Soft Tissue Fibrosis Research Articles

Role of Local Flaps in the Reconstruction of Extensive Anterolateral Noma Defect: A Case Report

Abstract The scarring stage of noma disease often presents with composite tissue loss involving hard and soft tissues with resultant fibrosis making reconstruction a challenge. Microvascular reconstruction option is associated with good outcomes when the expertise is available. Trismus, which is caused by either soft tissue fibrosis or the union of the coronoid to the zygomatic complex, is also a common presentation. Effective treatment necessitates the involvement of a diverse team of specialists and the establishment of clear treatment objectives. This report presents a case of an extensive composite noma defect with trismus in a 9-year-old female managed using local flaps.

Acute adverse events of ultra-hypofractionated whole-breast irradiation after breast-conserving surgery for early breast cancer in Japan: an interim analysis of the multi-institutional phase II UPBEAT study

BackgroundThe applicability of ultra-hypofractionated (ultra-HF) whole-breast irradiation (WBI) remains unknown in Japanese women. This study aimed to evaluate the safety and efficacy of this approach among Japanese women and report the results of an interim analysis performed to assess acute adverse events (AEs) and determine whether it was safe to continue this study.MethodsWe enrolled Japanese women with invasive breast cancer or ductal carcinoma in situ who had undergone breast-conserving surgery, were aged ≥ 40 years, had pathological stages of Tis–T3 N0–N1, and had negative surgical margins. Ultra-HF-WBI was delivered at 26 Gy in five fractions over one week. When the number of enrolled patients reached 28, patient registration was paused for three months. The endpoint of the interim analysis was the proportion of acute AEs of grade ≥ 2 (Common Terminology Criteria for Adverse Events v5.0) within three months.ResultsOf the 28 patients enrolled from seven institutes, 26 received ultra-HF-WBI, and 2 were excluded due to postoperative infections. No AEs of grade ≥ 3 occurred. One patient (4%) experienced grade 2 radiation dermatitis, and 18 (69%) had grade 1 radiation dermatitis. The other acute grade 1 AEs experienced were skin hyperpigmentation (n = 10, 38%); breast pain (n = 4, 15%); superficial soft tissue fibrosis (n = 3, 12%); and fatigue (n = 1, 4%). No other acute AEs of grade ≥ 2 were detected.ConclusionsAcute AEs following ultra-HF-WBI were within acceptable limits among Japanese women, indicating that the continuation of the study was appropriate.

Quantitative measurements of radiation-induced fibrosis for head and neck cancer: A narrative review.

To provide a comprehensive summary of the different modalities available to measure soft tissue fibrosis after radiotherapy in head and neck cancer patients. PubMed, Scopus, and Web of Sciences. A search was conducted using a list of medical subject headings and terms related to head and neck oncology, radiation fibrosis, and quantitative measurements, including bioimpedance, MRI, and ultrasound. Original research related to quantitative measurement of neck fibrosis post-radiotherapy was included without time constraints, while reviews, case reports, non-English texts, and inaccessible studies were excluded. Discrepancies during the review were resolved by discussing with the senior author until consensus was reached. A total of 284 articles were identified and underwent title and abstract screening. Seventeen articles had met our criteria for full-text review based on relevance, of which nine had met our inclusion criteria. Young's modulus (YM) and viscoelasticity measures have demonstrated efficacy in quantifying neck fibrosis, with fibrotic tissues displaying significantly higher YM values and altered viscoelastic properties such as increased stiffness rate-sensitivity and prolonged stress-relaxation post-radiation. Intravoxel incoherent motion offers detailed insights into tissue changes by assessing the diffusion of water molecules and blood perfusion, thereby differentiating fibrosed from healthy tissues. Shear wave elastography has proven to be an effective technique for quantifying radiation-induced fibrosis in the head and neck region by measuring shear wave velocity. There are various modalities to measure radiation-induced fibrosis, each with its unique strengths and limitations. Providers should be aware of these implications and decide on methodologies based on their specific clinical workflow. Step 5.

Utilizing a Second Flap to Address the Effect of Postradiotherapy Soft Tissue Fibrosis in Head and Neck Malignancy.

