Insights from an Italian Delphi panel: exploring resistance to first-generation somatostatin receptor ligands and guiding second-line medical therapies in acromegaly management.

PURPOSE: First-line medical therapy for acromegaly management includes first-generation somatostatin receptor ligands (fgSRLs), but resistance limits their use. Despite international guidelines, the choice of second-line therapy is debated. METHODS: We aim to discuss resistance to fgSRLs, identify second-line therapy determinants and assess glycemia's impact to provide valuable insights for acromegaly management in clinical practice. A group of Italian endocrinologists expert in the pituitary field participated in a two-round Delphi panel between July and September 2023. The Delphi questionnaire encompassed a total of 75 statements categorized into three sections: resistance to fgSRLs therapy and predictors of response; determinants for the selection of second-line therapy; the role of glycemia in the therapeutic management. The statements were rated on a 6-point Likert scale. RESULTS: Fifty-nine (79%) statements reached a consensus. IGF-1 levels resulted central for evaluating resistance to fgSRLs, that should be defined considering also symptomatic clinical response, degree of tumor shrinkage and complications, using clinician- and patient-reported outcome tools available. Factors to be evaluated for the choice of second-line medical therapy are hyperglycemia-that should be managed as in non-acromegalic patients-tumor remnant, resistant headache and compliance. Costs do not represent a main determinant in the choice of second-line medical treatment. CONCLUSION: The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients.

Isolated radial tears of the lateral meniscus midbody: a case series of professional athletes treated with outside-in repair.

PURPOSE: The main aim of the study is to assess clinical and functional outcomes of arthroscopic outside-in repair of isolated radial tears of the midbody of lateral meniscus in professional athletes and to evaluate the return to the sport activity after surgery. METHODS: A retrospective data collection on professional athletes with isolated complete lesion of the midbody of lateral meniscus, treated with arthroscopic outside-in repair was carried out. Outcome measures included functional assessment, Limb Symmetry Index (LSI) and Hamstring Quadriceps Ratio (HQR) and Lysholm score collected before surgery and at 4-month follow-up. Data on return to sport practice and re-injury were also retrieved. RESULTS: Fourteen patients satisfied the selection criteria. Full return to professional sport activity (Tegner 10) was registered in the 86% of the cohort at 4 months after the surgery. Functional testing of the athletes showed a return of the LSI and HQR to the pre-surgical condition, demonstrating a full recovery of the functional ability and muscle strength. Similarly, clinical evaluation through Lysholm score showed an improvement, reaching an average of 97.7 points at 4 months follow-up. CONCLUSION: A good functional recovery and a high rate of return to play has been observed in a population of professional athletes, at 4 months after outside-in repair.

Management of colorectal peritoneal metastases: Expert opinion.

When peritoneal metastases are diagnosed (strong agreement of experts): (i) seek advice from a multidisciplinary coordination meeting (MCM) with large experience in peritoneal disease (e.g. BIG RENAPE network); (ii) transfer (or not) the patient to a referral center with experience in hyperthermic intraperitoneal chemotherapy (HIPEC), according to the advice of the MCM. With regard to systemic chemotherapy (strong agreement of experts): (i) it should be performed both before and after surgery, (ii) for no longer than 6 months; (iii) without postoperative anti-angiogenetic drugs. With regard to cytoreductive surgery (strong agreement of experts): (i) Radical surgery requires a xiphopubic midline incision; (ii) no cytoreductive surgery via laparoscopy. With regard to HIPEC: HIPEC can be proposed for trials outside an HIPEC referral center (weak agreement between experts): (i) if surgery is radical; (ii) if the expected morbidity is "reasonable"; (iii) if the indication for HIPEC was suggested by a MCM, and; (iv) mitomycin is preferred to oxaliplatin (which cannot be recommended) for this indication.

What is the impact of neoadjuvant chemoradiation on outcomes in gastro-intestinal cancer?

