Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date.

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.

Effects of Comano Spring Water-derived Bacterial Lysates on Skin Regeneration: An Ex-vivo Study.

BACKGROUND/AIM: A native non-pathogenic bacterial microflora was identified in Comano (TN, Italy) spring water. The aim of this study was to investigate the regenerative effects of some of the bacterial lysates extracted from this water in a human ex-vivo skin experimental wound model. MATERIALS AND METHODS: Bacterial lysates were extracted from four new isolates: lysate 1 (L1) - closest relative Rudaea cellulosilytica, phylum Proteobacteria; lysate 2 (L2) - closest relative Mesorhizobium erdmanii, phylum Proteobacteria; lysate 3 (L3) - closest relative Herbiconiux ginseng, phylum Actinobacteria; lysate 4 (L4) - closest relative Fictibacillus phosphorivorans, phylum Firmicutes. Their regenerative effects were investigated in a human ex-vivo skin experimental wound healing model at 3 (T1), 5 (T2), and 10 days (T3). RESULTS: The samples cultured with the L2 lysate displayed both an earlier and complete restoration of all the skin layers and their features were the closest to the normal skin. The regenerated epidermis demonstrated a complete maturation as the normal epidermis. The papillary dermis appeared mature, and the reticular dermis displayed both collagen and elastic fibres regularly parallel to the skin surface. An anti-inflammatory effect was displayed by the L1 lysate, but this action did not constitute a regenerative effect, suggesting that pathways for inflammation and regeneration might be different. CONCLUSION: The therapeutic power of spring waters is not exclusively related to their mineral composition, but it may also be attributable to their native non-pathogenic bacterial microflora.

Immediate Postoperative Treatment of Keloids with Intraoperative Radiation Therapy Technology: A Pilot Study.

BACKGROUND: The combination of surgery and postoperative radiotherapy allows for the most effective results with keloids. In this trial, surgery and intraoperative radiation therapy (IORT) technology were used-the hypothesis being that the earlier the application of postoperative radiotherapy, the better the wound healing evolution. METHODS: The study included 16 patients with 21 keloids. The keloids were radically excised and repaired with direct suture or local skin flaps. Collimated electron radiotherapy was applied within 45 minutes of surgery. The outcomes were assessed according to the modified Patient and Observer Scar Assessment Scale; the modified Vancouver Scar Scale; and the modified Common Terminology Criteria for Adverse Events v. 4.0 for skin and subcutaneous tissue disorders. RESULTS: Recurrences were observed in one out of 16 patients, and in two out of 21 keloids (9.5%). The modified Patient and Observer Scar Assessment Scale demonstrated a statistically significant improvement in pain, itching, color, stiffness, thickness, and irregularity after the treatment. The modified Patient and Observer Scar Assessment Scale displayed a statistically significant improvement in the scar vascularity, pigmentation, thickness, and pliability after the treatment. The modified Vancouver Scar Scale demonstrated a statistically significant improvement in 90.48% of the scars after the treatment. The modified Common Terminology Criteria for Adverse Events v. 4.0 for skin and subcutaneous tissue disorders demonstrated an improvement in erythema multiforme and skin pain across the whole sample, with a temporary hyperpigmentation in 19% of the scars after the treatment. CONCLUSION: The combination of surgery and collimated electron radiotherapy with IORT technology demonstrated favorable results in 90.5% of the cases.

Pathological nerve patterns in human basal cell carcinoma.

