Pancreatic Cancer – fungal and Mast Cell connection

Malassezia is well known for its association with facial skin rash Seborrheic Dermatitis. It has been found teaming around pancreatic cancer tissue in mice and humans and there is even the suggestion it might be oncogenic. Mast cell are found around  pancreatic cancer cells as well, and a ketotifen, a drug to control mast cell degranuation, might help in pain control.  Pancreatic cancer tends to occur in cases who had previous pancreatic issues and diabetes, smokers and ppi users; prophylactic metformin could reduce those chances by over 50%

Pancreatic Cancer and Malassezia

Aykut, Berk, Smruti Pushalkar, Ruonan Chen, Qianhao Li, Raquel Abengozar, Jacqueline I. Kim, Sorin A. Shadaloey et al.
The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL.
Nature (2019): 1-4.
https://www.researchgate.net/profile/Wei_Wang439/publication/336224053_The_fungal_mycobiome_promotes_pancreatic_oncogenesis_via_activation_of_MBL/links/5d95fff6458515c1d3919a55/The-fungal-mycobiome-promotes-pancreatic-oncogenesis-via-activation-of-MBL.pdf
“Here we show that fungi migrate from the gut lumen to the pancreas, and that this is implicated in the pathogenesis of PDA [Pancreatic Duct Cancer].
PDA tumours in humans and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue.
The composition of the mycobiome of PDA tumours was distinct from that of the gut or normal pancreas on the basis of alpha- and beta-diversity indices. Specifically, the fungal community that infiltrated PDA tumours was markedly enriched for Malassezia spp. in both mice and humans.
Ablation of the mycobiome was protective against tumour growth in slowly progressive and invasive models of PDA, and repopulation with a Malassezia species—but not species in the genera Candida, Saccharomyces or Aspergillus—accelerated oncogenesis.”
For some unknown reason, Malassezia’s cancer effect is through activating C3 which activates complement system inflammatory immune responses
  • Risk factors for pancreatic ca include PPI ulcer drug use – I wonder if that means scratched/picked seborrhea patches (fomites) swallowed would more likely implant in bowel with no acid in stomach
————————————————

Re Pancreatitc Cancer and Mast Cells

Yu, Dawei, et al.
Inhibition of Mast Cell Degranulation Relieves Visceral Hypersensitivity Induced by Pancreatic Carcinoma in Mice.
Journal of Molecular Neuroscience (2019): 1-11.
  • a few studies found a potential correlation between the activation of abundant mast cells and visceral pain in
    – irritable bowel syndrome (IBS),
    – [interstial]cystitis,
    – complex regional pain syndrome,
    – chronic pancreatitis
    (Bicer et al.2015 ; Demir et al.2013 ;Xu etal.2017 )
    Bicer F, Altuntas CZ, Izgi K, Ozer A, Kavran M, Tuohy VK, DaneshgariF (2015) Chronic pelvic allodynia is mediated by CCL2 through mast cells in an experimental autoimmune cystitis model. Am J
    Physiol Ren Physiol 308:F103–F113
    https://www.physiology.org/doi/full/10.1152/ajprenal.00202.2014
    Demir IE, Schorn S, Schremmer-Danninger E, Wang K, Kehl T, GieseNA, Algül H, Friess H, Ceyhan GO (2013) Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. PLoS One 8:e60529.
    https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060529
    Xu XJ, Zhang YL, Liu L, Pan L, Yao SK (2017) Increased expression of nerve growth factor correlates with visceral hypersensitivity and impaired gut barrier function in diarrhoea-predominant irritable bowel syndrome: a preliminary explorative study. Aliment Pharmacol Ther 45:100–114
    https://onlinelibrary.wiley.com/doi/full/10.1111/apt.13848
  • Human and mice pancreatic ca tissues “Mast Cells Were Recruited to Tissues Surrounding Pancreatic Tumors in Patients with Severe Visceral Pain”
  • ketotifen had a dose dependent effect without sedation being the factor: -almost 50% reduction at top dose but took 21 days