Multimodal therapeutic strategies combining chemotherapy, radiation therapy and surgery have been shown to be feasible and to have a positive impact on outcomes by decreasing the risk of locoregional recurrence and often by increasing overall survival. The advantages of neoadjuvant chemo(radio)therapy include optimal tumor control combined with better tolerance and compliance to treatment while also increasing the number of candidates for surgery. Whereas indications for neoadjuvant therapy are increasing, its impact on surgical treatment and postoperative outcomes are not well-known. Surgeons frequently believe that chemo(radio)therapy may amplify intraoperative difficulties, thereby increasing postoperative morbidity and mortality. The aim of this review was to report the state of the art regarding: (i) the role of chemo(radio)therapy; (ii) its impact on surgical indications and modalities; and (iii) its impact on postoperative outcomes for the most frequently encountered gastro-intestinal cancers, i.e. esophageal, rectal, pancreatic, and anal canal cancer.

Circulating tumor cells and circulating tumor DNA: What surgical oncologists need to know?

As a result of recent progress in detection techniques, circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) can now be accurately detected in the blood of most cancer patients. While these new biomarkers can provide a better understanding of key biological mechanisms underlying cancer growth and dissemination, they also open up a wide range of possible clinical applications in medical oncology, radiation oncology and surgical oncology. In this review, we summarize the results obtained with ctDNA and CTC together with their potential future clinical applications in the field of surgical oncology, with particular focus on the perioperative setting of various types of cancer. These applications include, but are not limited to, cancer screening, early diagnosis, prognostic assessment, evaluation and management of preoperative systemic or local therapies, post-surgical detection of minimal residual disease and early detection of cancer relapse.

Enhanced recovery after gastro-intestinal surgery: The scientific background.

Enhanced recovery programs (ERP) are without any doubt a major innovation in the care of surgical patients. This multimodal approach encompasses elements of both medical and surgical care. The goal of this in-depth review is to analyze the surgical aspects of ERP, underlining the scientific rationale behind each element of ERP after surgery and in particular, the role of mechanical bowel preparation before colorectal surgery, the place of minimal access surgery, the utility of nasogastric tube, abdominal drainage, bladder catheters and early re-feeding. Publication of factual data has allowed many dogmas to be discarded.

Diffuse malignant peritoneal mesothelioma: Evaluation of systemic chemotherapy with comprehensive treatment through the RENAPE Database: Multi-Institutional Retrospective Study.

PURPOSE: Diffuse malignant peritoneal mesothelioma (DMPM) is a severe disease with mainly locoregional evolution. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the reported treatment with the longest survival. The aim of this study was to evaluate the impact of perioperative systemic chemotherapy strategies on survival and postoperative outcomes in patients with DMPM treated with curative intent with CRS-HIPEC, using a multi-institutional database: the French RENAPE network. PATIENTS AND METHODS: From 1991 to 2014, 126 DMPM patients underwent CRS-HIPEC at 20 tertiary centres. The population was divided into four groups according to perioperative treatment: only neoadjuvant chemotherapy (NA), only adjuvant chemotherapy (ADJ), perioperative chemotherapy (PO) and no chemotherapy before or after CRS-HIPEC (NoC). RESULTS: All groups (NA: n = 42; ADJ: n = 16; PO: n = 16; NoC: n = 48) were comparable regarding clinicopathological data and main DMPM prognostic factors. After a median follow-up of 61 months, the 5-year overall survival (OS) was 40%, 67%, 62% and 56% in NA, ADJ, PO and NoC groups, respectively (P = 0.049). Major complications occurred for 41%, 45%, 35% and 41% of patients from NA, ADJ, PO and NoC groups, respectively (P = 0.299). In multivariate analysis, NA was independently associated with worse OS (hazard ratio, 2.30; 95% confidence interval, 1.07-4.94; P = 0.033). CONCLUSION: This retrospective study suggests that adjuvant chemotherapy may delay recurrence and improve survival and that NA may impact negatively the survival for patients with DMPM who underwent CRS-HIPEC with curative intent. Upfront CRS and HIPEC should be considered when achievable, waiting for stronger level of scientific evidence.