The peculiar combined, or binary involvement of epithelium and stroma makes basal cell carcinoma (BCC) a unique tumour. Nerve fibres have been shown to play an active role in different cancers. A prospective observational study was carried out on punch biopsies harvested within BCC surgical excision specimens. A total of 10 samples of histologically diagnosed BCC, derived from 10 different patients (five females, five males), was included in the study. Within the BCCs, seven different histological sub-types were identified: morphea-like, basosquamous, micronodular, mixed nodular-micronodular, adenoid, nodular and superficial multifocal. Nerve fibres were stained for indirect immunofluorescence targeting protein gene product 9.5. Three different morphological patterns of nerve fibre distribution within the BCCs were identified. Pattern 1 displayed a normal skin nerve pattern, in which the fibres were dislodged by the growing tumour masses. Pattern 2 featured a ball of curved, tangled nerve fibres close to the tumour masses, slightly resembling piloneural collar nerve fibres, wrapped around hair follicles in the normal anatomical setting. Pattern 3 showed nerve fibres crowding in the sub-epidermal layer with focal epidermal hyperinnervation. Such a pattern is reminiscent of the typical anatomical neuro-epithelial interaction in mechanosensory organs. Our study may disclose a hidden third player, of nerves. Thus, tissue involvement of BCCs may be better represented by the triad of epithelium, stroma and nerves, each component retaining some features associated with its developmental setting.

Nonmelanoma Skin Cancers: Embryologically Relevant Sites and UV Exposure.

BACKGROUND: Traditionally, nonmelanoma skin cancers (NMSCs) are considered mainly UV-related malignancies. Nevertheless, a strong correlation between the embryologically relevant sites (ERS) of the head and neck and the preferential sites of onset of basal cell carcinomas (BCCs) has long been supposed and demonstrated. The aim of this research was the investigation of the potential correlation between the ERS of the head and neck and the sites of tumor onset in all of the NMSCs. METHODS: The distribution of 1165 NMSC was correlated with the ERS of the head and neck using the universally accepted anatomical diagrams featuring the congenital head and neck clefts and an original anatomical diagram showing the most credited sites of the embryonic fusion planes of the auricle. RESULTS: In our sample, both BCC and SSC display an increased likelihood of onset in the ERS of the head and neck. A proportion of 93.10% BCCs was distributed within ERS, while 6.90% derived from non-embryologically relevant sites (P < 0.001). A proportion of 69.70% SCCs was distributed within ERS, while 30.30% derived from non-embryologically relevant sites (P < 0.001). The probability of tumors within ERS was significantly higher for BCC versus SCC (P < 0.001), with BCCs having a 5-fold increase in the probability of occurring in ERS compared to SCCs (P < 0.001). CONCLUSIONS: The ERS might host areas of cellular instability yielding to the development of an NMSC. The environmental UV exposure plays a relatively main role versus dysontogenic factors in the pathogenesis of SCC.

The Role of Autologous Dermal Micrografts in Regenerative Surgery: A Clinical Experimental Study.

The aim of the study was the objective assessment of the effectiveness of a microfragmented dermal extract obtained with Rigenera™ technology in promoting the wound healing process in an in vivo homogeneous experimental human acute surgical wound model. The study included 20 patients with 24 acute postsurgical soft tissue loss and a planned sequential two-stage repair with a dermal substitute and an autologous split-thickness skin graft. Each acute postsurgical soft tissue loss was randomized to be treated either with an Integra® dermal substitute enriched with the autologous dermal micrografts obtained with Rigenera™ technology (group A-Rigenera™ protocol) or with an Integra® dermal substitute only (group B-control). The reepithelialization rate in the wounds was assessed in both groups at 4 weeks through digital photography with the software "ImageJ." The dermal cell suspension enrichment with the Rigenera™ technology was considered effective if the reepithelialized area was higher than 25% of the total wound surface as this threshold was considered far beyond the expected spontaneous reepithelialization rate. In the Rigenera™ protocol group, the statistical analysis failed to demonstrate any significant difference vs. the controls. The old age of the patients likely influenced the outcome as the stem cell regenerative potential is reduced in the elderly. A further explanation for the unsatisfying results of our trial might be the inadequate amount of dermal stem cells used to enrich the dermal substitutes. In our study, we used a 1 : 200 donor/recipient site ratio to minimize donor site morbidity. The gross dimensional disparity between the donor and recipient sites and the low concentration of dermal mesenchymal stromal stem cells might explain the poor epithelial proliferative boost observed in our study. A potential option in the future might be preconditioning of the dermal stem cell harvest with senolytic active principles that would fully enhance their regenerative potential. This trial is registered with trial protocol number NCT03912675.

Platelet Rich Plasma Enhancement of Skin Regeneration in an ex-vivo Human Experimental Model.

