Real-World Safety and Outcome of First-Line Pembrolizumab Monotherapy for Metastatic NSCLC with PDL-1 Expression ≥ 50%: A National Italian Multicentric Cohort ("PEMBROREAL" Study).

Results from the phase III Keynote-024 clinical trial established pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR, and ALK wild-type tumors. However, given the differences between patients treated in routine clinical practice and those treated in a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-ups, we designed an observational retrospective study of patients with metastatic NSCLC who were treated with pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were PFS and OS, determined using the Kaplan-Meier method. Response and safety were also evaluated. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6-10.0) and 25.5 months (95% CI: 21.8-31.6), respectively. We also found that ECOG PS, PD-L1 expression, and habitual smoking were prognostic factors for PFS, while age, sex, ECOG PS, habitual smoking and histology had an impact on OS. Multivariable analysis confirms the prognostic role of PD-L1 for PFS and of ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of pembrolizumab in the first-line setting, as well as a safety profile consistent with the results of Keynote-024. Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution.

A real-world retrospective, observational study of first-line pembrolizumab plus chemotherapy for metastatic non-squamous non-small cell lung cancer with PD-L1 tumor proportion score < 50% (PEMBROREAL).

Introduction: The phase III Keynote-189 trial established a first-line treatment combining pembrolizumab with pemetrexed and platinum as a standard treatment for patients with stage IV non-small cell lung cancer (NSCLC) without known EGFR and ALK driver mutations and independent of programmed cell death ligand 1 (PD-L1) expression. However, in Italy, eligibility for the National Health Service payment program is limited to patients with PD-L1 <50%. The PEMBROREAL study assesses the real-world effectiveness and safety of pembrolizumab in patients eligible for the National Health Service payment program. Methods: PEMBROREAL is a retrospective, observational study on patients with NSCLC who started pembrolizumab combined with pemetrexed and platinum within the reimbursability time window, considered as December 2019 to December 2020. The primary endpoints were to assess progression-free survival (PFS) and overall survival (OS; using the Kaplan-Meier method), response to therapy, and tolerability. Results: Until February 2022, 279 patients (median follow-up: 19.7 months) have been observed. The median PFS was 8.0 months (95% confidence interval: 6.5-9.2). OS was not reached, but we can estimate a 12- to 24-month survival rate for the combined treatment: 66.1% and 52.5%, respectively. PD-L1 expression and Eastern Cooperative Group (ECOG) Performance Status were both associated with PFS and OS. Overall, only 44.4% of patients reported an adverse event, whereas toxicity led to a 5.4% discontinuation rate. Conclusion: The results of the PEMBROREAL study have shown that the combined treatment of pembrolizumab with pemetrexed and platinum is effective for metastatic non-squamous NSCLC, even for patients with PD-L1 levels below 50%, despite the differences in patient demographics and pathological features compared to the Keynote-189 study. The adverse events reported during the study were more typical of chemotherapy treatment rather than immunotherapy, and physicians were able to manage them easily.

Towards a better understanding of light-glucose induced modifications on the structure and biological activity of formulated Nivolumab.

In the last years, monoclonal antibodies (mAbs) have rapidly escalated as biopharmaceuticals into cancer treatments, mainly for their target specificity accompanied by less side effects than the traditional chemotherapy, and stimulation of reliable long-term anti-tumoral responses. They are potentially unstable macromolecules under shaking, temperature fluctuations, humidity, and indoor and outdoor light exposure, all stressors occurring throughout their production, transport, storage, handling, and administration steps. The chemical and physical modifications of mAbs can lead not only to the loss of their bioactivity, but also to the enhancement of their immunogenicity with increasing risk of severe hypersensitivity reactions in treated patients because of aggregation. The photostability of Nivolumab, the active principle of Opdivo®, has been here studied. The chemical modifications detected by LC-MS/MS after the light stressor showed Trp and Met mono and double oxidations as primary damage induced by light on this mAb. The oxidations were stronger when the mAb was diluted in sterile glucose solution where 5-HMF, a major heat glucose degradation product, acted as singlet oxygen producer under irradiation. However, no significant changes in the mAb conformation were found. On the contrary, formation of a significant extent of aggregates has been detected after shining high simulated sunlight doses. This again took place particularly when Nivolumab was diluted in sterile glucose, thus raising a direct correlation between the aggregation and the oxidative processes. Finally, the biological activity under light stress assessed by a blockade assay test demonstrated the maintenance of the PD-1 target recognition even under high light doses and in glucose solution, in line with the preservation of the secondary and tertiary structures of the mAb. Based on our results, as sterile glucose is mostly used for children's therapies, special warnings, and precautions for healthcare professionals should be included for their use to the pediatric population.