Radiofrequency ablation and surgical resection of liver metastases from uveal melanoma.

BACKGROUND: The resection of liver metastasis from uveal melanoma (LMUM) remains controversial. In this study, we evaluated treatment with radiofrequency ablation (RFA) for liver metastases alone or in combination with surgical liver resection. METHODS: A total of 72 patients with LMUM were evaluated in this study. Of these, 57 patients underwent surgical resection (S) while 15 patients had RFA ± S. Clinicopathologic factors were evaluated in terms of recurrence and survival using Chi-square and log-rank tests, respectively. RESULTS: We studied 22 metastases treated by RFA. There were no statistically significant differences between the groups in terms of median age of onset, synchronous nature of the metastases, time from primary tumour treatment to liver metastasis, diameter of the largest metastasis, presence of liver miliary disease, and the type of liver resection. There was a statistically lower number of liver metastases and more bilobar metastases in the RFA group than in the S group. The median overall survival after liver surgery was 27 months in group S and 28 months in the RFA group ± S. The median disease-free survival was 10 months in group S and 7 months in the RFA group ± S. There were no statistically significant differences in the median overall survival and disease-free survival between groups. CONCLUSIONS: The results of this retrospective analysis show that RFA can be used to treat liver metastases to spare the hepatic parenchyma. RFA ± liver surgery and liver surgery alone demonstrate similar survival times.

Professional risks when carrying out cytoreductive surgery for peritoneal malignancy with hyperthermic intraperitoneal chemotherapy (HIPEC): A French multicentric survey.

BACKGROUND: Over the last two decades, many surgical teams have developed programs to treat peritoneal carcinomatosis with extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Currently, there are no specific recommendations for HIPEC procedures concerning environmental contamination risk management, personal protective equipment (PPE), or occupational health supervision. METHODS: A survey of the institutional practices among all French teams currently performing HIPEC procedures was carried out via the French network for the treatment of rare peritoneal malignancies (RENAPE). RESULTS: Thirty three surgical teams responded, 14 (42.4%) which reported more than 10 years of HIPEC experience. Some practices were widespread, such as using HIPEC machine approved by the European Community (100%), individualized or centralized smoke evacuation (81.8%), "open" abdominal coverage during perfusion (75.8%), and maintaining the same surgeon throughout the procedure (69.7%). Others were more heterogeneous, including laminar flow air circulation (54.5%) and the provision of safety protocols in the event of perfusate spills (51.5%). The use of specialized personal protective equipment is ubiquitous (93.9%) but widely variable between programs. CONCLUSION: Protocols regarding cytoreductive surgery/HIPEC and the associated professional risks in France lack standardization and should be established.

Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer.

BACKGROUND: HER3 activating mutations have been shown in preclinical models to be oncogenic and ligand-independent, but to depend on kinase-active HER2. PATIENTS AND METHODS: Whole-exome sequencing of the primary HER2-negative breast cancer and its HER2-negative synchronous liver metastasis from a 46-year-old female revealed the presence of an activating and clonal HER3 G284R mutation. RESULTS: HER2 dual blockade with trastuzumab and lapatinib as third-line therapy led to complete metabolic response in 2 weeks and confirmed radiological partial response after 8 weeks. Following the resection of the liver metastasis, the patient remains disease-free 40 weeks after initiation of the HER2 dual blockade therapy. Immunohistochemical analysis demonstrated a substantial reduction of phospho-rpS6 and phospho-AKT in the post-therapy biopsy of the liver metastasis. DISCUSSION: This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.

Prospective study of surveillance testing for metastasis in 100 high-risk uveal melanoma patients.

