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Gut May 2024Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known...
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies.
DESIGN
We used the KPC mouse model () and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent coculture assays, mouse and zebrafish tumorigenesis studies, and database approaches were performed.
RESULTS
Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC.
CONCLUSIONS
This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
PubMed: 38754953
DOI: 10.1136/gutjnl-2023-330995 -
European Journal of Surgical Oncology :... Apr 2024Neoadjuvant chemotherapy (NAC) has a profound impact on surgical management of breast cancer. For this reason, the Italian Association of Breast Surgeons (ANISC)...
Third national surgical consensus conference of the Italian Association of Breast Surgeons (ANISC) on management after neoadjuvant chemotherapy: The difficulty in reaching a consensus.
INTRODUCTION
Neoadjuvant chemotherapy (NAC) has a profound impact on surgical management of breast cancer. For this reason, the Italian Association of Breast Surgeons (ANISC) promoted the third national Consensus Conference on this subject, open to multidisciplinary specialists.
MATERIALS AND METHODS
The Consensus Conference was held on-line in November 2022, and after an introductory session with five core-team experts, participants were asked to vote on eleven controversial issues, while results were collected in real-time with a polling system.
RESULTS
A total of 164 dedicated specialists from 74 Breast Centers participated. Consensus was reached for only three of the eleven issues, including: 1) the indication to assess the response with Magnetic Resonance Imaging (79 %); 2) the need to re-assess the biological factors of the residual tumor if present (96 %); 3) the possibility of omitting a formal axillary node dissection for cN1 patients if a pathologic Complete Response (pCR) was confirmed with analysis of one or more sentinel lymph nodes (82 %). The majority voted in favor of mapping both the breast and nodal lesions pre-NAC (59 %), and against the omission of sentinel lymph node biopsy in cN0 patients in the case of pathologic or clinical Complete Response (69 %). In cases of cT3/cN1+ tumors with pCR, only 8 % of participants considered appropriate the omission of Post-Mastectomy Radiation Therapy.
CONCLUSION
There is still a wide variability in surgical approaches after NAC in the "real world". As NAC is increasingly used, multidisciplinary teams should be attuned to conforming their procedures to the rapid advances in this field.
PubMed: 38701582
DOI: 10.1016/j.ejso.2024.108351 -
JAMA Surgery Apr 2024Current short-term evidence has shown that uncomplicated acute appendicitis can be treated successfully with oral antibiotics alone, but longer-term results are lacking.
Three-Year Outcomes of Oral Antibiotics vs Intravenous and Oral Antibiotics for Uncomplicated Acute Appendicitis: A Secondary Analysis of the APPAC II Randomized Clinical Trial.
IMPORTANCE
Current short-term evidence has shown that uncomplicated acute appendicitis can be treated successfully with oral antibiotics alone, but longer-term results are lacking.
OBJECTIVE
To assess the treatment effectiveness of oral antibiotic monotherapy compared with combined intravenous (IV) and oral antibiotics in computed tomography-confirmed uncomplicated acute appendicitis at a longer-term follow-up.
DESIGN, SETTING, AND PARTICIPANTS
This secondary analysis of a predefined year 3 follow-up of the Appendicitis Acuta II (APPAC II) noninferiority, multicenter randomized clinical trial compared oral moxifloxacin with combined IV ertapenem plus oral levofloxacin and metronidazole for the treatment of uncomplicated acute appendicitis. The trial was conducted at 9 university and central hospitals in Finland from April 2017 to November 2018, with the last follow-up in November 2022. Participants included patients aged 18 to 60 years, who were randomized to receive either oral antibiotics monotherapy (n = 301) or combined IV and oral antibiotics (n = 298).
INTERVENTIONS
Antibiotics monotherapy consisted of oral moxifloxacin, 400 mg/d, for 7 days. Combined IV and oral antibiotics consisted of IV ertapenem sodium, 1 g/d, for 2 days plus oral levofloxacin, 500 mg/d, and metronidazole, 500 mg 3 times/d, for 5 days.
MAIN OUTCOMES AND MEASURES
The primary end point was treatment success, defined as the resolution of acute appendicitis and discharge from hospital without the need for surgical intervention and no appendicitis recurrence at the year 3 follow-up evaluated using a noninferiority design. The secondary end points included late (after 1 year) appendicitis recurrence as well as treatment-related adverse events, quality of life, length of hospital stay, and length of sick leave, which were evaluated using a superiority design.