Immune-Related Diarrhea and Colitis in Non-small Cell Lung Cancers: Impact of Multidisciplinary Management in a Real-World Setting.

INTRODUCTION: Immune-related adverse events (irAEs) constitute a challenge in the clinical management of solid tumors. This study aims to collect real-world data on the occurrence of immune-mediated diarrhea and colitis (IMDC) in advanced non-small cell lung cancer (aNSCLC) treated with immune checkpoint inhibitors (ICIs) and to assess the clinical impact of a multidisciplinary approach (MDA) on IMDC management. METHODS: We retrospectively collected data on patients with aNSCLC consecutively treated with ICIs, either as single agent or in combination with chemotherapy, between September 2013 and July 2022. Among patients developing IMDC, we conducted blinded revision of colonic biopsies and evaluated the clinical impact of the introduction of MDA through predefined indicators. RESULTS: Among the 607 patients included, 84 (13.8%) experienced IMDC. Pathological review highlighted a high prevalence of microscopic colitis (28%), with a collagenous pattern linked to longer symptoms duration (P = .01). IMDC occurred more frequently in females (P = .05) and PD-L1 expressors (P = .014) and was correlated with longer progression-free survival (17.0 vs 5.8, P < .001) and overall survival (28.3 vs 9.5, P < .001). The introduction of MDA was associated with increased employment of diagnostical tools such as fecal calprotectin test (P < .001), colonoscopy (P < .001), and gastroenterological evaluation (P = .017) and a significant decrease in both grade 3 conversion rate (P = .046) and recurrence after rechallenge (P = .016). Hospitalization rate dropped from 17.2% to 3.8% (P: ns). CONCLUSION: These findings highlight the clinical relevance of IMDC and support the incorporation of a MDA to optimize the clinical management of this irAE to improve patient care. Prospective validation has been planned.

Prolonging the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®): An orthogonal assessment of physicochemical, biological and microbiological properties of original opened glass vials and diluted saline preparations.

The two anti-epidermal growth factor receptor monoclonal antibodies (mAbs) cetuximab and panitumumab are the pillars for the treatment of EGFR-positive, KRAS wild-type metastatic colorectal cancers. However, stability data of these mAbs are generally missing or incomplete. Here, we report for the first time an orthogonal analysis of the stability of cetuximab (Erbitux®) and panitumumab (Vectibix®), either undiluted vial leftovers or saline dilutions in polyolefin/polyamide infusion bags. All samples were stored at 2-8 °C protected from light, according to their summary of product characteristics (SmPCs). Alternatively, opened vials and preparations were maintained at 25 °C for 15 h, and then stored again at 2-8 °C protected from light to mimic a temporary interruption of the cold chain. Vial leftovers proved stable up to 180 days when stored according to their SmPCs, while compounded preparations in infusion bags maintained their physiochemical, biological and microbiological stability up to 30 days. Additionally, no changes were detected up to 30 days for the same samples undergoing a thermal excursion. Our results provide additional rationale to the SmPCs, crucial especially in the case of reassignment and pre-preparation of bags. This information will allow hospitals to achieve significant cost savings, and better organization of the entire therapeutic process.

Laparoscopic Double Discoid Colorectal Resection for the Treatment of Two Distinct Deep Endometriotic Nodules.

