Regrowth Rate Research Articles

Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer – Multi-centre study

Background and purposeRadical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery. Materials and methodsThis retrospective multi-centre study (2009–2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer. ResultsWith a median follow-up of 26(IQR:12–49) months, initial clinical Complete Response (cCR) was 82(70–93)% with rates of local regrowth 18(8–29)%, 3-year actuarial local control (LC) 84(75–95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48–78)% and 58(44–75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients. ConclusionCXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery.

Cryopreservation of Arum palaestinum plant callus as a strategy for mitigating extinction risks

Arum palaestinum is a wild perennial plant commonly known as "Al-Loof" in Jordan. Due to overharvesting, climate change, and increasing demand, its natural populations are threatened with extinction. Cryopreservation, an effective method for conserving plant material at ultra-low temperatures, is explored for A. palaestinum calli. We investigated the applicability of encapsulation-vitrification (using different plant vitrification solutions (PVS) and incubation times), encapsulation-dehydration (using sucrose or sorbitol at different concentrations and dehydration times), and the v-cryoplate (using different pre-culture times and temperatures) techniques. In the encapsulation-vitrification experiment, a notable 82.4 % regrowth rate was achieved by desiccating calli in plant vitrification solution 2 (PVS2) for 10 minutes at 25 °C. The encapsulation-dehydration technique resulted in an 82.6 % regrowth rate by incubating calli for one day in low sucrose levels (0.1 M sucrose) following one hour of air dehydration, where the moisture content of the beads was 30 %. The moisture content of the beads decreased from 81 % before chemical and air dehydration to 71 % after 0 hours of air dehydration combined with chemical dehydration using 0.1 M sucrose or sorbitol. It further dropped to 30–34 % after one day of chemical dehydration with 0.1 M sucrose and 1 hour of air dehydration. The v-cryoplate technique successfully conserved calli, showing impressive survival and regrowth percentages (96.8 %) when the callus was pre-cultured with 0.3 M sucrose for three days at 5 °C. Temperature during pre-culture significantly influenced regrowth percentages in the v-cryoplate technique. The study establishes promising cryopreservation protocols for A. palaestinum calli, offering a means to conserve germplasm and contribute to environmental and biodiversity protection by reintroducing endangered plants to their native habitats.

A complete facet resection and cervical pedicle screw placement enhances both gross total resection and motion preservation for the cervical spinal dumbbell tumor

To describe single-index-level fusion surgery using a cervical pedicle screw (CPS) after the complete facet resection of spinal dumbbell tumors and to compare it with partial facet resection without fusion. We retrospectively reviewed patients who underwent surgery for dumbbell-shaped cervical spine tumors. They were categorized into the fused group (complete facet resection with fusion using CPS) and the unfused group (partial facet resection without fusion). We compared demographics, tumor characteristics, resection rates (gross total, subtotal, or partial), and regrowth rates between the groups. Complete facet resection was performed for maximal tumor removal. In the fused group, single-index-level fusion was achieved using CPS. Despite tumor-associated erosion of the index vertebra's pedicle and/or lateral mass, the CPS was directly inserted into the vertebral body through an imaginary virtual pedicle without a lateral mass or pedicle purchase. A total of 34 patients underwent surgery for dumbbell-shaped cervical tumors; half were classified into each group. There were no significant differences in demographic or tumor characteristics, including Asazuma classification, or histological diagnosis (P > 0.05). However, the gross total resection rate was significantly higher in the fused group (16/17, 94.1% vs 9/17, 52.9%; P-value = 0.011). Tumor recurrence was observed in three (17.6%) patients in the unfused group; no recurrence (0%) occurred in the fused group. Complete facet resection with fusion using CPS significantly increased the gross total tumor removal rate, compared with partial resection without fusion. Therefore, CPS improved fusion surgery for maximal motion preservation, resulting in single-level fusion surgery.