Despite advances in the local treatment of UM, half of patients develop metastases typically to the liver with poor survival. Microscopic complete surgical resection (R0) of liver metastases improves survival in high selected patients. Early identification of high-risk patients might allow detection of asymptomatic metastases, and increase R0 liver surgery rate. From October 2006 to December 2009, we conducted a prospective study to detect early minimal lesions with 6-monthly liver function tests (LFTs) and liver MRI in 100 high-risk patients. High risk was defined by primary tumor clinical or genomic criteria: thickness>8mm or diameter>15 mm, or extra-scleral extension, or monosomy 3 by FISH or aCGH. With a median follow-up of 49 months, the 5-year metastasis-free survival and overall survival were 47 and 33%, respectively. Of the 60 patients who became metastatic, 50 (83%) had exclusive liver metastasis. LFTs screening had no sufficient accurary, but biannual MRI showed high predictive value to detect metastasis and select patients eligible for curative surgery: 25/50 underwent laparotomy and among them, 8/25 (32%) had a R0 surgery. Median survival after metastasis was 14 months, mean survival reached 40 months in the R0 resected population. Six-monthly liver MRI screening is recommended in patients with large tumors or genomic high risk in order to detect early patient candidates to complete resection of liver metastases.

Treatment of Leaks Following Sleeve Gastrectomy by Endoscopic Internal Drainage (EID).

BACKGROUND: Leaks are considered one of the major complications of laparoscopic sleeve gastrectomy (LSG) with a reported rate up to 7 %. Drainage of the collection coupled with SEMS deployment is the most frequent treatment. Its success is variable and burdened by high morbidity and not irrelevant mortality. The aim of this paper is to suggest and establish a new approach by endoscopic internal drainage (EID) for the management of leaks. METHODS: Since March 2013, 67 patients presenting leak following LSG were treated with deployment of double pigtail plastic stents across orifice leak, positioning one end inside the collection and the other end in remnant stomach. The aim of EID is to internally drain the collection and at the same time promote leak healing. RESULTS: Double pigtails stent were successfully delivered in 66 out of 67 patients (98.5 %). Fifty patients were cured by EID after a mean time of 57.5 days and an average of 3.14 endoscopic sessions. Two died for event not related to EID. Nine are still under treatment; five failure had been registered. Six patients developed late stenosis treated endoscopically. CONCLUSIONS: EID proved to be a valid, curative, and safe mini-invasive approach for treatment of leaks following SG. EID achieves complete drainage of perigastric collections and stimulates mucosal growth over the stent. EID is well tolerated, allows early re-alimentation, and it is burdened by fewer complications than others technique. Long-term follow-up confirms good outcomes with no motility or feeding alterations.

[Guidelines for enhanced recovery after elective colorectal surgery]. / Réhabilitation rapide après une chirurgie colorectale programmée.

Early recovery after surgery provides patients with all means to counteract or minimize the deleterious effects of surgery. This concept is suitable for a surgical procedure (e.g., colorectal surgery) and comes in the form of a clinical pathway that covers three periods (pre-, intra- and postoperative). The purpose of this Expert panel guideline is firstly to assess the impact of each parameter usually included in the rehabilitation programs on 6 foreseeable consequences of colorectal surgery: surgical stress, postoperative ileus, water and energy imbalance, postoperative immobility, sleep alterations and postoperative complications; secondly, to validate the usefulness of each as criteria of efficiency criteria for success of rehabilitation programs. Two main criteria were selected to evaluate the impact of each parameter: the length of stay and frequency of postoperative complications. Lack of information in the literature forced experts to assess some parameters with criteria (duration of postoperative ileus or quality of analgesia) that mainly surrogate a positive impact for the implementation of an early recovery program. After literature analysis, 19 parameters were identified as potentially interfering with at least one of the foreseeable consequences of colorectal surgery. GRADE® methodology was applied to determine a level of evidence and strength of recommendation. After synthesis of the work of experts using GRADE® method on 19 parameters, 35 recommendations were produced by the organizing committee. The recommendations were submitted and amended by a group of reviewers. After three rounds of Delphi quotes, strong agreement was obtained for 28 recommendations (80%) and weak agreement for seven recommendations. A consensus was reached among anesthesiologists and surgeons on a number of approaches that are likely not sufficiently applied for rehabilitation programs in colorectal surgery such as: preoperative intake of carbohydrates; intraoperative hemodynamic optimization; oral feeding resume before ha24; gum chewing after surgery; patient out of bed and walking at D1. The panel also clarified the value and place of such approaches such as: patient information; preoperative immunonutrition; laparoscopic surgery; antibiotic prophylaxis; prevention of hypothermia; systematic prevention of nausea and vomiting; morphine-sparing analgesic techniques; indications and techniques for bladder catheterization. The panel also confirmed the futility of approaches such as: bowel preparation for colon surgery; maintain of the nasogastric tube; surgical drainage for colonic surgery.