OBJECTIVE: To show the surgical steps used to perform a laparoscopic double discoid colorectal resection for the excision of 2 distinct deep endometriotic nodules (DENs). DESIGN: Stepwise demonstration of the technique with narrated video footage. SETTING: To date there is agreement that discoid resection should be the first choice procedure in patients eligible for surgical treatment with rectal, unifocal DENs measuring ≤ 3 cm [1-3]. For surgical management of lesions of the sigmoid colon, current international guidelines suggest to perform segmental resections [3]. Data on surgical treatment of multiple colorectal DENs separated by a great distance from each other are very limited, mostly owing to the rarity of such a diagnosis. In particular, there is paucity of data concerning the efficacy and safety of a double discoid resection for surgical management of distinct DENs found in the sigmoid colon and rectum [4]. In a context of multiple colorectal DENs, the decision-making process with respect to a double discoid excision must take into consideration both the distance between the 2 nodules and the nodules' distance from anal verge. When technically feasible, such organ-sparing surgery allows preserving the healthy bowel interposed between the endometriotic lesions, seeming to offer advantages in terms of quicker return of bowel function and better rectal functional outcomes than segmental colorectal resection. INTERVENTIONS: The patient was a 36-year-old woman experiencing drug treatment failure and presenting with refractory constipation, dyschezia, dysmenorrhea, dyspareunia, cyclical abdominal bloating, and chronic pelvic pain. Preoperative ultrasonography revealed the presence of an endometriotic nodule of 19 × 6 × 16 mm deeply infiltrating the tunica muscularis of the sigmoid colon. A second DEN was found at the level of the rectum, the latter measuring 19 × 5 × 12 mm and having a distance of 9 cm from the anal verge. Both the intestinal lesions resulted to have a circumferential extent of 30%. The distance between the 2 nodules was 15 cm. A 3-dimensional laparoscopy was performed. Sigmoid colon and rectal mobilization were performed according to our standardized technique [5-7]. A 31-mm circular stapler was used to excise first the nodule of the sigmoid colon. The stapler, in its closed position, was gently introduced into the rectum via the anus and then progressively advanced inside the large bowel up to the level of the sigmoid nodule. After correct positioning, the stapler was completely opened and the nodule was imbricate between the anvil and staple housing of the stapler. Then, the stapler was closed and fired. The procedure was repeated using a second 31 mm circular stapler to resect the rectal endometriotic nodule. The overall operative time was 90 minutes. The estimated blood loss was 5 mL. Neither intra- nor postoperative complications occurred. The patient was discharged 3 days after surgery. The sigmoid colon and rectal endometriotic nodules measured, respectively, 20 × 6 × 15 mm and 20 × 5 × 12 mm on fresh unfixed specimens. Both nodules were found to have endometriosis-free surgical margins on definitive pathology. CONCLUSIONS: The operative technique displayed in this video may contribute to the standardization of a procedure, which could be included among the options available in the surgical armamentarium, to be used in selected cases of multiple colorectal DENs each having 3 cm or less in diameter. Surgeon experience and an adequate preoperative evaluation are of utmost importance to plan the operative strategy and have the best chance of surgical success.

Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study.

PURPOSE: Regorafenib demonstrated encouraging results in recurrent glioblastoma patients. Some studies showed that changes in circulating thyroid hormones (fT3, fT4, fT3/fT4 ratio) can be considered as prognostic factors in patients with various types of tumors. We designed this study to investigate the relationship between baseline thyroid variables and outcome in IDH-wild type GBM patients who were treated with regorafenib. METHODS: This multicenter retrospective study included recurrent IDH-wild-type glioblastoma patients treated with regorafenib. Only patients with baseline thyroid function values (TSH, fT3, fT4, fT3/fT4 ratio) available were evaluated. RANO criteria were used to analyze neuroradiological response. Survival curves were estimated using the Kaplan-Meier method. The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4) and survival (PFS, OS) were investigated with Cox regression models. RESULTS: From November 2015 to April 2022, 134 recurrent IDH-wildtype GBM patients were treated with regorafenib and 128 of these had information on baseline thyroid function value. Median follow-up was 8 months (IQR 4.7-14.0). Objective Response Rate was 9% and Disease Control Rate was 40.9%. Median PFS was 2.7 months (95%CI 2.2-3.6) and median OS was 10.0 months (95%CI 7.0-13.0). Lower baseline TSH value in the blood was correlated with a higher rate of disease progression to regorafenib (p = 0.04). Multivariable analyses suggested a non-linear relationship between PFS (p = 0.01) and OS (p = 0.03) with baseline fT3/fT4 ratio. CONCLUSION: In recurrent wild-type IDH glioblastoma patients, baseline fT3/fT4 ratio showed a non-linear relationship with survival, with different impacts across the spectrum of fT3/fT4 ratio. Moreover, baseline TSH may be a predictor of regorafenib activity.

A Method for Risk Assessment Evaluating the Safety, Stability and Efficacy in Clinical Practice of Anticancer Drug Preparations in the Centralized Compounding Unit of the Veneto Institute of Oncology-IRCCS.