8801 Towards Safe and Efficacious Medical Therapy for Patients with Clinically Non-Functioning Pituitary Tumors

Abstract Disclosure: D. Zhang: None. M. Bergsneider: None. W. Kim: None. M.B. Wang: None. H. Vinters: None. A.P. Heaney: None. Clinically non-functioning pituitary tumors (CNFTs) account for one-third of all pituitary adenomas. They do not cause clinical and/or biochemical evidence of tumor-related hormone hypersecretion, grow insidiously and typically present with mass effect symptoms such as headache and visual field deficits. Surgical resection is the current standard of care for CNFTs but complete resection is infrequently achieved due to their size and invariable invasion of locally adjacent structures. CNFT remnant tumor regrowth rates approach 50% and these patients may need repeat surgery and/or radiotherapy (RT). The latter is quite effective in achieving tumor control, but carries a risk of hypopituitarism of ∼ 40% at 10 years. Although dopamine agonists and somatostatin receptor ligands have been explored as medical therapy, there are currently no consistently effective medical treatments for CNFTs. There is a clear unmet need for novel safe and effective medical therapies for these comparatively common tumors. In a highly innovative approach we have used patient-derived ex vivo 3D tumoroid human CNFTs in an automated high throughput compound screen (HTS) to identify novel tumoricidal and growth inhibitory compounds for CNFTs. To date, we have screened ∼4,000 compounds and have identified 13 potential hits that inhibited tumor cell proliferation (a reduction of 76±15%) and induced apoptosis (induction rate of 8.2 ± 6.6) in the CNFT tumoroids respectively. The hit compounds to date fall into 3 categories based on their targets, namely Na+/K+-ATPase inhibitors (n=6), reactive oxygen species (ROS) regulators (n=4), and cell cycle inhibitors (n=3). Representative “hit” compounds from each group identified in our primary screen were rescreened in triplicate in 20 concentrations from 25µM to 50pM at 2-fold dilutions. Dose-response curves characterized compound doses that inhibited cell viability by 50% (IC50) and ranged from 13nM to 103nM. Two of these 3 compounds also induced 2-3-fold apoptosis at 0.1uM with the final compound displaying a potent 5-10-fold pro-apoptotic effect at 0.15uM concentration. In parallel, we used single cell RNA sequencing to validate targets that emerged from our HTS and to characterize the mechanism of action (MOA) of these hit compounds. As proof of concept, several of the known drug targets were noted to be amongst the highest differentially expressed genes in the CNFT tumor cell population. This approach validating a candidate target in conjunction with demonstrable activity of a drug for that same target in CNFTs may simultaneously provide us with a back-bone molecule to further develop with structural activity relationship analysis and/or allow us to individualize drug choice in patients based on immunocytochemical tumor target expression. Presentation: 6/1/2024

The use of electrical stimulation to enhance recovery following peripheral nerve injury.

Peripheral nerve injury is common and can have devastating consequences. In severe cases, functional recovery is often poor despite surgery. This is primarily due to the exceedingly slow rate of nerve regeneration at only 1-3 mm/day. The local environment in the distal nerve stump supportive of nerve regrowth deteriorates over time and the target end organs become atrophic. To overcome these challenges, investigations into treatments capable of accelerating nerve regrowth are of great clinical relevance and are an active area of research. One intervention that has shown great promise is perioperative electrical stimulation. Postoperative stimulation helps to expedite the Wallerian degeneration process and reduces delays caused by staggered regeneration at the site of nerve injury. By contrast, preoperative "conditioning" stimulation increases the rate of nerve regrowth along the nerve trunk. Over the past two decades, a rich body of literature has emerged that provides molecular insights into the mechanism by which electrical stimulation impacts nerve regeneration. The end result is upregulation of regeneration-associated genes in the neuronal body and accelerated transport to the axon front for regrowth. The efficacy of brief electrical stimulation on patients with peripheral nerve injuries was demonstrated in a number of randomized controlled trials on compressive, transection and traction injuries. As approved equipment to deliver this treatment is becoming available, it may be feasible to deploy this novel treatment in a wide range of clinical settings.