Background Late effects of adjuvant radiation therapy (RT) on soft tissues can lead to hair loss, pigmentary changes, loss of tissue volume, and fibrosis, which appear months to years after the treatment. These changes are often progressive and are because of tissue hypoxia due to radiation-induced capillary endothelial damage. Tissue hypoxia may be compounded by subclinical infection following minor trauma, exposed hardware, or associated osteoradionecrosis. The combined effect of these factors causes significant deformities in soft tissue, affecting both function and appearance. Such changes are also seen in primarily transferred flaps, which have been radiated, resulting in severe, progressive soft tissue fibrosis, compromising function and aesthetics. In selected cases, a second flap may be needed to restore function and volume. Methods Data of patients who underwent secondary soft tissue transfers for postradiotherapy-related soft tissue changes were collected from the hospital electronic medical records, from January 2019 to 2023. Details regarding the primary surgery, dose, duration of adjuvant RT, time interval between adjuvant RT and secondary soft tissue transfer, indications, and the choice of the second flap were analyzed. Results Twenty-one patients had undergone secondary soft tissue transfer for extensive soft tissue fibrosis. In addition, associated compounding features like exposed implant and volume loss were observed. Two patients with osteoradionecrosis also had associated extensive soft tissue fibrosis necessitating replacement. Out of these 21 patients, 13 had undergone free tissue transfers, while 7 locoregional tissue transfers. Conclusion Late sequelae of adjuvant RT changes usually present from 6 months onwards. The radiated hypoxic tissue, due to capillary damage, leads to a chronic progressive fibrotic stage, causing loss of soft tissue volume and fibrosis. Replacing this tissue with a vascularized flap helps to restore volume and correct these secondary changes, improving overall quality of life.

THE EPIGENETIC LANDSCAPE IN SOFT-TISSUE FIBROSIS

Dupuytren's disease (DD) is a fibroproliferative soft tissue disease affecting the palmar fascia of the hand causing permanent and irreversible flexion contracture. Aberrant fibrosis is likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in soft tissue fibrosis in diseases such as DD is not well established. Therefore, we conducted a comprehensive multi-omic study investigating the epigenetic profiles that influence gene expression in DD pathology. Using control (patients undergoing carpal tunnel release) and diseased fibroblasts (patients undergoing Dupuytren's fasciectomy), we conducted ATAC-seq to assess differential chromatin accessibility between control and diseased fibroblasts. Additionally, ChIP-seq mapped common histone modifications (histone H4; H3K4me3, H3K9me3, H3K27me3, H4K16Ac, H4K20Me3) associated with fibrosis. Furthermore, we extracted RNA from control and DD tissue and performed bulk RNA-seq.ATAC-seq analysis identified 2470 accessible genomic loci significantly more accessible in diseased fibroblasts compared to control. Comparison between diseased and control cells identified numerous significantly different peaks in histone modifications (H4K20me3, H3K27me3, H3K9me3) associated with gene repression in control cells but not in diseased cells. Pathway analysis demonstrated a substantial overlap in genes being de-repressed across these histone modifications (Figure 1). Both, ATAC-seq and ChIP-seq analysis indicated pathways such as cell adhesion, differentiation, and extracellular matrix organisation were dysregulated as a result of epigenetic changes. Moreover, de novo motif enrichment analysis identified transcription factors that possibly contributed to the differential gene expression between control and diseased tissue, including HIC1, NFATC1 and TEAD2. RNA-seq analysis found that these transcription factors were upregulated in DD tissue compared to control tissue.The current epigenetic study provides insights into the aberrant fibrotic processes associated with soft tissue diseases such as DD and indicates that epigenetic-targeted therapies may be an interesting viable treatment option in future.For any figures or tables, please contact the authors directly.