RESULTS
After exclusions, 599 patients (mean [SD] age, 36 [12] years; 336 males [56.1%]) were randomized; after withdrawal and loss to follow-up, 582 patients (99.8%) were available for the year 3 follow-up. The treatment success at year 3 was 63.4% (1-sided 95% CI, 58.8% to ∞) in the oral antibiotic monotherapy group and 65.2% (1-sided 95% CI, 60.5% to ∞) in the combined IV and oral antibiotics group. The difference in treatment success rate between the groups at year 3 was -1.8 percentage points (1-sided 95% CI, -8.3 percentage points to ∞; P = .14 for noninferiority), with the CI limit exceeding the noninferiority margin. There were no significant differences between groups in treatment-related adverse events, quality of life, length of hospital stay, or length of sick leave.
CONCLUSIONS AND RELEVANCE
This secondary analysis of the APPAC II trial found a slightly higher appendectomy rate in patients who received oral antibiotic monotherapy; however, noninferiority of oral antibiotic monotherapy compared with combined IV and oral antibiotics could not be demonstrated. The results encourage future studies to assess oral antibiotic monotherapy as a viable treatment alternative for uncomplicated acute appendicitis.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03236961.
PubMed: 38630471
DOI: 10.1001/jamasurg.2023.5947 -
JPRAS Open Jun 2024Scarless latissimus dorsi (LD) flap is a breast reconstruction technique, which allow to cover the lower pole of implant with a large portion of the LD muscle without...
INTRODUCTION
Scarless latissimus dorsi (LD) flap is a breast reconstruction technique, which allow to cover the lower pole of implant with a large portion of the LD muscle without skin paddle; it represents a surgical solution that transpose vascularized tissue avoiding the failure of breast reconstruction, following necrosis of mastectomy skin flaps.
MATERIAL AND METHOD
A retrospective review of patients undergoing immediate or delayed breast reconstruction using scarless LD flap reconstructions was performed. Clinical data obtained from follow-up visits were recorded. To evaluate breast shape contentment and patient satisfaction, the patients were requested to answer the Breast-Q, version 2.0 reduction module postoperative scales questionnaire at the 12-month follow-up.
RESULTS
We performed 19 scarless LD flap reconstructions between September 2019 and June 2022. The surgical time in average (considering minutes ± SD) was 130 (±15) minutes. The aesthetic assessment was good/excellent in 83% of patients. This was statistically significant (P=0.0).
CONCLUSIONS
The scarless LD flap reconstruction is a valid and reliable solution, which has the advantage to reduce the risk of exposed prosthesis if native skin necrosis occurs.
PubMed: 38601882
DOI: 10.1016/j.jpra.2024.03.004 -
The Journal of Heredity Mar 2024Similar to other insular birds around the world, the Galapagos rail (Laterallus spilonota Gould, 1841) exhibits reduced flight capacity following its colonization of the...
Similar to other insular birds around the world, the Galapagos rail (Laterallus spilonota Gould, 1841) exhibits reduced flight capacity following its colonization of the archipelago ~1.2 mya. Despite their short evolutionary history, rails have colonized seven different islands spanning the entire width of the archipelago. Galapagos rails were once common on islands with sufficiently high altitudes to support shrubs in humid habitats. After humans introduced goats, this habitat was severely reduced due to overgrazing. Habitat loss devastated some rail populations, with less than 50 individuals surviving, rendering the genetic diversity of Galapagos rail a pressing conservation concern. Additionally, one enigma is the reappearance of rails on the island of Pinta after they were considered extirpated. Our approach was to investigate the evolutionary history and geographic distribution of Galapagos rails as well as examine the genome-wide effects of historical population bottlenecks using 39 whole genomes across different island populations. We recovered an early divergence of rail ancestors leading to the isolated populations on Pinta and a second clade comprising the rest of the islands, historically forming a single landmass. Subsequently, the separation of the landmass ~900 kya may have led to the isolation of the Isabela population with more panmictic populations found on Santa Cruz and Santiago islands. We found that rails genomes contain long runs of homozygosity (>2Mb) that could be related to the introduction of goats. Finally, our findings show that the modern eradication of goats was critical to avoiding episodes of inbreeding in most populations.
PubMed: 38498380
DOI: 10.1093/jhered/esae017 -
Annals of Surgical Oncology May 2024Sentinel lymph node (SLN) biopsy for cN+ breast cancer patients after neoadjuvant chemotherapy (NAC) is controversial because the false-negative rate (FNR) is high....