A global dataset of forest regrowth following wildfires

Wildfires result in forest loss or degradation and release substantial emissions into the atmosphere. Forest regrowth following these fires allows for ecosystem repair and carbon replenishment. However, there is a lack of datasets explicitly characterizing the forest regrowth after fires. Here we employed multiple remotely sensed datasets to generate the first global maps of forest structure regrowth including forest height, aboveground biomass (AGB), leaf area index (LAI), and fraction of photosynthetically active radiation (FPAR) following wildfires at a 30 m spatial resolution. The regrowth index for each structural parameter includes regrowth ratio and rate at 5-year intervals, primarily from 2000 to 2020. The dataset developed in this study provides detailed insights into the characteristics of global forest regrowth following forest fires in both spatial and temporal dimensions, contributing to the assessment of forest ecology equilibrium and the quantification of forest carbon dynamics.

Evaluating mangrove community forestry outcomes: a mixed synthetic control and field-based approach

Abstract Contemporary evaluations of outcomes in human-managed systems have been constrained by a lack of counterfactual analysis. Community forestry (CF), a widely adopted strategy to achieve both conservation and management in coupled human-environment systems, is no exception, and counterfactual analysis would greatly enhance CF research. We used a mixed method approach incorporating quantification of deforestation and forest regrowth rates, synthetic control analysis, and focus groups discussions to evaluate mangrove CF outcomes in the Ayeyarwady Delta, Myanmar, from to 1990–2021. CF resulted in an overall increase in net forest gain and reduction in net forest loss across sites. More than two-thirds of CF sites had superior outcomes relative to synthetic controls for at least one metric (deforestation or forest regrowth); however, CF tended to perform better for only one outcome while avoiding underperformance in the other. The annual rate of forest regrowth in CFs accelerated beginning three years prior to certification and peaked two years after certification, likely related to pre-certification engagement with the Forest Department or non-government organizations. Moreover, control sites near CFs experienced more rapid forest regrowth than controls further from CFs, suggesting spillover effects. The predominant challenge facing successful CF management was illegal extraction and overharvesting, and poor performing CFs experienced a complex array of challenges facing forest regrowth, likely related to the private nature of individual land claims within the CFs. Most supporting factors for CF were related to community management capacity, strongly indicating a need for extended close engagement with competent government and non-government actors to develop long-term management and governance capacities, which are sustainably funded. Our mixed-method approach can be replicated in other human-managed systems to evaluate the biophysical impacts of policies and gain insights into the underlying drivers of outcomes.

Cryopreservation of zygotic embryos derived from BBTV resistant accessions of wild banana Musa acuminata

The wild banana species Musa acuminata encompasses numerous subspecies, some of which serve as ancestors of edible bananas. Preserving these subspecies is critical for food security, especially in regions where bananas are staple crops. While cryopreservation of M. acuminata subsp. burmanicoides zygotic embryos using air dehydration have shown high success rates, this method has not been effective for other subspecies. With at least 15 subspecies displaying various morphological traits, including seed morphology, alternative cryopreservation methods warrant exploration. In a recent study, successful cryopreservation using the droplet-vitrification method was achieved for mature zygotic embryos of accession of M. acuminata subspecies tomentosa, rutilifes, and malaccensis, all of which are resistant to the Banana bunchy top virus (BBTV). Using this approach, subjecting embryos to dehydration for 20 min in PVS2 solution and employing a regeneration medium comprising MS medium supplemented with benzyladenine and thidiazuron resulted in a success rate of 77.4 % (86 % survival rate × 90 % regrowth rate) for subsp. tomentosa and 50.4 % (70 % survival rate × 72 % regrowth rate) for subsp. malaccensis. Conversely, for subsp. rutilifes, dehydration for 10 min led to a success rate of 15.6 % (30 % survival rate × 52 % regrowth rate). Subspecies emerged as the primary factor influencing embryo regrowth, suggesting the need for protocol optimizations tailored to other subspecies. These findings highlight the potential of droplet-vitrification as a long-term preservation method for certain subspecies, while underscoring the necessity for further optimization for the other subspecies of M. acuminata.