Safety of Total Skin Electron Therapy with Concurrent Systemic Therapy

Introduction: Mycosis fungoides has a long, waxing and waning course. Multimodality therapy is needed to control disease. Total skin electron beam therapy (TSE) is an effective means of controlling cutaneous disease, though response duration is limited necessitating incorporation of additional therapeutics. There are limited data informing the safety of systemic agents used concurrently with TSE. We characterize acute toxicities of patients undergoing TSE +/- concurrent or recent systemic therapy. Methods: We retrospectively analyzed 114 patients comprising a total of 121 consecutive courses of full body TSE from 2013-2023. Median follow up was 1.75 years from start of TSE. Toxicities occurring up to 3 months following radiation were recorded and graded per CTCAEv5 criteria when applicable; grade was characterized as low (grades 1-2) and high (3-4). Given conflating cutaneous symptoms prior to TSE, toxicities were further characterized as “new or worsened” (N/W) from baseline. Incidence of N/W toxicity was further categorized by class of systemic therapy: interferon, retinoic acid derivative, immunotherapy, systemic steroid, histone deacetylase inhibitor, folic analogue antimetabolite, and other. Recent systemic therapy included receipt of therapy within 1 and 3 months preceding TSE given multi-month half lives of some systemics. Results: During 75 courses, patients received systemic therapy concurrently with TSE (CS), and 46 had no concurrent systemic therapy (NCS). The majority of concurrent systemic therapies were interferons (49, 41%) and retinoic acid derivatives (32, 27%); “other” concurrent systemics included lenalidomide, imatinib, and ibrutinib. TSE dose included 36Gy (5%), 24Gy (6%), 12Gy (84%), and other (5%). Most patients had ECOG performance status 0-1 (88% overall). Patient characteristics were well balanced, excepting stage at TSE (stage III/IV CS 45.3% vs NCS 26.1%, p<0.05), though T stage and blood involvement were evenly distributed. At baseline among CS and NCS patients, 29% vs 30% had skin ulceration, 27% vs 35% had large cell transformation, and 12% vs 13% had concurrent infection, respectively (all p>0.05). Incidence of any N/W toxicity was 98.7% and 100% ( p>0.05)among CS and NCS patients, respectively (95% vs 94% low grade and 13% vs 26% high grade, both p>0.05). Prior to TSE, baseline rates of common symptoms among CS vs NCS courses were as follows: dermatitis 96% vs 94%, hyperpigmentation 28% vs 28%, edema 15% vs 24%, pruritus 97% vs 87%, and skin pain 32% vs 45%, respectively (all p>0.05). From start of TSE through 3 month follow up, the overall incidences of CS vs NCS N/W common toxicities included the following: N/W dermatitis 73% vs 83%, N/W hyperpigmentation 33% vs 37%, and N/W edema 21% vs 24% (all p>0.05). Twenty-five percent of CS patients experienced skin pain flare during TSE vs 13% NCS, and 20% of CS patients vs 11% NCS experienced pruritus flare (all p>0.05). At end of treatment, 59% of CS patients with baseline pruritus experienced improvement compared to 68% NCS, with 73% vs 70% experiencing improvement at 1-3 months in follow up (all p>0.05). One patient received a known concurrent radiosensitizer - methotrexate - and developed N/W grade 3 dermatitis (baseline grade 3), new grade 2 hyperpigmentation, worsened grade 1 anorexia, new grade 2 superficial soft tissue fibrosis, and pain flare. The median number of all reported N/W toxicities among systemic classes when given concurrently was low and well balanced. This persisted when the number of toxicities per class were assessed among systemics administered within 1 month preceding TSE, and within 3 months preceding TSE. Conclusions: Concurrent or recent receipt of systemic therapy can be safe among most commonly used concurrent agents that are not radiosensitizers. There was no notable increase in incidence of low or high grade toxicity, or median number of low or high grade toxicities recorded in CS vs NCS patients. Most patients experienced some acute toxicity, which is not unexpected given radiation to a tissue with high cell turnover, and the interplay of toxicity with expected disease response to TSE. High rates of baseline dermatitis and high rates of N/W dermatitis highlight this observation. Notably most systemic therapies included interferons and retinoic acid derivatives. Additional data is needed to better characterize the toxicity profile of other systemic therapies used concurrently with TSE.

Metallosis in Total Hip Arthroplasty.

» Metallosis is a rare but significant complication that can occur after total hip arthroplasty (THA) for a variety of reasons but most commonly in patients with metal-on-metal implants.» It is characterized by the visible staining, necrosis, and fibrosis of the periprosthetic soft tissues, along with the variable presence of aseptic cysts and solid soft tissue masses called pseudotumors secondary to the corrosion and deposition of metal debris.» Metallosis can present with a spectrum of complications ranging from pain and inflammation to more severe symptoms such as osteolysis, soft tissue damage, and pseudotumor formation.» Workup of metallosis includes a clinical evaluation of the patient's symptoms, imaging studies, serum metal-ion levels, and intraoperative visualization of the staining of tissues. Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein along with intraoperative frozen slice analysis may be useful in certain cases to rule out concurrent periprosthetic joint infection.» Management depends on the severity and extent of the condition; however, revision THA is often required to prevent rapid progression of bone loss and tissue necrosis.

Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.

Magnesium implant degradation provides immunomodulatory and proangiogenic effects and attenuates peri-implant fibrosis in soft tissues.