BACKGROUND: Preparation of injectable anticancer drugs in hospital pharmacies is a high-risk activity that requires a proper risk assessment (RA) and quality assurance system (QAS) to ensure both a decrease in risk associated with chemotherapy compounding and high quality of the final product, especially in terms of its microbiological stability. METHODS: At the centralized compounding unit (UFA) of the Italian Hospital IOV-IRCCS, a quick and deductive method was applied to evaluate the "added value" provided by each prescribed preparation, and its RA was calculated applying a formula that integrates different pharmacological, technological and organizational aspects. According to specific RA range values, the preparations were divided into different risk levels, in order to determine the QAS to be adopted, according to the Italian Ministry of Health guidelines, whose adherence was meticulously evaluated through a specific self-assessment procedure. A review of the scientific literature was carried out to integrate the risk-based predictive extended stability (RBPES) of drugs with data concerning their physiochemical and biological stability. RESULTS: Based on the self-assessment comprising all microbiological validations of the working area, personnel and products, the microbiological risk level within the IOV-IRCCS' UFA was defined through the creation of a transcoding matrix, conferring a microbiological stability to preparations and vial leftovers of a maximum of 7 days. The calculated RBPES were successfully integrated with stability data from the literature, leading to the drafting of a stability table of drugs and preparations in use in our UFA. CONCLUSIONS: Our methods allowed us to perform an in-depth analysis of the highly specific and technical process of anticancer drug compounding in our UFA, ensuring a certain grade of quality and safety to preparations, especially in terms of microbiological stability. The resulting RBPES table represents an invaluable tool with positive repercussions at organizational and economic levels.

Analysis of the relation between adverse events and overall survival in patients treated with pembrolizumab as a first-line treatment for metastatic NSCLC.

BACKGROUND: Many trials supported pembrolizumab as a first-line monotherapy to significantly improve overall survival (OS) in selected patients with previously untreated metastatic Non-Small Cell Lung Cancer (mNSCLC) and a PD-L1 TPS of ≥50% without EGFR/ALK mutations. The aim of this study was to reveal the correlation between OS and adverse events in real-world settings after 42 months. METHODS: This retrospective observational study involved 98 patients with mNSCLC, TPS ≥ 50%, and no EGFR/ALK aberrations. Patients were treated with pembrolizumab (200 mg q3w) as a first-line treatment. Clinical data, including PD-L1 expression, Performance Status (ECOG-PS), treatment duration, toxicity, and outcomes were retrieved from local electronic medical records and from the Italian Regulatory Agency Registry. RESULTS: The cohort's main characteristics were as follows: median age 73 [44-89] years, 64.3% were male and 35.7% were female, an ECOG-PS score of 0 (n = 73) and 1 or 2 (n = 25), and a PD-L1 > 90% in 29.6% of patients. The entire cohort had stage IV NSCLC at diagnosis. The median number of cycles was 8.5 at a median follow-up of 13 months. The median OS of 13.6 months (95% CI: 11.7-NA) was not influenced by sex and PD-L1, but was significantly associated with ECOG-PS (p = 0.02). Immune-Related Adverse Events (irAEs) occurred in 77.5% of patients (30.1% cutaneous, 27.5% gastrointestinal, and 20.4% endocrinological), but no grade 4 or 5 irAEs were identified. Patients experiencing any type of toxicity had a significantly longer median OS (20.39 months, 95% CI: 13.08-NA) than those with no toxicities (6.46 months, 95% CI: 1.41-NA, p = 0.006). CONCLUSION: The percentage of irAEs detected was comparable to that reported in KEYNOTE-024 and KEYNOTE-042. These real-world findings demonstrated the significant correlation between OS and cutaneous toxicities.

Ultrasound Evaluation of Retrocervical and Parametrial Deep Endometriosis on the Basis of Surgical Anatomic Landmarks.