BACKGROUND
Sentinel lymph node (SLN) biopsy for cN+ breast cancer patients after neoadjuvant chemotherapy (NAC) is controversial because the false-negative rate (FNR) is high. Identification of three or more SLNs with a dual tracer improves these results, and inclusion of a clipped lymph node (CLN) (targeted axillary dissection [TAD]) may be even more effective.
METHODS
A retrospective, single-institution analysis of consecutive cN+ patients undergoing NAC from 2019 to 2021 was performed. Patients routinely underwent placement of a clip in the positive lymph node before NAC, and TAD was performed after completion of therapy.
RESULTS
The study analyzed 73 patients, and the identification rate for CLN was 98.6% (72/73). A complete response in the lymph nodes was achieved for 43 (59%) of the 73 patients. Overall, the CLN was not a SLN in 18 (25%) of 73 cases, and for women who had one or two and those who had three or more SLNs identified, this occurred in 11 (32%) and 7 (21%) of 34 cases, respectively. Failure of SLN or TAD to identify a positive residual lymph node status after NAC occurred in 10 (15%) of 69 and 2 (3%) of 73 cases, respectively (p = 0.01). In four cases, a SLN was not retrieved (5.5%), and two of these cases had a positive CLN. In three cases, the CLN was the only positive node and did not match with a SLN, directing lymphadenectomy and oncologic management change in two cases. Therefore, 7 (10%) of 73 cases had a change in surgical or oncologic management with TAD.
CONCLUSIONS
For a conservative axillary treatment in this setting, TAD is an effective method. It is more accurate than SLN alone and allows management changes. Further studies are warranted.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Retrospective Studies; Lymphatic Metastasis; False Negative Reactions; Sentinel Lymph Node Biopsy; Lymph Nodes; Lymph Node Excision; Axilla; Neoplasm Staging; Sentinel Lymph Node
PubMed: 38427160
DOI: 10.1245/s10434-024-15052-y -
Foods (Basel, Switzerland) Jan 2024Parboiling influences chemical compositions in rice grains. The objectives of this study were to evaluate the change in chemical content, total phenolic content and...
Parboiling influences chemical compositions in rice grains. The objectives of this study were to evaluate the change in chemical content, total phenolic content and antioxidant capacity of landrace rice genotypes under parboiling conditions and to identify the genotypes suitable for production of parboiled rice. Landrace rice varieties used in this study consisted of Glam Feang, Glam Tonkeaw, Kawgum, Glam Luem Phua, Medmakham, Deang Sakonnakhon, Sang Yod, Kawniewd-eang, Mali Deang, KDML105 and RD6. Parboiling reduced fiber content, total phenolic content and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity in rice grains. Fiber contents were 1.46% in brown rice (unpolished rice) and 1.40% in parboiled rice (24 h of soaking and 48 h of incubation). Total phenolic contents were 205.67 mg/100 g seed in brown rice and 35.34 mg/100 g seed in parboiled rice. Antioxidant capacity (DPPH) reduced from 68.45% in brown rice to 26.23% in parboiled rice. Ash content and protein content were not significantly affected by the parboiling process. Medmakham cv. had the highest total phenolic content and antioxidant capacity in brown rice and parboiled rice. Gum Leamphea cv. and Medmakham cv. were the best genotypes for ash content, protein content, total phenolic content and antioxidant capacity (DPPH) in brown rice and parboiled rice. Glam Feang cv. had the highest protein contents in brown rice and parboiled rice although it had low total phenolic content and antioxidant capacity. Cluster analysis further showed variation among genotypes, revealing distinct groupings in brown rice and parboiled rice based on chemical properties, phenolic content and antioxidant capacity. This research significantly contributes to a better understanding on how parboiling affects rice compositions and nutritional values. It emphasizes the importance of nuanced comprehension of how different rice varieties respond to parboiling, aiding informed decisions in rice processing and selection to meet specific nutritional needs.
