Personalized neoadjuvant immunotherapy for stage III malignant melanoma: notes on the PRADO study

F.F. van den Berg¹, M.A. Boermeester<sup>2

1</sup>Department of Medical Microbiology, Amsterdam UMC, Amsterdam, the Netherlands
²Department of Surgery, Amsterdam UMC, Amsterdam, the Netherlands

Article review Long, D. R. et al. Contribution of the patient microbiome to surgical site infection and antibiotic prophylaxis failure in spine surgery. Sci. Transl. Med.16, eadk8222 (2024). https://www.science.org/doi/10.1126/scitranslmed.adk8222

Kanad Ghosh, MD¹; Hannes Prescher, MD¹; Summer E. Hanson, MD, PhD, FACS^1
1Section of Plastic and Reconstructive Surgery, Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, IL, 60637

With the advent of cellular targets and immunotherapy, cancer treatment has undergone significant improvement over the past several decades. While curative treatment of malignancy often relies on surgical excision, adjuvant modalities such as loco-regional irradiation remain important tools in comprehensive cancer care. Adjuvant radiotherapy (RT) is highly effective in reducing cancer burden, limiting the need for extensive surgery and decreasing the risk of local recurrence.1-3 However, RT brings collateral damage to the healthy surrounding soft tissues. Exposure to ionizing radiation results in a series of tissue changes marked by erythema, ulceration and oedema in the acute phase, followed by chronic inflammation and skin fibrosis, which may persist after treatment 4,5. As cancer survival rates continue to improve, an increasing number of patients are living with chronic morbidity related to RT.   Autologous fat transfer (AFT) has emerged as a possible treatment to the harmful effects of irradiation.6,7 Here, adipose tissue is suctioned from one part of the body, processed and then injected in small aliquots directly into the irradiated tissues.8 The mechanism through which lipoaspirate exerts a reparative effect is poorly understood but thought to be through direct and indirect actions: direct differentiation of transferred adipose-derived stem cells (ASCs) into new adipocytes, and paracrine signalling of cytokines and growth factors (HGF, TGF-ß, FGF-1,2, VEGF) that inhibit profibrotic signalling pathways and contribute to the recruitment of proangiogenic cells 9. Like a skin graft, the adipose graft in AFT is dependent on the recipient tissue bed for nutrition and engraftment to achieve adequate ‘take.’ One of the challenges of fat grafting, in particular into a poorly perfused, irradiated tissue bed, is its unreliable retention rate, which is cited at between 30%-70%. Repeat procedures are often performed.10,11 As an alternative to AFT, decellularized adipose matrices (DAM) derived from discarded lipoaspirate have been developed. The allografts are processed through physical, chemical, and enzymatic purification techniques to develop decellularized scaffolds that retain the complex macromolecular architecture of the adipose tissue, and potentially its paracrine function via key growth factors retained in the graft. In recent studies, DAMs have been shown to promote adipose tissue regeneration, and have become a promising alternative to traditional fat grafting for soft tissue defects. 12 However, DAMs have not been studied in the context of radiation or a former tumour bed.

Jason Xiao¹, John Alverdy¹¹Department of Surgery, University of Chicago Medicine, Chicago, IL, 60637

Paper for discussion: Fachi JL, Felipe JS, Pral LP, Silva BK, Correa RO, Cristiny M et al.Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism. Cell Rep. 2019 Apr 16; 27: 750-761.e7. Although rare, Clostridium difficile-induced diarrhoea or colitis can complicate what otherwise appeared to be an uneventful elective operation. This rare, but potentially lethal complication results from multiple factors inherent to performing surgery, such as prolonged periods of starvation, antibiotic exposure, major physiological stress, and sleep deprivation1. C. difficile spores can spread easily, can resist multiple methods of decontamination and can remain viable for long periods of time. In many cases, the bacteria can remain hidden within the host’s gut microbiome and transferred to the healthcare setting by the patient themselves, rather than vice versa. While prevention is the best treatment, C. difficile infections (CDI) often prove resistant to antibiotics, and other modalities may be needed to restore homeostasis to the gut microbiome. Although faecal microbiota transplant has been proposed as a method for both prevention and treatment of CDI, even when severe colitis is present, many believe the most important action of the microbiome is to preserve its ability to produce key multifunctional metabolites 2. For example, the ability of the microbiota to produce the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate has been identified to be an important therapeutic aspect in the prevention and treatment of CDI. SCFAs are absorbed by host intestinal epithelial cells (IECs) and participate in several immunoregulatory roles that influence the host response to inflammation and infection. Past studies have detected reduced SCFA concentrations, particularly butyrate, in patients with CDI3. Elevation of butyrate via dietary modulation or provision of SCFA-producing bacteria has been shown to attenuate CDI severity in animal studies4,5.