STUDY OBJECTIVES: To assess the value of combined transvaginal/transabdominal ultrasonographic evaluation performed by experienced examiners for deep infiltrating endometriosis (DIE) lesions of the retrocervical (torus uterinus and uterosacral ligaments) and parametrial areas and summarize the features and anatomic criteria for identification of these lesions and their extent in the above-mentioned pelvic compartments. DESIGN: Retrospective study. SETTING: A specialized endometriosis center in Avellino, Italy. PATIENTS: A retrospective cohort of patients who underwent laparoscopic surgery for clinically suspected DIE between January 1, 2014, and December 31, 2018, with a dedicated ultrasound (US) evaluation performed no more than 1 month before the intervention. INTERVENTIONS: Preoperative US findings and surgical reports were reviewed. Using the findings of laparoscopic surgery as the gold standard, the sensitivity and specificity of preoperative US evaluation for retrocervical and parametrial endometriotic lesions were calculated with the corresponding 95% confidence intervals. MEASUREMENTS AND MAIN RESULTS: A total of 4983 patients were included. US evaluation showed high diagnostic accuracy for DIE detection in the examined pelvic compartments, with sensitivity and specificity of 97% to 98% and 98% to 100%, respectively, for both retrocervical (torus uterinus and uterosacral ligaments insertion) and parametrial lesions. CONCLUSION: Parametrial extension of DIE indicates major surgical technical difficulties and risk of complications, and urologic and nerve-sparing procedures may be required in such cases. Preoperative evaluation of such scenarios will allow proper counseling of patients and facilitate adequate surgical planning in referral centers; moreover, when necessary, it can guide the constitution of a dedicated multidisciplinary surgical team as an alternative to treatment by a pelvic surgeon alone. Detailed imaging evaluation of DIE lesions and their extension is crucial for clinical management of affected patients. It can facilitate optimization of surgical timing and strategies, thereby potentially preventing ineffective, or even harmful, repeated procedures.

Safety of COVID-19 Vaccine in Patients with Cancer in a High-Volume Comprehensive Cancer Center.

BACKGROUND: Few data are available on the safety of COVID-19 vaccines in cancer patients undergoing active cancer-directed treatment. PATIENTS AND METHODS: This case series analyzes outcomes in terms of adverse events in 5297 patients undergoing anti-cancer treatment who were vaccinated with anti-SARS-CoV-2 Pfizer-BioNTech vaccine at a single cancer center from March 6, 2021 to May 9, 2021. Adverse events were retrieved from the national Italian pharmacovigilance platform (http://www.vigicovid.it). RESULTS: Of the 5297 patients treated for either solid tumors (87%) or onco-hematologic malignancies (13%) who were vaccinated, 8 adverse drug reactions (ADRs) were reported. One was a severe ADR and 7 were non-severe ADRs. Non-severe ADRs resolved within 48 hours. CONCLUSION: BNT162b2 Pfizer-BioNTech vaccine was safely administered in the largest cohort of cancer patients reported to date.

Totally Laparoscopic Resection with Transanal Natural Orifice Specimen Extraction for Deep Endometriosis Infiltrating the Rectum.

OBJECTIVE: To show the surgical steps used to perform a totally laparoscopic segmental rectal resection, with intracorporeal anastomosis and transanal natural orifice specimen extraction (NOSE), in a context of deep endometriosis. DESIGN: Step-by-step video demonstration of the technique. SETTING: Even though the combined use of intracorporeal anastomosis and NOSE has increasingly been investigated during the last decade, there is still lack of defined consensus, both in terms of patient eligibility and operative technique. In particular, experience with intracorporeal anastomosis and NOSE for treatment of deep rectal endometriosis is very limited. Preliminary reports have documented that a totally laparoscopic rectal resection is equally effective and safe compared with the conventional approach using an abdominal minilaparotomy for extracorporeal anastomosis and specimen retrieval. In comparison to the latter, intracorporeal anastomosis with NOSE seems to offer advantages in terms of less postoperative pain, fewer wound-related complications, better cosmetic results, quicker return of bowel function and shorter hospital stay. PATIENT: A 31-year-old woman with a history of constipation, dyschezia, dysmenorrhea, dyspareunia, and chronic pelvic pain unresponsive to hormonal therapies. Preoperative ultrasonography showed partial obliteration of the Douglas' pouch due to a rectal endometriotic nodule of 42 × 12 × 18 mm in contiguity with a deeply infiltrating retrocervical lesion of 13 × 3 × 17 mm. The rectal nodule resulted in the infiltration of the tunica muscularis with a distance of 12 cm from the anal verge and a circumferential extent of 45%. INTERVENTIONS: A 3-dimensional laparoscopic system was used. Rectal mobilization was performed according to our standardized technique [1]. After determining the proximal and distal resection margins, the rectum was transected using a tissue sealing-device. The resected specimen was placed in a retrieval bag and pulled out through the anus. Proximal and distal resection lines were closed using a 60 mm linear endo-stapler, and a totally intracorporeal, side-to-end anastomosis was performed using a 29 mm circular stapler. MAIN RESULTS: The overall operative time was 85 minutes. The estimated blood loss was 10 mL. Neither intra- nor postoperative complications occurred. The patient was discharged 5 days after surgery. The bowel endometriotic nodule measured 41 × 12 × 18 mm on the fresh unfixed specimen. CONCLUSIONS: Advanced surgical skills are needed to perform an effective and safe, totally laparoscopic rectal resection. The operative technique displayed in this video may contribute to the standardization of such surgical procedure. Accurate patient selection, including adequate preoperative evaluation, is of utmost importance for the best chance of surgical success.