PubMed: 38338528
DOI: 10.3390/foods13030393 -
The British Journal of Surgery Jan 2024
Topics: Humans; Anastomosis, Surgical; Colectomy; Laparoscopy; Retrospective Studies; Colonic Neoplasms; Treatment Outcome; Robotic Surgical Procedures
PubMed: 38298068
DOI: 10.1093/bjs/znad444 -
The British Journal of Surgery Jan 2024The rate of incisional hernia after closure of a temporary loop ileostomy is significant. Synthetic meshes are still commonly avoided in contaminated wounds. The Preloop... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The rate of incisional hernia after closure of a temporary loop ileostomy is significant. Synthetic meshes are still commonly avoided in contaminated wounds. The Preloop trial was a multicentre RCT designed to evaluate the benefits of synthetic mesh in incisional hernia prevention, and its safety for use in a contaminated surgical site compared with biological mesh.
METHODS
Study patients who underwent closure of a loop ileostomy after anterior resection for rectal cancer were assigned to receive either retrorectus synthetic or biological mesh to prevent incisional hernia. The primary outcomes were surgical-site infections within 30 days, and clinical or radiological incisional hernia incidence at 10 months. Secondary outcomes were reoperation rate, operating time, duration of hospital stay, other complications within 30 days of surgery, 5-year quality of life measured by RAND-36, and incisional hernia incidence within 5 years of follow-up.
RESULTS
Between November 2018 and September 2021, 102 patients were randomised, of whom 97 received the intended allocation. At 10-month follow-up, 90 patients had undergone clinical evaluation and 88 radiological evaluation. One patient in each group (2 per cent) had a clinical diagnosis of incisional hernia (P = 0.950) and one further patient in each group had a CT-confirmed incisional hernia (P = 0.949). The number of other complications, reoperation rate, operating time, and duration of hospital stay did not differ between the study groups.
CONCLUSION
Synthetic mesh appeared comparable to biological mesh in efficacy and safety for incisional hernia prevention at the time of loop ileostomy closure.
REGISTRATION NUMBER
NCT03445936 (http://www.clinicaltrials.gov).
Topics: Humans; Ileostomy; Incisional Hernia; Quality of Life; Surgical Mesh; Surgical Wound Infection
PubMed: 37944025
DOI: 10.1093/bjs/znad362 -
Acta Obstetricia Et Gynecologica... Dec 2023Chronic pelvic pain (CPP) affects over one fifth of women worldwide, and endometriosis is one of the most common causes. In the present study, we examined whether sacral...
INTRODUCTION
Chronic pelvic pain (CPP) affects over one fifth of women worldwide, and endometriosis is one of the most common causes. In the present study, we examined whether sacral neuromodulation (SNM) is effective in the treatment of refractory chronic pelvic pain in women with endometriosis.
MATERIAL AND METHODS
This multicenter prospective pilot study was started in 2017 and includes patients with chronic pelvic pain with no other obvious pathology than endometriosis. Other treatment options have been tried or they are unsuitable. Patients underwent SNM implantation. The main outcome was postoperative pain reduction and secondary outcome was quality of life. The following questionnaires were used to assess the outcomes: Brief pain inventory (BPI), clinical global impression - improvement (CGI-I), 15D-measure of health-related quality of life, and Biberoglu and Behrman (B&B) score.
RESULTS
A total of 35 patients underwent the SNM procedure and, at the time of analysis, 15 patients had returned one-year questionnaires. The patients had a history of endometriosis for a median of 5.5 (interquartile range 2-9) years, with no correlation between the severity of symptoms and the duration of the disease (p = 0.158). A total of 31 patients (89%) were implanted with the internal pulse generator. There were statistically significant changes in BPI pain-related items. Worst experienced daily pain decreased among those who returned 12-month questionnaires from median 9 to 5 (p = 0.006), average daily pain from 6 to 3.5 (p = 0.004), and least daily pain from 3 to 1 (p = 0.004). Based on the CGI questionnaire (n = 14), at 12 months nine patients (60%) experienced great improvement in their symptoms, three patients (20%) much improvement and two patients (13%) minimal improvement. None of the patients experienced worsening of their symptoms. There was a statistically significant change in overall 15D score at 1 month (p < 0.001), 6 months (p = 0.001) and 12 months (p = 0.018), when the results were compared to baseline values. Median B&B score also improved significantly and decreased from a baseline value of 8 (4-12) to 4.5 (0-6), p = 0.002.
CONCLUSIONS
Based on the preliminary findings of our study, SNM might be a promising treatment of CPP in endometriosis patients.
Topics: Humans; Female; Endometriosis; Prospective Studies; Quality of Life; Pilot Projects; Pelvic Pain; Treatment Outcome; Electric Stimulation Therapy; Chronic Pain
PubMed: 37814355
DOI: 10.1111/aogs.14690