Perseverance of management is needed – Efficient long-term strategy of Reynoutria management

One of the most problematic invasive species in Europe are knotweeds from genus Reynoutria (Fallopia) which have significant negative impact on the native communities as well on human activities. Therefore, they are a target of many control programmes. Due to their high regeneration potential, their management is problematic, and only chemical treatment is reported to be sufficiently effective. The aim of this paper was to describe and analyse the patterns of Reynoutria invasion under long-term chemical treatment with glyphosate-based herbicide in The Morávka river floodplain, Czech Republic. The data covers 17 years of management which started with the European project “Preservation of alluvial forest habitats in the Morávka river basin”. We focus on (i) assessment of Reynoutria distribution during long-term management, (ii) analysis of the change of distribution according to the habitat, and (iii) discussion of the optimal management strategy based on the long-term data. Distribution data was obtained using GNSS field mapping. Before the start of the study in 2007, Reynoutria stands covered 29% of the study area (96.9 ha). As a result of systematic whole area chemical management, the extent decreased to 19.6% (65.3 ha) in 2009, and even reached 14.5% (48.2 ha) in 2013, three years after its end. Due to implementation of local chemical management in the following years, the area of Reynoutria was maintained at similar level, with minimum value 41.8 ha in 2018 and a slight increase in recent mapping in 2023. Beside the extent, the structure and coverage of invaded sites was analysed. There was a clear trend of fragmentation of larger polycormons with high coverage into many smaller and less dense ones as a result of chemical spraying. The average size of Reynoutria stand decreased from 0.61 ha in 2007 to half in 2013 (0.32 ha) to 0.15 ha in 2023. Testing of the effects of time, habitat, and biotope did not reveal significant differences of changes of extent and abundance over different environments (forest, open, bare ground), which indicates that there are no differences in reaction to management in the studied habitat and vegetation types. Our study provides a robust and unique overview of the invasion, reinvasion, and suppression dynamics for an important invasive species. If herbicide management is used, chemical treatment must be quite long-term as even three years of intensive glyphosate foliar spray application was not sufficient for the complete eradication of Reynoutria. Therefore, we propose the following procedure for effective chemical management of Reynoutria: 1) In largely infested sites, the first step is to reduce the distribution of Reynoutria stands to isolated polycormons. This phase can last 3–5 years. 2) After reaching the state of sparse distribution of Reynoutria, we recommend herbicide application only in periods of every 3–5 years depending on the local context and rate of regrowth. 3) At sites exposed to soil disturbances, where the soil is contaminated by fragments of Reynoutria rhizomes, there is a need to apply herbicide immediately to target newly resprouting individuals.

Topical immunotherapy with diphenylcyclopropenone in paediatric patients with alopecia areata-A retrospective study of 97 patients.

Alopecia areata (AA) is an autoimmune disease causing chronic non-scarring hair loss. Different therapeutic regimens have been suggested for AA, which depend on patients' age, scalp involvement extent and duration. Topical immunotherapy with diphenylcyclopropenone (DPCP) is one of the treatment options for these patients. We aimed to investigate the response to DPCP in paediatric AA patients. This retrospective study included 97 paediatric AA patients followed in the DPCP clinic from March 2016 to March 2021 at a referral dermatology hospital. In a cohort of 97 paediatric patients with AA under treatment with DPCP, with a mean age of 11.10±0.9, 53.6% of the patients were male. Patchy alopecia was the most prevalent type (45.4%). After 6months of DPCP treatment, 51.5% showed no response, while 3.1% achieved complete response. At the 12-month evaluation, among the 68 patients who continued treatment, complete response was observed in 8.8%. A significant positive correlation was found between alopecia type, specifically patchy, and treatment response (p=0.031). Additionally, treatment duration emerged as a significant predictor of positive response at both six (OR 1.450, p=0.026) and 12months (OR 1.310, p=0.043). A higher initial Severity of Alopecia Tool score was inversely correlated with treatment response (Spearman's rho -0.14, p=0.002), indicating that initial disease severity may predict treatment efficacy. One year after the onset of DPCP in paediatric AA patients, the complete response and any hair regrowth rates were 8.8% and 61.8%, respectively. The milder initial disease severity and longer duration of treatment resulted in a better response.