This study reports on the development of an original, ex-vivo wounded skin culture protocol using autologous Platelet Rich Plasma (PRP) and enriched Dulbecco's Modified Eagle's Medium (DMEM). Human skin samples obtained from specimens harvested during reduction mammoplasty procedures, were injured in their central portion-to create a standard wound-and cultured under three different conditions: - enriched DMEM with saline solution in the central wound (control)- enriched DMEM with the same medium in the central wound- enriched DMEM plus 2.5% autologous PRP, with the same PRP added medium in the central wound. Morphological analysis was carried out at 0 h (T0) and on days 1, 3, 5 and 10 (T1-T3-T5-T10) using Hematoxylin and Eosin; Masson's trichrome staining; Weigert staining and Ki-67 staining to identify the skin histological features in the different experimental conditions. The combination of DMEM and PRP allowed a favorable modulation of the epithelial cells and fibroblasts proliferation, and a relevant anti-inflammatory action. PRP also demonstrated an inhibitory effect on both the collagen and elastic fibers' de-structuration and a favorable modulation of the re-organization of these fibers. The step by step histological and immune-histo-chemical regenerative effects of PRP on human skin wound repair and regeneration process was observed over a period of 10 days.

Correlation Between the Sites of Onset of Basal Cell Carcinoma and the Embryonic Fusion Planes in the Auricle.

OBJECTIVES: This study aims at the identification of the distribution of basal cell carcinomas (BCCs) in the auricle in correlation with the currently most credited sites of the embryonic fusion planes of the auricle. METHODS: An overall number of 69 patients with 72 BCCs of the auricle were enrolled in the study over a period of 14 years, from June 2003 to October 2017. All the cases underwent medical preoperative digital photography and the specific location of each BCC was coded on an original full-size anatomical diagram of the auricle derived from the reports by Streeter, Wood-Jones, Park, Porter, and Minoux showing the currently most credited sites of the embryonic fusion planes arbitrarily featured as two 5-mm-wide ribbon-like areas: (1) the hyoid-mandibular fusion plane (HM-FP) running from the upper margin of the tragus toward the concha and then deflecting toward the lower margin of the tragus and (2) the free ear fold-hyoid fusion plane (FEFH-FP) running from the cranial-most portion of the helix to the mid-portion of the ascending helix. The latter fusion planes were comprehensively termed embryological fusion planes (EFP) while all of the remaining surface of the auricle was comprehensively termed non-fusion area (NFA). The surfaces of all of the latter areas were calculated using the ImageJ software. RESULTS: According to our data, the greatest number of BCCs was observed within the currently most credited sites of the embryonic fusion planes of the auricle. The latter sites displayed a 12-fold increased tumor incidence in comparison with the remaining surface of the ear. CONCLUSIONS: A correspondence between the sites of onset of BCCs and the sites of merging and/or fusion of embryonal processes was demonstrated in the auricle. Therefore, the latter sites might be considered as high-risk areas for the development of a BCC. Such an evidence provides further support to the hypothesis of an embryological pathogenesis of BCC.

[Regeneration and rehabilitation. Plastic surgery practice in a rehabilitation centre.] / Rigenerazione e Riabilitazione. Esperienza di chirurgia plastica in un centro di riabilitazione.

OBJECTIVES: Regenerative Surgery aims at the restoration of the loss of structures and functions of the body using four innovative approaches: physical energies, biomaterials, cell products and stem cells. METHODS: The Authors provide an overview of their experience with Regenerative Surgery procedures at the Plastic Surgery Unit of the University of Pavia, Istituti Clinici Scientifici Salvatore Maugeri, in a 10 years period, from 2007 to 2017, for the treatment of extensive acute soft tissue loss, chronic ulcers, disabling scars and degenerative pathologies with different aethiology. RESULTS: Regenerative Surgery is a well-established and effective practice in a modern Plastic Surgery Unit. CONCLUSIONS: Regenerative methods are effectively used both as exclusive options in case of absolute contraindication to traditional surgery and as alternative to the latter in order to provide the same outcome with less invasiveness or in combination with minor traditional surgical procedures to reduce the overall surgical burden.