Implants made of magnesium (Mg) are increasingly employed in patients to achieve osteosynthesis while degrading in situ. Since Mg implants and Mg2+ have been suggested to possess anti-inflammatory properties, the clinically observed soft tissue inflammation around Mg implants is enigmatic. Here, using a rat soft tissue model and a 1-28d observation period, we determined the temporo-spatial cell distribution and behavior in relation to sequential changes of pure Mg implant surface properties and Mg2+ release. Compared to nondegradable titanium (Ti) implants, Mg degradation exacerbated initial inflammation. Release of Mg degradation products at the tissue-implant interface, culminating at 3d, actively initiated chemotaxis and upregulated mRNA and protein immunomodulatory markers, particularly inducible nitric oxide synthase and toll-like receptor-4 up to 6d, yet without a cytotoxic effect. Increased vascularization was demonstrated morphologically, preceded by high expression of vascular endothelial growth factor. The transition to appropriate tissue repair coincided with implant surface enrichment of Ca and P and reduced peri-implant Mg2+ concentration. Mg implants revealed a thinner fibrous encapsulation compared with Ti. The detailed understanding of the relationship between Mg material properties and the spatial and time-resolved cellular processes provides a basis for the interpretation of clinical observations and future tailoring of Mg implants.

Deconstructing Fat to Reverse Radiation Induced Soft Tissue Fibrosis.

Adipose tissue is composed of a collection of cells with valuable structural and regenerative function. Taken as an autologous graft, these cells can be used to address soft tissue defects and irregularities, while also providing a reparative effect on the surrounding tissues. Adipose-derived stem or stromal cells are primarily responsible for this regenerative effect through direct differentiation into native cells and via secretion of numerous growth factors and cytokines that stimulate angiogenesis and disrupt pro-inflammatory pathways. Separating adipose tissue into its component parts, i.e., cells, scaffolds and proteins, has provided new regenerative therapies for skin and soft tissue pathology, including that resulting from radiation. Recent studies in both animal models and clinical trials have demonstrated the ability of autologous fat grafting to reverse radiation induced skin fibrosis. An improved understanding of the complex pathologic mechanism of RIF has allowed researchers to harness the specific function of the ASCs to engineer enriched fat graft constructs to improve the therapeutic effect of AFG.

RETRIEVAL ANALYSIS OF DUAL MOBILITY POLYETHYLENE LINERS FOR TOTAL HIP ARTHROPLASTY

Dual Mobility (DM) Total Hip Replacements (THRs) were introduced to reduce dislocation risk, which is the most common cause of early revision. The in-vivo mechanics of these implants is not well understood, despite their increased use in both elective and trauma settings. Therefore, the aim of this study was to comprehensively assess retrieved DM polyethylene liners for signs of damage using visual inspection and semi-quantitative geometric assessment techniques.Retrieved DM liners (n=20) were visually inspected for the presence of seven established modes of polyethylene damage. If embedded debris was identified on the external surface, its material composition was characterised using energy-dispersive x-ray analysis (EDX). Additionally, each liner was geometrically assessed for signs of wear/deformation using a validated methodology.Visual inspection of the liners revealed that scratching and pitting were the most common damage modes on either surface. Burnishing was observed on 50% and 15% of the internal and external surfaces, respectively. In addition, embedded debris was identified on 25% of the internal and 65% of the external surfaces. EDX analysis of the debris identified several materials including iron, titanium, cobalt-chrome, and tantalum. Geometric analysis demonstrated highly variable damage patterns across the liners.The results of this study provide insight into the in-vivo mechanics of DM bearings. For example, the results suggest that the internal bearing (i.e., between the head and liner) acts as the primary articulation site for DM-THRs as evidenced by a higher incidence of burnishing and larger, more concentrated regions of penetration across the liners’ internal surfaces. Furthermore, circumferential, and crescent-shaped damage patterns were identified on the articulating surfaces of the liners thus providing evidence that these components can rotate within the acetabular shell with varying degrees of mobility. The mechanics of DM bearings are complex and may be influenced by several factors (e.g., soft tissue fibrosis, patient activities) and thus further investigation is warranted.Finally, the results of this study suggest that DM liners may be susceptible to ex-vivo surface damage and thus caution is advised when handling and/or assessing these types of components.