Safety and efficacy of stent-assisted coiling ruptured intracranial aneurysms: A single-center experience

ABSTRACT Objective: Endovascular coiling is a minimally invasive method to manage intracranial aneurysms. However, patients who undergo stent-assisted coiling (SAC) for acutely ruptured intracranial aneurysms need dual antiplatelet treatment. We reported our experience and outcomes of SAC for ruptured intracranial aneurysm. Materials and Methods: We retrospectively collected data on procedure-related complications, rates of aneurysm rebleeding and recurrence, and clinical outcomes of patients with ruptured aneurysms managed by SAC over 2 years. Results: Among the 17 patients included in this study, there were 14 (82.4%) women and 3 (17.6%) men, with a mean age of 58.59 years (standard deviation = 13.57; range: 40–82 years). There were no periprocedural hemorrhagic complications and no aneurysm rebleeding before discharge. However, two patients developed acute brain infarction because of symptomatic vasospasm. Linear regression revealed significant associations of posterior circulation involvement with the Glasgow Outcome Score and modified Rankin Scale (mRS) at discharge and 6 months after. Besides, Hunt and Hess grade ≥3 has a significant association with mRS at discharge, 6 months, and 1 year after. Conclusion: SAC for ruptured aneurysm was technically feasible and did not carry an additional risk of postoperative aneurysm rebleeding secondary to antiplatelet treatment. Moreover, it had relatively low rates of aneurysm regrowth and coil compaction. Therefore, it can be a safe and effective endovascular treatment for acutely ruptured intracranial aneurysm.

The Norwegian Watch and Wait study: Norwait for rectal cancer. A report from a failed study-a word of caution.

The paucity of prospective data on the subject of Watch and Wait for rectal cancer prompted the implementation of Norwait, a population-based study including rectal cancer patients after neoadjuvant therapy. The aim of the study was to assess the accuracy of clinical complete response (cCR) and quantify the regrowth rates. Norwait was a prospective population-based observational study with ethical approval (2017/935) registered at clinicaltrials.com (NTC03402477). Residents of Norway with histologically proven rectal cancer located within 15cm from anal verge were eligible following completion of radiotherapy or chemoradiation at seven hospitals. cCR was the disappearance of tumour and of any ulcer with/without the appearance of whitening of prior tumour site and telangiectasia evaluated at 12weeks by digital rectal exam, and endoscopic imaging. The study aimed to include 100 cCR patients with regrowth rates as primary endpoint. The data are presented in crude form. Eighty-two patients were included in seven hospitals from 2018 to 2020 when the study was terminated. Fifty-one patients were included in six hospitals, whereas protocol violations were identified in one hospital, where thirty-one (rather than protocol-estimated 12) patients were enrolled. Amongst the 31 patients, there were only 2 with documented cCR. Of the latter 29, there were 16 with ulcer or persistent tumour, and 13 without any documentation of cCR. Of these, 23 underwent surgery with a delay up to 50weeks. At median 54-month follow-up of 31 patients, there were 77% local regrowths (n = 23), 40% metachronous metastases (n = 12) and 23% deaths (n = 7). At median 54-month follow-up of 51 cCR patients, there were 53% local regrowths (n = 27), 14% metachronous metastases (n = 7) and 4% deaths (n = 2). Norwait admonishes a word of caution reaching beyond the inconclusive results of a population-based study jeopardised by serious violation to protocol and legislation for conducting safe research.