Versatile use of dermal substitutes: A retrospective survey of 127 consecutive cases.

BACKGROUND: Dermal substitutes are currently largely used for the treatment of huge skin loss in patients in critical general health conditions, for the treatment of severe burns and to promote the healing process in chronic wounds. AIMS: The authors performed a retrospective assessment of their experience with bioengineered skin to possibly identify the most appropriate clinical indication and management for each substitute. MATERIALS AND METHODS: The study involved 109 patients with 127 skin defects repaired with dermal substitutes over a 9 years period, from 2007 to 2016. Hyalomatrix® was used in 63 defects, whereas Integra® and Nevelia® were used in 56 and 8 defects, respectively. RESULTS: The statistical analysis failed to reveal a correlation between the choice of a specific dermal substitute and any possible clinical variable except in the soft-tissue defects of the scalp where Hyalomatrix® was electively used. CONCLUSIONS: In the authors' experience, the scalp defects followed a radical excision of skin tumours that included the periosteum. Here, the preliminary cover with a hyaluronan three-dimensional scaffold constantly allowed for the regeneration of a derma-like layer with a rich vascular network fit for supporting a split-thickness skin graft. Nevertheless, the authors still prefer Integra® when the goal is a better cosmetic outcome and Hyalomatrix® when a faster wound healing is required, especially in the management of deep wounds where the priority is a fast obliteration with a newly formed tissue with a rich blood supply. However, these clinical indications still are anecdotally based.

Unrecognized Cell Torpidity as a Risk Factor in Elective Plastic Surgery.

Supplemental Digital Content is available in the text.

Ex vivo regenerative effects of a spring water.

Previous experiments by our group have indicated the regenerative effects of a spring water (Comano), which was possibly associated with the native non-pathogenic bacterial flora. The present study aimed to confirm these regenerative properties in a human ex vivo experimental model in the context of physiological wound healing. Human 6-mm punch skin biopsies harvested during plastic surgery sessions were injured in their central portion to induce skin loss and were cultured in either conventional medium (controls) or medium powder reconstituted with filtered Comano spring water (treated samples). At 24, 48 and 72 h the specimens were observed following staining with hematoxylin and eosin, Picrosirius Red, orcein and anti-proliferating cell nuclear antigen. Compared with the controls, the treated samples exhibited reduced overall cell infiltration, evidence of fibroblasts, stimulation of cell proliferation and collagen and elastic fiber regeneration. In the spring water, in addition to 12 resident non-pathogenic bacterial strains exhibiting favorable metabolic activities, more unknown non-pathogenic species are being identified by genomic analysis. In the present study, the efficacy of this 'germ-free', filtered spring water in wound regeneration was indicated. Thus, the Comano spring water microbiota should be acknowledged for its regenerative properties.

Scar Remodeling with the Association of Monopolar Capacitive Radiofrequency, Electric Stimulation, and Negative Pressure.

OBJECTIVE: A study was established to objectively assess the effects of low-intensity electromagnetic and electric stimulation plus negative pressure on mature scars. BACKGROUND: Radiofrequency plus negative pressure therapy demonstrated a favorable reorganization and regeneration of the collagen and elastic fibers and was proposed for the treatment of cellulitis and skin stretch marks. METHODS: Twenty-six mature scars in 20 Caucasian patients (15 females and 5 males) were enrolled in the study. The treatments were carried out with a Class I, BF-type electromedical device equipped with a radiofrequency generator, an electric pulse generator, and a vacuum pump twice a week for 3 months. Corneometry, transepidermal water loss, elastometry, colorimetry, and three-dimensional skin surface pattern were objectively assessed with Multi Probe Adapter System MPA and PRIMOS pico. A subjective assessment was carried out with the VAS and PSAS scales. Each scar was compared before and after the treatment and with the skin in the corresponding healthy contralateral anatomical area at the same times. RESULTS: Reduction of the scar surface wrinkling and overall scar flattening were demonstrated after the treatment. The scar slightly tended to approach the color and elasticity of healthy skin too. CONCLUSIONS: The combined local treatment of mature scars with low-intensity electromagnetic and electric stimulation in association with negative pressure might suggest a favorable synergic effect on the scar collagen and elastic fiber remodeling.