RETRIEVAL ANALYSIS OF DUAL MOBILITY POLYETHYLENE LINERS FOR TOTAL HIP ARTHROPLASTY

Dual mobility (DM) total hip replacements (THRs) were introduced to reduce dislocation risk, which is the most common cause of early revision. Although DM THRs have shown good overall survivorship and low dislocation rates, the mechanisms which describe how these bearings function in-vivo are not fully understood. Therefore, the study aim was to comprehensively assess retrieved DM polyethylene liners for signs of damage using visual inspection and semi-quantitative geometric assessment methods.Retrieved DM liners (n=18) were visually inspected for the presence of surface damage, whereby the internal and external surfaces were independently assigned a score of one (present) or zero (not present) for seven damage modes. The severity of damage was not assessed. The material composition of embedded debris was characterised using energy-dispersive x-ray analysis (EDX). Additionally, each liner was geometrically assessed for signs of wear/deformation [1].Scratching and pitting were the most common damage modes on either surface. Additionally, burnishing was observed on 50% of the internal surfaces and embedded debris was identified on 67% of the external surfaces. EDX analysis of the debris identified several materials including titanium, cobalt-chrome, iron, and tantalum. Geometric analysis demonstrated highly variable damage patterns across the liners.The incidence of burnishing was three times greater for the internal surfaces, suggesting that this acts as the primary articulation site. The external surfaces sustained more observable damage as evidenced by a higher incidence of embedded debris, abrasion, delamination, and deformation. In conjunction with the highly variable damage patterns observed, these results suggest that DM kinematics are complex and may be influenced by several factors (e.g., soft tissue fibrosis, patient activities) and thus further investigation is warranted.

Microgroove Cues Guiding Fibrogenesis of Stem Cells via Intracellular Force

Groove patterns are widely used in material surface modifications. However, the independent role of ditches/ridges in regulating fibrosis of soft tissues is not well-understood, especially the lack of linkage evidence in vitro and in vivo. Herein, two kinds of combinational microgroove chips with the gradient ditch/ridge width were fabricated by photolithography technology, termed R and G groups, respectively. In group R, the ridge width was 1, 5, 10, and 30 μm, with a ditch width of 30 μm; in group G, the groove width was 5, 10, 20, and 30 μm, and the ridge width was 5 μm. The effect of microgrooves on the morphology, proliferation, and expression of fibrous markers of stem cells was systematically investigated in vitro. Moreover, thicknesses of fibrous capsules were evaluated after chips were implanted into the muscular pouches of rats for 5 months. The results show that microgrooves have almost no effect on cell proliferation but significantly modulate the morphology of cells and focal adhesions (FAs) in vitro, as well as fibrosis differentiation. In particular, the differentiation of stem cells is attenuated after the intracellular force caused by stress fibers and FAs is interfered by drugs, such as rotenone and blebbistatin. Histological analysis shows that patterns of high intracellular force can apparently stimulate soft tissue fibrosis in vivo. This study not only reveals the specific rules and mechanisms of ditch/ridge regulating stem cell behaviors but also offers insight into tailoring implant surface patterns to induce controlled soft tissue fibrosis.

Proton Therapy for Bilateral Breast Cancer Maximizes Normal-Tissue Sparing.

Treatment for bilateral breast cancer with radiation therapy is technically challenging. We evaluated the clinical and dosimetric outcomes of a small series of patients with synchronous bilateral breast cancer, including a photon dosimetric comparison, to identify optimal treatment planning approaches. We reviewed a registry of patients (simultaneously) diagnosed with synchronous bilateral breast cancers who underwent postoperative definitive adjuvant proton therapy at our institution between 2012 and 2021. All patients were treated with double-scattered proton or pencil-beam scanning therapies. For comparison, intensity-modulated radiation therapy photon plans optimized for organ sparing and coverage were generated after treatment. Six patients were included. The median patient age was 66 years; all were female with no history of breast cancer or radiation therapy. Two (33%) patients received breast/chest wall-only treatments, 1 (17%) required breast plus level I axillary treatment to one side and breast plus regional nodal irradiation (RNI) to the other, and 3 (50%) received bilateral breast/chest plus RNI; dosimetric results are reported for each group's median. Analysis showed clinical target coverage was comparable between proton and photon techniques (V95% of 96.4% with proton, 97.8% with photon). However, protons could deliver superior organ sparing at clinically relevant dose metrics for virtually all structures: a 6.7 Gy absolute reduction in the mean heart dose (7.5 Gy with photons to 0.7 Gy with protons), a 47% to 57% relative reduction in D0.1cm3 to coronary arteries, a 54% relative reduction in lung V20 Gy, and an absolute 7.6 Gy reduction to the brachial plexus. There was also greater esophagus and spinal cord sparing. The overall survival rate was 100% at 1.5 years of median follow-up (0.5-4.9), and all patients were free of disease. For toxicity, all patients had some form of acute side effects: 66% experienced grade 2 breast/chest pain or soreness; 100% had grade 2 radiation dermatitis or skin induration; 33% had grade 2 fatigue; and 17% had grade 2 esophagitis (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0; US National Cancer Institute, Bethesda, Maryland). Subacute toxicity (within 6 months) was observed for 17% of patients with delayed onset of grade 3 dermatitis in the setting of preexisting lupus, 17% with a delayed surgical wound complication, and 17% with grade 2 soft tissue fibrosis. No grade 4 or 5 events were observed. Substantial dose reductions to multiple organs at risk while maintaining target coverage make proton the preferred modality for bilateral breast cancer treatment when available.