The Rates of Natural Regrowth of Fagus orientalis L. Species in Forest Coexistences of Gugark Region of Lori Marz

The Rates of Natural Regrowth of Fagus orientalis L. Species in Forest Coexistences of Gugark Region of Lori Marz

A 6-year single-center prospective follow-up study of the efficacy of radiofrequency ablation for thyroid nodules.

Radiofrequency ablation (RFA) is an alternative modality for thyroid nodules (TNs) and many studies have also confirmed its favorable efficacy and safety. The scope of RFA increases in clinical practice and the aim of our study was to evaluate the efficacy of RFA. We conducted a prospective study to evaluate the efficacy of RFA for thyroid nodules between January 2017 and December 2022 at our institution. We assessed the change in nodal volume, volume reduction ratio (VRR), technique effective (TE) rate, complete ablation (CA) rate, and nodal regrowth rate and time after RFA. We performed RFA for 1703 patients with TNs between January 2017 and December 2022, of which a total of 970 eligible patients were enrolled in the study. The preoperative volume of TNs was 6.23 ± 8.11ml, with 821 benign and 149 malignant nodules. The post-RFA TE and adjusted TE rate were 80% and 88.8%, respectively. CA was achieved in 145 (14.9%) patients with a mean time of 18.32± 12.98 months; nodal regrowth occurred in 15 (1.5%) patients with a mean time of 29.80 ± 12.47 months. TNs volume and VRR changed significantly at years 1 and 2 after RFA and stabilized after 5 years. A serious postoperative adverse event occurred in one patient with cervical sympathetic chain injury resulting in Horner's syndrome. A transient or permanent damage of the recurrent laryngeal nerve could not be evaluated due to the lack of postoperative laryngoscopy, and this is a significant limitation of the study. The expanded RFA indications were also effective for TNs, with no significant change in long-term efficacy.

Satellite glial cell manipulation prior to axotomy enhances developing dorsal root ganglion central branch regrowth into the spinal cord.

The central and peripheral nervous systems (CNS and PNS, respectively) exhibit remarkable diversity in the capacity to regenerate following neuronal injury with PNS injuries being much more likely to regenerate than those that occur in the CNS. Glial responses to damage greatly influence the likelihood of regeneration by either promoting or inhibiting axonal regrowth over time. However, despite our understanding of how some glial lineages participate in nerve degeneration and regeneration, less is known about the contributions of peripheral satellite glial cells (SGC) to regeneration failure following central axon branch injury of dorsal root ganglia (DRG) sensory neurons. Here, using in vivo, time-lapse imaging in larval zebrafish coupled with laser axotomy, we investigate the role of SGCs in axonal regeneration. In our studies we show that SGCs respond to injury by relocating their nuclei to the injury site during the same period that DRG neurons produce new central branch neurites. Laser ablation of SGCs prior to axon injury results in more neurite growth attempts and ultimately a higher rate of successful central axon regrowth, implicating SGCs as inhibitors of regeneration. We also demonstrate that this SGC response is mediated in part by ErbB signaling, as chemical inhibition of this receptor results in reduced SGC motility and enhanced central axon regrowth. These findings provide new insights into SGC-neuron interactions under injury conditions and how these interactions influence nervous system repair.

Micropropagation and Shoot Tip Cryopreservation of 'Sunny Gold' Freesia.