Indocyanine green fluorescence angiography after full-thickness bowel resection for rectosigmoid endometriosis: A multicentric experience with quantitative analysis.

OBJECTIVE: To evaluate effectiveness and reproducibility of qualitative and quantitative near-infrared indocyanine green (NIR-ICG) analyses as a tool for anastomotic perfusion assessment after full-thickness bowel resection for rectosigmoid endometriosis (RSE). METHODS: Symptomatic women with RSE undergoing minimally invasive full-thickness surgical excision of RSE and NIR-ICG evaluation from November 2019 to July 2020 were included. Study outcomes were the accuracy of qualitative and quantitative NIR-ICG analyses in predicting bowel fistula and their reproducibility. NIR-ICG predictive accuracy was assessed by calculating sensitivity, specificity, and area under the curve on receiver operating characteristic curves with 95% confidence intervals (CI). NIR-ICG reproducibility was assessed through Cohen's k coefficient to determine interoperator agreement between two observers. RESULTS: Of 33 patients, 2 (6%) developed bowel fistula. In predicting bowel fistula, qualitative and quantitative NIR-ICG evaluations showed sensitivity of 100% and 100%, specificity of 71% and 93%, and area under the curve of 0.86 (95% CI 0.67-1.00) and 0.96 (95% CI 0-1.00), respectively. Regarding interoperator agreement rate, it was reported as excellent for the qualitative analysis and very good for the quantitative analysis. CONCLUSION: Qualitative and quantitative NIR-ICG evaluations might be effective and reproducible tools for anastomotic perfusion assessment after discoid or segmental resection for RSE. Quantitative evaluation might be even more effective than qualitative evaluation in predicting bowel fistula.

Preparation of intravenous chemotherapy bags: evaluation of a dose banding approach in an Italian oncology hospital.

Introduction: Dose banding is an original approach that manages intravenous (IV) chemotherapy preparation by generating on a weekly basis a series of bags containing scaled dosages of the active agent. These predetermined, fixed dosage bags are intended to replace the traditional bags prepared daily that contain fully individualized dosages. Methods: Three different scenarios were examined: (1) the current method of daily preparation of individualized bags at the hospital pharmacy; (2) the weekly preparation at the hospital pharmacy of non-individualized bags containing discrete, predefined doses covering an adequate range of doses (dose banding); (3) the use of commercial ready-to-use bags based on the same approach of dose banding. The objective of this study was to compare these three different approaches in terms of cost per patient. We considered five cancer drugs (gemcitabine, oxaliplatin, paclitaxel, trastuzumab and 5-fluorouracil) that were suitable for the dose ranging approach. Appropriate dose bands for these five agents were identified. Costs were estimated for each of the three approaches. Results: A total of 13,490 fully individualized bags were studied, which corresponded to the real bags prepared at our institution for these five agents in 2018. Dose banding was predicted to determine savings ranging from €10,998 (-0.84%) for trastuzumab to €169,429.60 (-8.39%) for paclitaxel. Conclusion: The introduction of dose banding can determine economic savings along with other advantages, such as improved work conditions, management reorganization and containment of waste. The pharmaceutical industry can hopefully support these experiences by producing ready-to-use bags in predetermined dosages.

Laparoscopic Technique for Discoid Resection of Rectal Endometriotic Nodules.