Abstract P1-10-02: FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer

Abstract Problem Statement: Radiation therapy (RT) for breast cancer (BC) can induce skin and soft tissue fibrosis, raises concerns over cardiac and pulmonary injury, is associated with higher rates of lymphedema and shoulder dysfunction with regional nodal irradiation, and significantly increases complication rates in women undergoing implant-based reconstruction due to radiation toxicity. Although these toxicities are not generally associated with higher mortality, in general, they can represent significant setbacks with respect to quality of life. These toxicities dissuade some patients from breast conservation leading to unnecessary mastectomy and can lead patients to omit reconstruction after mastectomy or choose more extensive autologous breast reconstruction. Women with implant-based reconstruction and radiotherapy have known higher rates of reconstruction failure. Purpose: Ultra-high dose rate radiation (FLASH) has been shown to induce less normal tissue toxicity, therefore if tumor control of FLASH-RT would be comparable to conventional radiotherapy (CONV) then it has the potential to lower morbidity associated with radiotherapy for breast cancer and allow overall improved outcomes. At first, we aimed to determine the effectiveness of FLASH-RT compared to CONV in eradicating small breast tumors in an orthotopic BC model using single-fraction 20 or 30Gy RT to compare effectiveness of FLASH-RT vs CONV. Methods: Radiation sensitive, syngeneic mammary tumor cell line Py117, that efficiently forms non-metastatic orthotopic tumors in C57BL/6 mice, were injected (106 cells) into the left 4th mammary fat pad. 30mm3 tumors or a range of greater volumes (200-800mm3) were irradiated with single-fraction 20 or 30Gy with a 2x2cm radiation field (~17MeV beams), exposing only 5mm of the surrounding tissue. FLASH RT was delivered with 2Gy per pulse at dose rate ~200Gy/s compared to CONV dose rate of 0.13Gy/s Results: Single-fraction 20Gy suppressed 30mm3 tumor growth until ~day 15 post-RT then regrew for both FLASH and CONV, while 30mm3 tumors were eradicated with both FLASH and CONV at 30Gy. Larger tumors irradiated with 30Gy regressed until ~day 12 post-RT then regrew for both FLASH and CONV. There was no significant difference in growth suppression or tumor eradication between FLASH and CONV in any cohort. Conclusion: In this murine model of breast cancer, FLASH is as effective as CONV in controlling tumor growth. Future studies will extend the evaluation of the tumor control using clinically relevant fractionated dose schedules to be followed by comparisons of tumor control in xenograft models. Additional studies will assess normal tissue toxicity of FLASH vs CONV in murine models of implant-based breast reconstruction. We have established collaborations to understand differences in molecular pathways activated by FLASH vs CONV in tumor and normal tissue to explain the observed experimental differences in normal tissue, tumor, and cancer stem cells. Citation Format: Frederick Dirbas, Stavros Melemenidis, Bill Loo, Kathleen Horst, Edward E. Graves, Suparna Dutt, Vignesh Viswanathan, Brianna Lau, Amy Yu. FLASH-RT, ultra-high dose rate rate radiotherapy, is as effective as conventional dose rate radiotherapy in eradicating tumor in a preclinical model of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-02.

Secondary Reconstruction of Head and Neck Cancer Defects-Principles in its Practice.

