methods still take days, increasing the odds of failed empiric therapy.

  • The inadequate pipeline of new antibiotics, stymied by broken commercial incentives.

  • The danger of stalling or canceling oncologic treatment due to untreatable infections—especially in LMICs, but increasingly a threat even in high-income countries.

Implications for Genomic Medicine

For leaders in genomic and microbiology diagnostics:

  • Rapid AMR profiling (e.g., NGS-based resistance gene panels, metagenomic sequencing) could be transformative in both inpatient and outpatient oncology care.

  • There's a clear need for cancer-specific diagnostic stewardship, optimizing empiric and targeted antimicrobial use based on patient immunologic status and treatment context.

  • These findings may spur new reimbursement models for rapid resistance diagnostics, similar to oncology companion diagnostics for targeted therapies.

The silent AMR crisis in oncology is no longer silent. It’s time for diagnostic and microbiology innovators to respond.

Let me know if you'd like a graphical summary, citation formatting, or to tailor this for LinkedIn, Substack, or conference slides.

Caris: Brief Blog: Her2 Testing in 65000 patients

While several HER2-directed drugs are approved in breast cancer, the antibody conjugate trastuzumab-deruxtecan (Enhertu) is FDA-approved in any HER2 3+ cancer (if the patient lacks alternative therapies).  Caris reports on the rate of HER2 positivity in 65,000 clinical cases.

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See Bryant et al., June 26, 2025:
https://pubmed.ncbi.nlm.nih.gov/40569617/

Rates of 3+ HER2 ranged from 14% in bladder cancer to 5% in cervical cancer to 0% in gliomas.

Enhertu is approved in both HER2-high and HER2-low (1+) breast cancer.



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AI CORNER

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Trastuzumab deruxtecan (Enhertu) is FDA-approved for two key indications. First, in breast cancer, it is approved for patients with unresectable or metastatic disease who are either HER2-positive (defined as IHC 3+ or IHC 2+ with ISH amplification) or HER2-low (defined as IHC 1+ or IHC 2+ with ISH-negative), making it the first HER2-targeted therapy approved for HER2-low tumors. Second, it holds a tumor-agnostic approval for use in unresectable or metastatic solid tumors that are HER2-positive (defined as IHC 3+ or ISH+) when no satisfactory alternative treatments are available. This tumor-agnostic indication applies to a range of cancers outside the breast, but only when they meet both the HER2 positivity and unmet-need criteria.



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