Surgical or percutaneous hepatic artery cannulation for chemotherapy.

The principle underlying administration of hepatic arterial chemotherapy (HACT) is to increase the local concentration of cytotoxic chemotherapy while limiting systemic toxicity. The chemotherapy agent is infused into the hepatic artery distal to branches that serve the stomach, duodenum, and pancreas. The intra-arterial catheter is connected to a subcutaneously implanted reservoir to allow repeated sessions of chemotherapy. Percutaneous placement is now a reliable and reproducible technique in the hands of well-trained interventional radiologists. Hepatic arterial cannulation by an open surgical approach is currently reserved for cases where the decision for HACT is made in the course of an hepatic surgical procedure.

French guidelines for enhanced recovery after elective colorectal surgery.

Enhanced recovery after surgery provides patients with optimal means to counteract or minimize the deleterious effects of surgery. This concept can be adapted to suit a specific surgical procedure (i.e., colorectal surgery) and comes in the form of a program or a clinical pathway covering the pre-, intra- and postoperative periods. The purpose of these Expert Panel Guidelines was firstly to assess the impact of each parameter typically included in the fast-track programs on six foreseeable consequences of colorectal surgery: surgical stress, postoperative ileus, fluid and electrolyte imbalances, decreased postoperative mobility, sleep disorders and postoperative complications; secondly, to validate the value of each parameter in terms of efficacy criteria for success of rapid rehabilitation programs. Two primary endpoints were selected to evaluate the impact of each parameter: the duration of hospital stay and rate of postoperative complications. For some of the parameters, the lack of information in the literature forced the experts to assess the parameter using different criteria (i.e., the duration of postoperative ileus or quality of analgesia); improvement in endpoints favored the implementation of a rapid rehabilitation program. After analysis of the literature, 19 parameters were identified as potentially impacting at least one of the foreseeable consequences of colorectal surgery. GRADE(®) methodology was applied to determine a level of evidence and the strength of recommendation regarding each parameter. After synthesis of the work of experts on the 19 parameters using GRADE(®) methodology, the organizing committee reached 35 formal recommendations. The recommendations were submitted and amended by a group of reviewers. After three rounds of Delphi quotes, strong agreement was obtained for 28 recommendations (80%) and weak agreement for seven recommendations. Consensus was reached among anesthesiologists and surgeons on a number of tactics that are insufficiently applied in current rehabilitation programs in colorectal surgery such as: pre-operative intake of carbohydrates; optimization of intra-operative volume control; resumption of oral feeding within 24 hours; gum chewing after surgery; getting the patient out of bed and walking on D1. The panel also clarified the value and place of such approaches as: patient information; pre-operative immunonutrition; laparoscopic surgery; antibiotic prophylaxis; prevention of hypothermia; systematic medication to prevent nausea and vomiting; morphine-sparing analgesia techniques; indications and techniques for bladder catheterization. The panel also confirmed the futility of other methods such as: bowel preparation for colon surgery; maintaining a nasogastric tube; surgical drainage for colorectal surgery.

Liver metastases from breast cancer: Surgical resection or not? A case-matched control study in highly selected patients.