OBJECTIVE: To show the surgical steps used to perform a rectal disc excision in the context of deep infiltrating endometriosis characterized by contiguity between an intestinal lesion and the retrocervical region. DESIGN: Step-by-step video demonstration of the technique. SETTING: Although surgical options for the management of rectosigmoid endometriosis have been investigated increasingly, there is no consensus regarding patient eligibility for shaving, discoid resection, or segmental resection. In our practice, women with nodules ≤3 cm in size and >7 mm deep were considered as candidates for rectosigmoid disc excision [1]. Therefore patients' selection, together with the adoption of a standardized surgical technique, has allowed us to maximize the chance of a successful discoid resection, minimizing the complications potentially derivable from this surgical procedure. INTERVENTIONS: The patient was a 30-year-old woman with a history of constipation, dyschezia, dysmenorrhea, dyspareunia, and chronic pelvic pain unresponsive to hormonal therapies. A preoperative ultrasonography showed complete obliteration of the pouch of Douglas owing to a rectal endometriotic nodule (21 × 7 × 12 mm) in contiguity with a deeply infiltrating retrocervical lesion (28 × 10 × 27 mm). As a result, the rectal nodule infiltrated the tunica muscularis with a distance from the anal verge of 9 cm and an estimated stenosis of 35%. A 3-dimensional laparoscopy was performed. After rectal mobilization and rectovaginal space opening, the intestinal nodule was isolated in its entire circumference (Fig. 1). A 33-mm transanal circular stapler was inserted into the rectum through the anus and used to perform disc excision and suture the rectal wall. The overall operative time was 55 minutes. No intraoperative complication occurred. A complete excision of endometriosis was achieved. The estimated blood loss was 10 mL. An intra-abdominal drain was not placed, and the urinary catheter was removed at the end of the surgery. The patient was discharged 3 days after surgery and did not experience postoperative complications. The diameters of the bowel endometriotic nodule, on measuring fresh specimen, were 20 × 7 × 13 mm. CONCLUSIONS: Advanced laparoscopic surgical skills are needed to perform an effective and safe rectal discoid resection. Subspecialization and an adequate preoperative evaluation are of utmost importance to appropriately plan the treatment strategy against bowel endometriosis.

Preoperative Ultrasound Indications Determine Excision Technique for Bowel Surgery for Deep Infiltrating Endometriosis: A Single, High-Volume Center.

STUDY OBJECTIVE: To identify bowel nodule features of deep infiltrating endometriosis (DIE) measured through preoperative ultrasound scanning that influence laparoscopic surgical strategy. DESIGN: A retrospective study. SETTING: Malzoni Clinic-Endoscopica Malzoni Department, Center for Advanced Endoscopic Gynecological Surgery, Avellino, Italy. PATIENTS: Patients undergoing laparoscopic surgery between January 1, 2014, and December 31, 2018, for clinically suspected DIE with previous ultrasound evaluation ≤1 month before intervention. INTERVENTION: Use of sonographic measurements to determine laparoscopic excision technique (segmental bowel resection, discoid resection, shaving) for DIE with bowel involvement.``` MEASUREMENTS AND MAIN RESULTS: Of 5051 DIE surgeries, 4983 were included; 1494 (29.9%) bowel resections (512 bowel segmental resections and 982 nodulectomies [967 shaving and 15 discoid resections]) were performed, accounting for 34.3% and 65.7% of all bowel procedures, respectively. Preoperative sonographic findings and surgical reports were collected. Sensitivity and specificity of preoperative ultrasound evaluation for all types of DIE lesions were calculated, and sonographic measurements of bowel nodules and different surgical techniques were compared. According to preoperative sonographic measurements, most nodules excised by segmental resection had a longitudinal diameter of 3 to 7 cm, none were <3 cm; all nodules excised by nodulectomy (shaving or discoid resection) had a longitudinal diameter <3 cm. Mean thickness (maximum depth of muscular layer infiltration) of identified bowel nodules estimated through ultrasound scanning was 13.4 mm ± 4.8 mm (mean ± standard deviation) and 5.8 mm ± 2.7 mm for lesions removed by segmental resection and nodulectomy, respectively, and there was a statistically significant difference between them (p <.05). Of the 512 segmental resected bowel nodules, 143 (28%) had a maximum depth ≥9 mm, 354 (69%) had 7 to 9 mm, and 15 (3%) had <7 mm (6 mm, with length >4 cm). All shaved nodules had thickness ≤7 mm. The 15 nodules excised by discoid resection (1.5% of nodulectomies) were <25 mm, but thickness ranged from 7 to 9 mm. CONCLUSION: The need for segmental resection in DIE with bowel-infiltrating nodules depends on the degree of muscular layer infiltration and corresponding thickness (muscularis rule) in addition to nodule length and can be accurately identified by preoperative ultrasound evaluation.

