That's odd. This was content that was still on the MCAT when I took it last year. I even remember keeping the formation of objection permanence occuring ~0-2 years of age on my flashcards.
You're mostly correct but immunotherapies do work for a many different type of cancer. The issue is differences in tumor biology plays a major factor. The even bigger caveat is that given a sufficient amount of tumor mutational burden (TMB), immunotherapies are found to be effective for any solid tumor. Granted most patients don't have the sky had TMBs needed for it to be effective
I believe he got just got either Ipilimumab and Nivolumab as a combo therapy or Pembrolizumab. He's a researcher who focuses on neo-adjuvant (use therapy before resection) therapy in melanomas. It was a good gamble to try the same paradigm in Glioblastomas
It's neo-adjuvant (treat prior to surgery) with a three mAbs: Ipi + Nivo, which is a well established combo of immunotherapeutics for many solid tumors, rounded out with relatlimab which I'm less familiar with (LAG-3 inhibition). Neoadjuvant use of immunotherapies is established concept and is utilized in clinical practice for non-small cell lung cancer and colon cancer. This is the first time I've seen a use of 3 immunotherapies used at once: Ipi + Nivo isn't the most tolerable treatment regimen. Other novel aspect is use of neoadjuvant therapy in GBM.
• Prostate cancers are known to have a wide spectrum of outcomes.
• Stage IV (metastatic) disease tends to have genetic testing. These panels tend to be on the order of a few hundred genes to 1000s of genes.
• Classically prostate cancer is driven by androgen receptor upregulation. Disease progression is often due to the disease overcoming treatment with antiandrogenic such as enzalutamide.
Correction: enzalutamide was designed to overcome castrate resistant prostate cancer. abiraterone would have been more appropriate to bring up here.
• Upon review of NCCN guidelines: there are two main genetic indicators for targeted therapies. Both of these mutations are indicated for germline and somatic contexts: BRCA1/2 for parp inhibition and dMMR/MSI-H for pembrolizumab
o Note that there are some somatic mutations with HRD pathway that are indicated for treatment. But that is only if they are somatic
• This study aims to figure out the etiology of the disease in an evolutionary manner. That is what are the key events that lead to oncogenesis.
edit note: the word that escaped me was epistasic given that we are looking into the nuts and bolts cause and effects of different mutations.
edit note 2: I'm going to be honest, most of the time I've read about prostate cancer is in the metastatic setting and thus it has already become castrate resistant. Abiraterone is also meant to aid in sensitizing castrate resistant prostate cancer. Let's just say androgen deprivation therapy for now. On the other hand, I hope this was instructive in showing how important AR is as a pathway for prostate cancer
• Quick thought: this could be useful if this matches with molecular screening in earlier stage disease. If we can reliable map out which chain of events (tumor suppressor loss of function mutations/ gain of function mutations for oncogenes, chromosomal level mutations) lead to more aggressive disease, we can inform changes in surveillance and earlier/ more aggressive treatment.
• Granted this isn’t too out there, tissues cores are taken out to begin with to get initial snapshot into how aggressive disease (it’s how you get the Gleason score after all).
• Regarding switching pathways, that’s not too crazy given neuroendocrine transformations exist in prostate + lung cancer
Personally, I think confabulations would be a better term. To the best of my understanding, these AI rely on a model similar to the reconstructive theory of memory in humans. The connotation of the word confabulation indicates no maliciousness while highlighting the erroneous nature of the action.
Edit: My best read of the article is as follow, please correct me if I am wrong. RB is retinoblastoma gene which is a well known tumor suppressor gene who's loss of function contributes to oncogenesis. It's main role is to keep a hold of a transcription factor called E2F from trying to go forward and initiating mitosis. INK4a AKA p16 is a CDK inhibitor. It basically puts the breaks on cyclin dependent kinases which help move the cell cycle forward. It is also a tumor suppressor gene. Note that CDKs which (but not p16) are targeted by drugs such as ribociclib. Both of these genes are part of the apoptosis (planned cell death: https://upload.wikimedia.org/wikipedia/commons/b/b0/Signal_t...). The theory is that this pathway is way more active in naked mole rats. Where it gets interesting is that up regulation of p16 in particular leads to more activity in the monoamine oxidase pathway that turns serotonin into 5'-HIAA (fun fact, this is monitored for carcinoid syndrome in neuroendocrine tumors). Anyways the breakdown of serotonin leads to a byproduct of H2O2. Hydrogen peroxide leads to general oxidative stress (read DNA damage) and that is a signal for the cell to undergo apoptosis. Thus cell that are senescent and normally don't undergo apoptosis get culled more often. Thus these cells don't get to hang around for a long enough time to undergo aging and oncogensis. Somatic stem cells will fill in the gap. Thus to live longer you gotta kill yourself a little more on the inside.
TBH I'm surprised how hard Illumina is already pushing Galleri as a product. Current ctDNA/cfDNA are imperfect for advanced cancers which should have a lot of shedding to begin with. Additionally CHIP is and outstanding issue. DNA methylation sequencing has promise but I feel more data would be needed to truly make diagnostic findings. So to see Illumina market it as a ready to go product is quite worrying. It may burn a lot of people
