HER2 mutation as an emerging target in advanced breast cancer.

HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.

Posterior and Para-Aortic (D2plus) Lymphadenectomy after Neoadjuvant/Conversion Therapy for Locally Advanced/Oligometastatic Gastric Cancer.

Super-extended (D2plus) lymphadenectomy after chemotherapy has been reported in only a few studies. This retrospective study evaluates survival outcomes in a Western cohort of locally advanced or oligometastatic gastric cancer patients who underwent D2plus lymphadenectomy after neoadjuvant chemotherapy. A total of 97 patients treated between 2010 and 2022 were included. Of these, 62 had clinical stage II/III disease, and 35 had stage IV disease. Most patients (65%) received preoperative DOC/FLOT chemotherapy. The mean number of lymph nodes harvested was 39. Pathological positive nodes in the posterior/para-aortic stations occurred in 17 (17.5%) patients. Lymphovascular invasion, ypN stage, clinical stage, and perineural invasion were predictive factors for positive posterior/para-aortic nodes. Postoperative complications occurred in 21 patients, whereas severe complications (grade III or more) occurred in 9 cases (9.3%). Mortality rate was 1%. Median overall survival (OS) was 59 months (95% CI: 13-106), with a five-year survival rate of 49 ± 6%; the five-year OS after R0 surgery was 60 ± 7%. In patients with positive posterior/para-aortic nodes, the median OS was 15 months (95% CI: 13-18). D2plus lymphadenectomy after chemotherapy for locally advanced or oligometastatic gastric cancer is feasible and associated with low morbidity/mortality rates. The incidence of pathological metastases in posterior/para-aortic nodes is not negligible even after systemic chemotherapy, with poor long-term survival.

Surgical site infections in patients undergoing breast oncological surgery during the lockdown: An unexpected lesson from the COVID-19 pandemic.

Background: The present study aims to evaluate how the measures to contain the SARS-CoV-2 spreading affected the surgical site infections (SSIs) rate in patients who underwent nondeferrable breast cancer surgery (BCS). Methods: This study is a retrospective analysis of prospectively collected data from a consecutive series of patients underwent nondeferrable BCS in a regional Italian Covid-free hub during two different period: March to April 2020 (pandemic cohort [PC]) and March till April 2019 (control cohort [CC]). SSIs were defined according to the criteria established by the Center for disease control and prevention (CDC) and additional treatment, serous discharge, erythema, purulent exudate, separation of deep tissues, isolation of bacteria, and stay (ASEPSIS) scoring systems. Results: One hundred ninety-nine patients were included in the present study: 100 and 99 patients who underwent nondeferrable BCS from March to April 2020 (PC) and from March to April 2019 (CC), respectively. The overall SSIs rate in this series was 9.1% according to CDC criteria and 6.5% according to ASEPSIS criteria. The SSIs incidence decreased during the pandemic period. Moreover, the SSIs rate according to ASEPSIS criteria was statistically lower in the PC than in the CC. We observed significant evidence of higher SSIs, both in terms of CDC and ASEPSIS score, in patients having undergone breast reconstruction compared with patients not undergoing immediate reconstruction. Conclusions: The restrictive measures issued during the lockdown period seemed to lower the SSIs rates in patients undergoing nondeferrable BCS.

The Percentage of Signet Ring Cells Is Inversely Related to Aggressive Behavior and Poor Prognosis in Mixed-Type Gastric Cancer.

Background and Objectives: Only recently the percentage of signet ring cells (SRCs) in gastric cancer (GC) has been proposed as an independent predictor of survival. High amounts of SRCs have been related to lower recurrence and mortality rates, better prognosis, and favorable clinicopathological features in a poorly cohesive histotype. It is not known what the effect of SRC percentage in mixed-type GC is. We investigate the role of SRCs as a prognostic marker in mixed-histotype GC. Methods: A retrospective analysis was performed through a prospectively maintained database of patients with diagnosed "mixed-type" gastric carcinoma, defined according to 2019 WHO classification. These patients underwent surgery between 1995 and 2016, and their tissue samples were stored in a tissue bank. All slides were analyzed, and patients were divided into three groups according to the percentage of SRCs: "Group 1" (displaying ≤10% of SRCs), "Group 2" (displaying <90% but >10% of SRCs), and "Group 3" (displaying ≥90% of SRCs). We compared clinical and pathological features as well as prognostic factors between the different groups. Results: Among 164 enrolled patients, 68.9% were male and 31.1% were female (p = 0.612). The mean (±SD) age at diagnosis was 71.4 ± 9.6 years. Ninety-eight (59.7%) patients were classified as "Group 1", 66 (40.3%) as "Group 2", and none as "Group 3". Five-year overall survival was remarkably higher in Group 2 (73.8%) in comparison to Group 1 (35.4%), p < 0.001. Mortality risk was three times higher in patients with ≤10% SRC pattern compared to those with >10% [HR 2.70 (95% CI 1.72-4.24)]. After adjusting according to potential confounding factors, SRC percentage was still an independent predictor of survival. Conclusions: The proportion of SRCs is inversely related to aggressive behavior and poor prognosis in mixed-type GCs, highlighting the role of SRC amount as an independent predictor of survival.

Signet ring cell percentage in poorly cohesive gastric cancer patients: A potential novel predictor of survival.