Cryopreservation is a promising method for the long-term preservation of plant germplasm, especially for vegetatively propagated species like freesias. In this study, we investigate streamlining the cryopreservation process for 'Sunny Gold' Freesia, starting from effective in vitro initiation and proliferation using various plant growth regulator combinations. We also assess the impact of subculture on regrowth rates after cryopreservation. The shoot tips were successfully initiated in vitro after sterilization. The shoots were multiplied an average of three times in media containing N6-benzyladenine and kinetin. The regrowth rates of non-cryopreserved shoot tips excised from different subculture cycles did not differ significantly, with rates of 44% observed for plants from more than five subcultures and 47% for those from three subcultures. However, only the shoot tips excised from cultures subjected to three subculture cycles were able to recover after cryopreservation, with a regrowth rate of 31%. Our findings lay the groundwork for the development of an efficient cryopreservation protocol for freesias in the future.

Genome-Wide DNA Methylation Profiling as a Prognostic Marker in Pituitary Adenomas-A Pilot Study.

The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been proposed, but no study has linked this epigenetic variance with regrowth potential and the clinical heterogeneity of nonfunctioning pituitary adenomas. This study aimed to investigate whether DNA methylation profiling can be useful as a clinical prognostic marker. A DNA methylation analysis by Illumina's MethylationEPIC array was performed on 54 pituitary macroadenomas from patients who underwent transsphenoidal surgery during 2007-2017. Twelve patients were excluded due to an incomplete postoperative follow-up, degenerated biobank-stored tissue, or low DNA methylation quality. For the quantitative measurement of the tumor regrowth rate, we conducted a 3D volumetric analysis of tumor remnant volume via annual magnetic resonance imaging. A linear mixed effects model was used to examine whether different DNA methylation clusters had different regrowth patterns. The DNA methylation profiling of 42 tissue samples showed robust DNA methylation clusters, comparable with previous findings. The subgroup of 33 nonfunctioning pituitary adenomas of an SF1-lineage showed five subclusters with an approximately unbiased score of 86%. There were no overall statistically significant differences when comparing hazard ratios for regrowth of 100%, 50%, or 0%. Despite this, plots of correlated survival estimates suggested higher regrowth rates for some clusters. The mixed effects model of accumulated regrowth similarly showed tendencies toward an association between specific DNA methylation clusters and regrowth potential. The DNA methylation profiling of nonfunctioning pituitary adenomas may potentially identify adenomas with increased growth and recurrence potential. Larger validation studies are needed to confirm the findings from this explorative pilot study.

Predicting overall survival from tumor dynamics metrics using parametric statistical and machine learning models: application to patients with RET-altered solid tumors.

In oncology drug development, tumor dynamics modeling is widely applied to predict patients' overall survival (OS) via parametric models. However, the current modeling paradigm, which assumes a disease-specific link between tumor dynamics and survival, has its limitations. This is particularly evident in drug development scenarios where the clinical trial under consideration contains patients with tumor types for which there is little to no prior institutional data. In this work, we propose the use of a pan-indication solid tumor machine learning (ML) approach whereby all three tumor metrics (tumor shrinkage rate, tumor regrowth rate and time to tumor growth) are simultaneously used to predict patients' OS in a tumor type independent manner. We demonstrate the utility of this approach in a clinical trial of cancer patients treated with the tyrosine kinase inhibitor, pralsetinib. We compared the parametric and ML models and the results showed that the proposed ML approach is able to adequately predict patient OS across RET-altered solid tumors, including non-small cell lung cancer, medullary thyroid cancer as well as other solid tumors. While the findings of this study are promising, further research is needed for evaluating the generalizability of the ML model to other solid tumor types.

Double-modified, thio and methylene ATP analogue facilitates wound healing in vitro and in vivo

Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP analogue—alpha-thio-beta,gamma-methylene-ATP as a potential therapeutic agent for a skin regeneration. For the better understanding of structure–activity relationship, beside tested ATP analogues, the appropriate single-modified derivatives of target compound, such as alpha-thio-ATP and beta,gamma-methylene-ATP, were also tested in the context of their involvement in the activation of ATP-dependent purinergic signaling pathway via the P2Y2 receptor. The diastereomerically pure alpha-thio-modified-ATP derivatives were obtained using the oxathiaphospholane method as separate SP and RP diastereomers. Both the single- and double- modified ATP analogues were then tested for their impact on the viability and migration of human keratinocytes. The involvement of P2Y2-dependent purinergic signaling was analyzed in silico by molecular docking of the tested compounds to the P2Y2 receptor and experimentally by studying intracellular calcium mobilization in the human keratinocytes HaCaT. The effects obtained for ATP analogues were compared with the results for ATP as a natural P2Y2 agonist. To confirm the contribution of the P2Y2 receptor to the observed effects, the tests were also performed in the presence of the selective P2Y2 antagonist—AR-C118925XX. The ability of the alpha-thio-beta,gamma-methylene-ATP to influence cell migration was analyzed in vitro on the model HaCaT and MDA-MB-231 cells by wound healing assay and transwell migration test as well as in vivo using zebrafish system. The impact on tissue regeneration was estimated based on the regrowth rate of cut zebrafish tails. The in vitro and in vivo studies have shown that the SP-alpha-thio-beta,gamma-methylene-ATP analogue promotes regeneration-related processes, making it a suitable agent for enhance wound healing. Performed studies indicated its impact on the cell migration, induction of epithelial–mesenchymal transition and intracellular calcium mobilization. The enhanced regeneration of cut zebrafish tails confirmed the pro-regenerative activity of this ATP analogue. Based on the performed studies, the SP-alpha-thio-beta,gamma-methylene-ATP is proposed as a potential therapeutic agent for wound healing and skin regeneration treatment.

Cost-effectiveness of short-course radiotherapy versus long-course chemoradiation in organ preservation for locally advanced rectal cancer.

11089 Background: Short-course radiation therapy (SCRT) has previously been found to be cost-effective compared to long-course chemoradiation (LCRT) for patients with locally advanced rectal cancer undergoing operative management. However, non-operative management protocols have recently become a standard treatment option for patients diagnosed with locally advanced rectal cancer achieving a complete clinical response after total neoadjuvant therapy (TNT) as surgery has significant impacts on quality of life. Recent data suggests higher rates of local regrowth and a correspondingly lower rate of organ preservation with SCRT-TNT compared to LCRT-TNT. With this study, we evaluated the cost-effectiveness of SCRT versus LCRT in the setting of non-operative management for locally advanced rectal cancer. Methods: We built a microsimulation model to simulate 5-year outcomes for 1 million hypothetical patients aged 65 years with locally advanced rectal cancer treated with TNT including either SCRT or LCRT. Patients achieving a complete clinical response with TNT opted for a non-operative management approach, undergoing surgery only with subsequent local progression. Patients not achieving a complete clinical response went directly to surgery. The model incorporated costs, quality of life (measured by health utility), and probabilities of disease progression and death. We extracted probabilities of disease progression and death and health utilities from published literature. We assessed costs from the healthcare payer perspective. We measured cost-effectiveness with incremental cost-effectiveness ratio (ICER), with ICERs under $100,000 per quality-adjusted life-year (QALY) considered cost-effective. One way and probabilistic sensitivity analyses were used to test model uncertainty. Results: We found that compared to SCRT, LCRT increased overall cost by $10,457 and improved effectiveness by 0.16 QALYs resulting in an ICER of $67,200/QALY. The model was most sensitive to assumptions about risks of local recurrence in the non-operative setting, the health utility of non-operative management, and the costs of LCRT and SCRT. The model was not sensitive to assumptions about costs of diagnostic evaluation (i.e. flexible sigmoidoscopy) and probability of distant recurrence. Probabilistic sensitivity analysis demonstrated that LCRT was cost-effective in 91% of iterations. Conclusions: Long-course chemoradiation could represent a cost-effective strategy compared with short-course radiotherapy in the non-operative management of patients with locally advanced rectal cancer. The ongoing ACO/ARO/AIO-18.1 trial testing the hypothesis that LCRT-TNT will increase organ preservation rates relative to SCRT-TNT will help confirm these findings.