AIM: To determine whether, in a highly selected patient population, medical treatment combined with surgical resection of liver metastases from breast cancer is associated with improved survival compared with medical treatment alone. PATIENTS AND METHODS: Between 1988 and 2007, 100 liver resections for metastatic breast cancer were performed at Institut Curie, 51 of which met the criteria for inclusion in this case-control study. With the exception of bone metastases, patients with other distant metastasis sites were excluded. Surgery was only performed in patients with stable disease or disease responding to medical treatment evaluated by imaging evaluation. Surgical cases were individually matched with 51 patients receiving medical treatment only. All patients had 4 or fewer resectable liver metastases. The study group was matched with the control group for age, year of breast cancer diagnosis, time to metastasis, TNM stage, hormone receptor status and breast cancer tumour pathology. RESULTS: Univariate analysis confirmed a survival advantage for patients lacking bone metastases and axillary lymphadenopathy at the time of breast cancer diagnosis and for surgically treated patients. Multivariate analysis indicated that surgery and the absence of bone metastases were associated with a better prognosis. A multivariate Cox model adapted for paired data showed a RR = 3.04 (CI: 1.87-4.92) (p < 0.0001) in favour of surgical treatment. CONCLUSION: Surgical resection of liver metastases from primary breast cancer appears to provide a survival benefit for highly selected patients.

Assessment of NGAL as an early biomarker of acute kidney injury in adult cardiac surgery patients.

Early and predictive acute kidney injury (AKI) markers may be decisive for the clinical outcome of heart surgery. Hence, this study set out to evaluate the biological variability of urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels in adult cardiac surgery patients, to test their feasibility as a biomarker of early AKI in a routine laboratory setting. uNGAL levels were measured with an automated immunoassay in urine samples from patients undergoing cardiac surgery using cardiopulmonary bypass, at the time of admission (T0) and 4 hours (T1) and 24 hours (T2) after surgery. Patients without post-operative AKI did not show significant differences in urine NGAL levels after surgery. In contrast, patients developing AKI displayed a significant increase (P=0.011) in uNGAL levels compared to T0. This increase was detectable at an earlier time point (T1, 4 hours) with respect to serum creatinine (T2, 24 hours). Confirming its utility as a biomarker, at T1 the uNGAL levels were significantly higher in AKI patients than in non-AKI patients (P=0.021). A receiver operating characteristic curve analysis of the uNGAL assay gave a sensitivity of 55.3 (95percent confidence interval, 26.59-78.73), a specificity of 72.9 (95 percent CI, 55.88-86.21), and a cut-off value for AKI prediction of 55.2. These results support the notion that urinary NGAL is an earlier marker of AKI than serum creatinine. However, the cut-off value of the assay was too low to consider it as a positive or negative diagnostic marker in AKI patients with moderate degree of severity. Likewise, its sensitivity and specificity were not high enough for it to be considered better than the others currently in use.

New strategy in hepatic metastatic colorectal cancer: tomotherapy and capecitabine followed by hepatic surgical resection.

The majority of patients who develop liver metastases in metastatic colorectal cancer (mCRC) has often unresectable disease. Several new methods of nonsurgical ablation have been tested with variable success. Helical tomotherapy (HT), such as intensity-modulated radiation therapy (IMRT) or stereotactic body radiotherapy therapy, is a recent radiation therapy technique which can provide simultaneous and precise targeting of multiple lesions, while sparing normal tissues. We retrospectively assess the feasibility and the tolerance of IMRT with capecitabine followed by hepatic surgery in mCRC patients. This original observation suggests that HT could be safely integrated in the multidisciplinary management of patients with metastatic colorectal cancer as an alternative to surgery or other local ablation therapies.

Three different KRAS statuses in three synchronous colorectal cancers.

Treatments with monoclonal antibodies targeting the epidermal growth factor receptors (EGFR) have improved the prognosis of metastatic colorectal cancer (CRC). Mutated KRAS status is predictive of resistance to anti-EGFR agents and allows the selection of KRAS wild-type patients who may benefit from these targeted therapies. We report an original case of metastatic CRC including three synchronous primary tumors with three different KRAS statuses. We discuss the possible therapeutic impact of this clinical case and the role of multiple samplings for KRAS status determination.