Novel perspectives on the role of the human microbiota in regenerative medicine and surgery.

Plastic surgery is transitioning from a fine craftsmanship to a regenerative science. In wound healing, the role of microorganisms is no longer considered to be just counteracting, but also promoting. Furthermore, host-microbe interactions are essential for numerous aspects of normal mammalian physiology, from metabolic activity to immune homeostasis. Each area of the human body hosts a unique microbial community, and the composition of microbiota is dependent on the host, age and the anatomical area, and it changes according to the characteristics of the microenvironment. Every squared centimeter of skin contains ~1 billion bacteria. The majority of microorganisms of the skin are commensal or temporary passing members. Skin flora mechanisms interacting or influencing the human physical skin barrier are not well defined. Resident skin bacteria provide the first line of defence against potentially dangerous pathogens and produce small molecules that influence their microbial neighbours. Furthermore, the microbiota activates and assists innate immunity and influences adaptive immunity. Various types of immune and non-immune cells contribute to wound healing. The proliferative phase of wound healing is inversely proportional to the extent of the post-traumatic inflammatory reaction. Topical bacterial lipopolysaccharide application markedly affects wound healing by accelerating the resolution of inflammation, increasing macrophage infiltration, enhancing collagen synthesis and altering the secretion of mediators involved in skin regeneration. Various studies have investigated the biological contents of thermal spring waters, and their anti-inflammatory and immune protective roles. In addition, the regenerative properties of thermal spring waters were analysed in an experimental animal wound model. The areas treated with thermal water healed faster than the areas treated with conventional dressings, and exhibited a collagen and elastic fiber network comparable with the normal skin. Thus, the microbial environment may be considered as a potential tool in regenerative medicine and surgery.

Non-pathogenic microflora of a spring water with regenerative properties.

The Comano spring water (Comano, Italy) has been demonstrated to improve skin regeneration, not only by increasing keratinocyte proliferation and migration, but also by modulating the regenerated collagen and elastic fibers in the dermis. However, such biological properties may not be entirely explained by its mineral composition only. As the non-pathogenic bacterial populations have demonstrated an active role in different biological processes, the potential presence of non-pathogenic bacterial species within the Comano spring water was investigated in order to identify any possible correlation between these bacterial populations and the demonstrated biological properties of this water. The water was collected at the spring using an aseptic procedure and multiple cultures were carried out. A total of 9 different strains were isolated, which were Aeromonas hydrophila, Brevundimonas vesicularis, Chromobacterium violaceum, Citrobacter youngae, Empedobacter brevis, Pantoea agglomerans, Pseudomonas putida, Pseudomonas stutzeri and Streptococcus mitis. All the isolated bacterial strains, although showing a rare potential virulence, demonstrated peculiar and favorable metabolic attitudes in controlling environmental pollution. The therapeutical effects of certain spring waters are currently being proven as correlated not only to their peculiar mineral composition, but also to the complex activity of their resident non-pathogenic bacterial populations. Although the present study provided only preliminary data, some of the non-pathogenic bacterial populations that were identified in the Comano spring water are likely to produce molecular mediators with a role in the wound healing process that, thus far, remain unknown. Numerous other unknown bacterial species, comprehensively termed DNA-rich 'dark matter', are likely to contribute to the Comano water regenerative properties as well. Therefore, the non-pathogenic bacterial populations of the Comano spring water are possibly credited for its demonstrated regenerative properties.

Prefabricated Composite Graft for Eyelid Reconstruction.