Secondary reconstruction is requested by patients who have completed their head and neck cancer treatment. The reason for the request for reconstruction may be to improve the functional deficits, achieve aesthetic refinements or most commonly both.The article looks at various issues related to reconstruction in the secondary setting and suggesting the ways to approaching patients requesting secondary reconstruction. While considering secondary reconstruction, various factors need to be considered. These include issues related to the disease, the treatment received as well as the patient's comorbid conditions. Aggressive disease and multiple recurrences should deter from undertaking complex reconstructions. Lack of tissue pliability resulting in a woody neck due to radiation makes dissection difficult and wound healing poor. The reconstructive requirements include release of contractures inside the mouth, reconstruction of the missing jaws, replacement of the missing volume of the tongue and correction of the incompetent angle of mouth. Goals of reconstruction should be prioritized by the surgical team. Free soft tissue or bone containing flaps would be provided ideal tissue to meet the reconstructive requirements in secondary reconstruction. However, several impediments could exist for their safe use. Release of contractures and provision of adequate soft tissue should be given priority and must be addressed before bony reconstruction is contemplated. Bony reconstruction of both mandible and maxilla is possible, with the former being more difficult to deliver good results due to the associated soft tissue fibrosis. Virtual surgical planning with the aid of Stereo lithographic models and planning software will improve the quality of bony reconstruction. Detailed counseling sessions involving patient and the family are essential before embarking on secondary reconstruction as the patient expectations and the surgical outcome may not be easy to match. However excellent improvement in function and appearance will be possible in many patients with appropriate reconstructive procedure.

Spotlight in Plastic Surgery: January 2023.

Spotlight in Plastic Surgery: January 2023.

Clinical Outcomes in Patients Receiving Pencil Beam Proton Re-Irradiation for New or Locoregionally Recurrent Breast Cancer

<h3>Purpose/Objective(s)</h3> Local-regional recurrence of breast cancer (BC) after prior radiation (RT) presents clinical and dosimetric challenges. Proton beam therapy (PBT), and in particular pencil beam scanning (PBS), offers a unique dosimetric advantage due to its lack of exit dose and high conformality, which may allow safer delivery of a second RT course. Recently, there has been a retrospective report of 46 patients (pts) treated with uniform or PBS PBT. Here, we present the largest series to date using PBS PBT. We analyzed treatment patterns, toxicities, and clinical outcomes of BC pts receiving PBS-proton reradiating (reRT). Our hypothesis was that PBS PBT reRT to breast/chest wall (CW) provides reasonable local control (LC) and toxicities. <h3>Materials/Methods</h3> A single-institution retrospective IRB-approved analysis was conducted of all pts who underwent reRT for recurrent or new BC, between 4/2017 and 11/2021. Descriptive statistics were used to describe pt, tumor and treatment characteristics. Local failure-free survival (LFFS), distant metastasis-free survival (DMFS), and overall survival (OS) were measured from reRT start to the first event, by Kaplan-Meier method. Pts who remained alive were censored at last follow-up. Toxicities were scored according to CTCAE v4.0. Comparisons of pts, tumor, and treatment characteristics between those with any grade ≥ 3 acute toxicity (AT) or any late toxicity (LT) vs. none were performed using two-sample t-tests and chi-square tests. Multivariable analysis for LFFS and OS was conducted using cox-proportional hazards models. Statistical software used for analysis. <h3>Results</h3> A total of 68 pts with breast/CW reRT with PBS PBT were identified. Only pts who completed treatment were included in analyses (3 pts were excluded; final N=65). Median follow-up was 26.6 months. The median age was 61 yrs (range 30-89). 60% of pts were white, 32% black and 8% from other races. 65% of treated BCs were hormone positive, 1% HER2/neu enriched and 34% triple negative. Median time between initial and reRT was 52 months (range 6-328). Median cumulative previous RT dose (EQD2) was 48.4 Gy (range 43.2-66.0). Median cumulative PBS PBT dose (EQD2) was 57.0 Gy (range 30.2-76.9). 8 pts (12%) underwent BID treatment, 22 pts (34%) received concurrent hyperthermia and 13 pts (20%) underwent concurrent chemotherapy. 14 pts (22%) experienced grade 3 AT, including 13 dermatitis (20%) and 1 fatigue and pain (1.5%). No grade 4/5 toxicities were observed. 6 pts were lost in follow-up. 33 pts (56%) experienced any grade LT (skin changes [N=21; 36%], soft tissue fibrosis [N=7; 12%], CW discomfort [N=10; 17%], arm discomfort [N=6; 10%], lymphedema [N=11; 19%] and rib fracture [N=3; 5%]). At 2 yrs, LFFS=93% and DMFS=88%. OS was 89%. No explanatory variables were associated with toxicity or survival outcomes <h3>Conclusion</h3> Our analysis indicates that PBS PBT reRT for BC is well tolerated and offers meaningful rates of LC, toxicities and survival.