Surgical Principles of Segmental Rectosigmoid Resection and Reanastomosis for Deep Infiltrating Endometriosis.

STUDY OBJECTIVE: To demonstrate the surgical steps involved in segmental rectosigmoid resection and reanastomosis in a deep infiltrating endometriosis (DIE) setting. DESIGN: Step-by-step video demonstration of the technique. SETTING: Despite efforts made to identify criteria able to reliably predict which patients would be more likely to benefit from segmental bowel resection, such predictability remains an area of controversy and ambiguity. Furthermore, a standardized surgical technique has not yet been defined. Based on our experience, patients with DIE and colorectal involvement should be considered for segmental resection followed by anastomosis if they present with lesions not suitable for shaving/nodulectomy (i.e., large, deeply infiltrating nodules with extensive circumferential involvement). In our practice, careful patient selection together with the adoption of a standardized surgical technique allowed us to minimize the potential complications associated with segmental bowel resection. INTERVENTION: The patient was a 27-year-old woman diagnosed by ultrasonography with a bowel endometriotic nodule of 33 × 8 × 14 mm infiltrating the inner layer of the muscularis propria at the rectosigmoid junction, with a distance from the anal verge of approximately 12 cm and an estimated stenosis of 50%. A 3-dimensional laparoscopic segmental rectosigmoid resection was performed, and indocyanine green-enhanced fluorescent angiography was used to assess perfusion of the bowel before completion of the anastomosis. The total operative time was 135 minutes, and no intraoperative complications occurred. Complete excision of endometriosis was achieved. The estimated blood loss was 30 mL. An intra-abdominal drain was not placed, and the urinary catheter was removed at the end of surgery. The patient was discharged at 6 days after surgery and did not experience any postoperative complications. The bowel endometriotic nodule measured 34 × 8 × 13 mm in a fresh specimen. CONCLUSION: Advanced laparoscopic surgical skills are needed to properly perform segmental rectosigmoid resection. Subspecialization and adequate pretreatment evaluation are crucial to ensure the correct decision making process within a complex algorithm for surgical management of bowel endometriosis.

Combined Transvaginal/Transabdominal Pelvic Ultrasonography Accurately Predicts the 3 Dimensions of Deep Infiltrating Bowel Endometriosis Measured after Surgery: A Prospective Study in a Specialized Center.

STUDY OBJECTIVE: To assess the sensitivity and accuracy of combined transvaginal/ transabdominal ultrasonography (TV/TA US) for evaluation of deep infiltrating bowel endometriosis nodules measured after surgery. DESIGN: Prospective study (Canadian Task Force classification II.1). SETTING: A center for advanced endoscopic gynecologic surgery. PATIENTS: All women undergoing laparoscopic surgery and scheduled for segmental resection for clinically suspected bowel endometriosis between January 2014 and December 2016. INTERVENTIONS: In all women with clinically suspected bowel endometriosis, a US scan was performed before surgery to detect and measure the 3 diameters of bowel endometriotic lesions: longitudinal, anteroposterior, and transverse. These diameters were compared with those obtained by direct measurement on a fresh specimen. The sensitivity and specificity values of US evaluation were calculated, with 95% confidence intervals. MEASUREMENTS AND MAIN RESULTS: The sensitivity and specificity of TV/TA US in the 328 patients of this study were 100% when rectal endometriotic lesions were investigated. The specificity was 100%, whereas the sensitivity decreased to 91.4% when sigmoid lesions were investigated. Bowel muscularis infiltration was histologically confirmed in all cases in which endometriotic lesions were detected by US (284 of 284; 100%). All missed sigmoid lesions (12 of 296) were located >25 cm from the anal verge. The mean diameters of endometriotic nodules calculated by US evaluation and by direct measurement on the fresh specimen were 43.19 × 19.87 × 10.79 mm and 42.76 × 19.64 × 10.62 mm, respectively, with no statistically significant differences between the 2 methods. CONCLUSION: We believe that US can be considered an accurate diagnostic technique for the evaluation of deep infiltrating bowel endometriosis when performed by a dedicated experienced sonographer in a specialized center.