The authors propose a prefabricated chondromucosal composite graft to reconstruct full-thickness defects of the lower eyelid. The technique was used in a patient suffering from a locally invasive basal cell carcinoma of the lower eyelid, who had previously undergone an extensive submucosal nasal septum resection. One week prior to the eyelid resection, the anterior skin surface of the auricular concha was replaced with a full-thickness oral mucosa graft. One week later, a full-thickness excision of the right lower eyelid was performed and the prefabricated chondromucosal auricular graft was used to restore the posterior lamella. The anterior lamella was reconstructed with a bipedicled myocutaneous flap from the upper eyelid. Because of the patient's scheduling needs, the medial pedicle of the flap was divided 28 days later and the lateral one after further 37 days. All the procedures were performed under local anesthesia. This technique adds a simple key detail to other time-honored reliable techniques, thus outlining an extremely convenient sequence for full-thickness eyelid reconstruction. The easily prepared prefabricated chondromucosal graft might be associated with any of the previously described flaps, thus providing a versatile and reliable method of posterior lamella reconstruction.

Objective Clinical Assessment of Posture Patterns after Implant Breast Augmentation.

BACKGROUND: An increased weight of the breasts causes several spinal postural alterations that reduce the ability to perform dynamic tasks requiring a stable balance. The effects of the increased weight of the breasts on static posture after implant breast augmentation have not been investigated yet. METHODS: Forty volunteer healthy women were asked to wear different sized breast implants (800, 400, and 300 g) inside a dedicated sports bra for 6½ consecutive hours during their everyday life activities, 1 day for every implant size. Posture changes were assessed with the association of a physiatric clinical examination with a static force platform analysis. RESULTS: A significant increase in cervical lordosis after the use of 400-g breast implants and upward was demonstrated. This alteration was stable between the 400-g and 800-g breast implants. The 400-g (per breast) implant might therefore be the load threshold that breaks the cervical postural physiologic balance. A significant increase in lumbar lordosis was demonstrated only after the use of the 800-g breast implants. The static force platform assessment demonstrated a worsening of the balance independent from the visual control with the use of 400-g and 800-g implants. CONCLUSIONS: Heavy breast implants proved to induce reversible alterations in the spinal curve, and 400 g is the cutoff for functional physiologic compensation in the short term. Such a weight might be considered the safety limit for the use of breast implants for cosmetic purposes.

The three-bite technique: a novel method of dog ear correction.

The closure of any circular or asymmetric wound can result in puckering or an excess of tissue known as a 'dog ear'. Understanding the mechanism of dog ear formation is a fundamental requirement necessary to facilitate an appropriate treatment. Many solutions have been reported in the literature, but in all cases, the correction entails the extension of the scar and the sacrifice of the dermal plexus. Here, we propose a novel technique of dog ear correction by using a three-bite suture that sequentially pierces the deep fascial plane and each dog ear's margin, thus allowing for flattening the dog ear by anchoring the over-projecting tissue to the deep plane. The three-bite technique proved to be a fast, easy, and versatile method of immediate dog ear correction without extending the scar, while maintaining a full and complete local skin blood supply.

Long-term in vivo assessment of bioengineered skin substitutes: a clinical study.

The aim of the study was an objective in vivo assessment of skin properties after reconstruction with two artificial dermal substitutes, Integra® and Hyalomatrix®. Twenty-seven patients underwent reconstruction of 36 skin-loss sites with full-thickness skin graft, split-thickness skin graft, Hyalomatrix® bioengineered skin substitute and sequential split-thickness skin graft and Integra® bioengineered skin substitute and sequential split-thickness skin graft. Objective assessments were carried out using three instrumental devices: Multi Probe Adapter System MPA; 22 MHz ultrasound skin scan; and Primos Pico for a three-dimensional (3D) skin scan. The skin parameters under study in our sample were: corneometry, transepidermal water loss, elastometry, colorimetry, skin thickness and 3D skin surface pattern. A skin reconstruction with Hyalomatrix seemed to most closely approach the hydration, transepidermal water loss and skin surface 3D pattern of normal skin. A skin reconstruction with Integra seemed to demonstrate the best skin colour feature and elastic properties. Although no statistically significant differences were observed, the descriptive analysis of the outcomes might suggest a better cell regulation, regenerated extracellular matrix and neoangiogenesis with the use of Hyalomatrix, and the formation of a more elastic regenerated dermis, with overall better physical, mechanical and optical properties, with the use of Integra.