  • Mast cell deficit bred mice still had some pancreatic cancer pain so no panacea. – they called it “incomplete development of chronic visceral hypersensitivity and the spontaneous nociceptive response in mast cell–deficient mice”\

 Pancreatic Cancer Risk Factors

Two major factors in predicting pancreatic cancer include
–  previous pancreatic damage  – ie pancreatitis
 – development of diabetes

Another recent article found it this way – “Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus before their cancer diagnosis”

So they looked at what factors in in diabetics: – smoking, PPI ulcer med use, and severity DM requiring more than just metformin were worst factors

On ultrasound, “Main pancreatic duct dilatation (≥ 2.5 mm) and presence of a pancreatic cyst (≥ 5 mm) were both strong independent predictors of the subsequent development of pancreatic cancer”:

Tanaka, Sachiko, et al. “Slight dilatation of the main pancreatic duct and presence of pancreatic cysts as predictive signs of pancreatic cancer: a prospective study.” Radiology 254.3 (2010): 965-972.
https://pubs.rsna.org/doi/full/10.1148/radiol.09090992

  • Pancreatic cancer found with cyst or duct dilation in 10% of cases
  • The interval from enrollment to the detection of cancer ranged from 15 to 82 months (mean, 45.7 months ± 19.8).

 

 in Pancreatic cancer Recommendations

1) Ablation Malassezia with – I would try flucanazole 100 mg 1/2 tab bid x2 weeks as 50 mg/day only 74% effective:
Zisova, Lilija G.
Fluconazole and its place in the treatment of seborrheic dermatitis–new therapeutic possibilities.
Folia medica 48.1 (2006): 39-45.
https://europepmc.org/abstract/med/16918053

preventitively I would use it every 3 months…

Malassezia is a nasty bug and is seen in alzheimer brains:
Front Aging Neurosci. 2018 May 24;10:159. doi: 10.3389/fnagi.2018.00159
Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer’s Disease.
Alonso R et al.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976758/
“the fungal genera more prevalent in AD patients were Alternaria, Botrytis, Candida, and Malassezia

I suspect colonization is pretty common in gut and is seen in aggravation of crohn’s disease:
Limon, Jose J., et al. “Malassezia is associated with Crohn’s disease and exacerbates colitis in mouse models.” Cell host & microbe 25.3 (2019): 377-388.
https://www.sciencedirect.com/science/article/abs/pii/S1931312819300459

2) Ketotifen is an anti-histamine like agent –  in adults is usually used at 1 mg twice daily though at half dose first week re sedation. One has to be prepared to use it at least 3 week to see effect.
a precaution with its use in diabetics is as in product monogram:
https://pdf.hres.ca/dpd_pm/00017437.PDF
“A reversible fall in the thrombocyte count in patients receiving Zaditen concomitantly with oral antidiabetic agents has been observed in rare cases. Thrombocyte counts should therefore be carried out in patients taking oral antidiabetic agents concomitantly.”

Pancreatic Cancer Prevention

High risk cases are those with diabetes, smoking, pancreatic injury or prior pancreatitis, and PPI use. I would consider use of Metformin
Oncol Lett. 2018 Jan;15(1):683-690. doi: 10.3892/ol.2017.7412.
Metformin and cancer: An existing drug for cancer prevention and therapy.
Zi F et al
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772929/
“Compared with those who were not treated with metformin, diabetic patients treated with metformin exhibited an ~62% reduced risk of developing pancreatic cancer”. If one gets diarrhea, use of the long acting agent Glumetza could be used but is expensive.

It offers benefits of mood stabilization, lower cancer, and 5 years increased longevity. Suggested to reduce cardiovascular issues and alzheimers disease.

I hope you enjoy article as was a bigger job than thought.

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