Reirradiation with Photon Radiotherapy for Recurrent or New Primary Breast Cancer after Prior Breast Irradiation

<h3>Purpose/Objective(s)</h3> Recurrent or new primary breast cancer may benefit from the local and/or regional recurrence risk reduction provided by RT, but delivery of a repeat course of RT is challenging due to risks of potential serious toxicities to organs at risk. This has led to limited use and heterogeneous practice patterns of salvage RT delivery. We hypothesize that breast cancer reirradiation (reRT) may be feasible using modern photon treatment techniques, and we present clinical outcomes and toxicities from a large single institution cohort. <h3>Materials/Methods</h3> In an IRB-approved retrospective study, all consecutive patients with recurrent or new primary non-metastatic breast cancer treated with breast or chest wall (CW) RT and photon reRT from a single institution were identified. Patient and tumor characteristics, treatment parameters, clinical outcomes and toxicities were collected. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) were defined from reRT start to date of any recurrence, distant recurrence, and death or last follow-up and estimated using Kaplan-Meier methodology. <h3>Results</h3> In total, 126 consecutive patients treated with reRT from 2013-2020 met criteria for analysis. Median age at reRT was 65 years (range 39-88). ReRT was delivered with 3DCRT in 47.6%, VMAT in 46.0%, and static IMRT in 6.4%. Median first, second, and cumulative prescription doses were 60.0 Gy, 46.4 Gy, and 105.0 Gy, respectively. Most received whole breast (WB) (80.2%) or partial breast (PB) (8.7%) initial RT. At reRT, 30.9% were treated to the PB, 11.1% WB/CW, 37.3% WB/CW with comprehensive regional lymph nodes (LN), and 12.8% WB/CW with partial regional LN. Median time between RT courses was 95 months (range 10-361). At a median follow-up of 26.5 months, 9 patients had died. Locoregional, distant, and any recurrence developed in 15 (11.9%), 22 (17.5%), and 28 (22.2%) patients, respectively. Estimated 3-year RFS was 80.7%, DMFS was 80.9%, and OS was 93.2%. Eleven (8.7%) patients developed grade 3 (G3) toxicities (dermatitis (n=8), acute (n=1) and late (n=1) CW pain, decreased joint range of motion (ROM) (n=1)); no G4 or G5 toxicities occurred. Five (4.0%) patients developed rib fracture. Of 23 patients retreated to a reconstructed CW, 30.4% and 34.8% developed Baker G1-2 or G3-4 implant contracture, respectively. Four patients had significant brachial plexus overlap, of whom 1 developed G2 decreased joint ROM and G2 soft tissue fibrosis and 1 developed G3 decreased joint ROM. <h3>Conclusion</h3> In the largest institutional experience to date on the use of photon reRT for recurrent or new primary breast cancer, reRT is associated with low rates of severe adverse events. In this high-risk population, locoregional and distant disease control rates are high. Further prospective study is needed to define the optimal treatment volume, prescription dose selection, and cumulative dose constraints with reRT to maximize the likelihood for successful and safe salvage therapy.

The role of Vitamin D3 in ocular fibrosis and its therapeutic potential for the glaucomatous trabecular meshwork.

Glaucoma is the leading cause of irreversible blindness globally. The most prevalent subtype, Primary Open Angle Glaucoma (POAG), is characterized by increased intraocular pressure (IOP), damage to the optic nerve head and irreversible visual loss. IOP increases aqueous humor (AqH) outflow is reduced through the trabecular meshwork (TM) and Schlemm's canal (SC). Increased outflow resistance is partly due to TM/SC dysregulation, including loss of normal trabecular meshwork cell (TMC) function, following increased levels of oxidative stress within TMC, dysregulated extracellular matrix (ECM) deposition and remodeling alongside alterations in TMC phenotype and apoptosis. Current widely available POAG treatments do not target the aberrant expression of ECM in the TM directly. As a result, most drug treatments can fail as the underlying pathological process continues unabated. Rho-kinase inhibitors have demonstrated the benefit of restoring TM/SC function, however there is a clear need to develop further treatment strategies that can target the underlying cellular processes which become dysregulated within the TMC during POAG pathogenesis. Vitamin D is suggested to be beneficial in alleviating the symptoms of fibrosis and inflammation in soft tissues. It has important functions in many major organ systems, including regulation of calcium, phosphate and parathyroid hormone. Evidence suggests that Vitamin D3 modulates ECM turnover through the conventional TGFβ-SMAD signaling, which is associated with the development of POAG. The link between Vitamin D3, inflammation and fibrosis within ocular tissues will be discussed and the potential roles of Vitamin D3 in the management of POAG patients will be explored within this review.