BACKGROUND AND OBJECTIVES: Signet ring cells (SRC) are widely acknowledged as a prognostically unfavorable histotype amongst poorly cohesive gastric cancer. In this study we evaluated the impact of SRC percentage on the clinical, pathological and prognostic features of these tumors according to the classification by the European Chapter of the IGCA. METHODS: We retrospectively reviewed records of patients with poorly cohesive gastric cancer that underwent surgery between 1995 and 2016, whose tissue specimens were available in a biological bank. All slides were put under revision, patients were reclassified into three groups according to the proportion of signet ring cells: "pure" SRC (containing ≥90% of SRCs), Poorly Cohesive-Not Otherwise Specified (PC-NOS) (containing ≤10% of SRCs), and PC-NOS/SRC (containing <90% but >10% of SRCs). The clinicopathological factors between different types were analyzed and prognostic differences were compared. RESULTS: Among 143 enrolled patients, 51% were male and 49% were female. The mean (±SD) age at diagnosis was 61 ± 13.9 years. Eighty-seven patients (60.8%) were reclassified as PC-NOS, 56 (39.2%) as PC-NOS/SRC and none as "pure" SRC. Five-years overall survival was significantly higher in PC-NOS/SRC group (63.3%) compared with PC-NOS group (12.7%). The increase in mortality risk was more than four-fold in patients with PC-NOS pattern compared to those with PC-NOS/SRC (HR 4.32 [95% CI 2.5-7.4]. After adjustment for potential confounding factors, SRC pattern was still an independent predictor of survival. CONCLUSIONS: The percentage of SRCs is inversely related to tumor aggressiveness, confirming the role of SRC pattern as an independent predictor of survival.

Reverse strategy to locally advanced breast implant-associated anaplastic large cell lymphoma: A case report.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma associated with textured breast implants. The most common presentation is a periprosthetic seroma that occurs at least 1 year after an aesthetic or reconstructive implantation, and in these cases, the surgical treatment seems to be successful. More rarely, BIA-ALCL presents with locally advanced mass-formed disease and a related regional lymph node involvement. In all these cases with worse prognosis, a multidisciplinary approach is required, including adjuvant chemotherapy, radiation therapy, and surgery. We present a clinical case of a 49-year-old woman who developed on the left side of the breast a mass-formed stage 3 BIA-ALCL 15 years after a bilateral breast augmentation with textured silicone implant. Our multidisciplinary team (MDT) scheduled the patient for a "reverse-strategy" sequential approach consisting of induction chemotherapy, hematopoietic stem cell mobilization, and harvest followed by autologous stem cell transplant (ASCT). After 100 days from the stem cell transplant, the patient showed a complete pathologic response and was a candidate for radical surgery. She underwent removal of both implants with total en bloc capsulectomy. On the left site, the periprosthetic mass was also en bloc removed. We did not perform any axillary dissection. Our surgical and hemato-oncological teams followed the patient every 3 months, and no local or systemic recurrences were observed 24 months after surgery. This case report has demonstrated the effectiveness of neoadjuvant chemotherapy as part of a "reverse strategy" in selected cases of advanced-stage BIA-ALCL in which it was not possible to perform an immediate radical surgery. Furthermore, in our case, the de-escalation strategy adopted permitted a less demolitic surgery with good functional and aesthetic results.

Breast cancer surgery during the Covid-19 pandemic: a monocentre experience from the Regina Elena National Cancer Institute of Rome.

The Covid-19 pandemic has challenged hard the national health systems worldwide. According to the national policy issued in March 2020 in response to the evolving Covid-19 pandemic, several hospitals were re-configured as Covid-19 centers and elective surgery procedures were rescheduled according to the most recent recommendations. In addition, Covid-19 protected cancer hubs were established, including the Regina Elena National Cancer Institute of Rome, Central Italy. At our Institute, the Breast Surgery Department continued working under the sign of a multidisciplinary approach. The number of professional figures involved in case evaluation was reduced to a minimum and interactions took place in the full respect of the required safety measures. Treatments for benign disease, pure prophylactic surgery and elective reconstructive procedures were all postponed and priority was assigned to the histologically-proven malignant breast tumors and highly suspicious lesions. From March 15th though April 30th 2020, we treated a total of 79 patients. This number is fully consistent with the average quantitative standards reached by our Department under ordinary circumstances. Patients were mostly discharged the day after surgery and none was readmitted due to surgery-related late complications. More generally, post-operative complications rates were unexpectedly low, particularly in light of the relatively high number of reconstructive procedures performed in this emergency situation. A strict follow up was performed based on the close contact with the surgical staff by telephone, messaging apps and telemedicine.Patients ascertainment for their Covid-19 status prior to hospital admission and hospital discharge allowed to maintain the "no-Covid-19" status at our Institution. In addition, during the aforementioned time window, none of the care providers developed SARS-CoV-2 infection or disease, as shown by the results of anti-SARS-CoV-2 immunoglobulin M and G profiling. In conclusions, elective breast cancer surgery procedures were successfully performed in a lockdown situation due to a novel viral pandemic. The well-coordinated regional and hospital efforts in terms of medical resource re-allocation and definition of clinical priorities allowed to maintain high quality standards of breast cancer care while ensuring safety to the cancer patients and care providers involved.

Schwannomas of the sciatic nerve: A rare and neglected diagnosis. A review of the literature with two illustrative cases.

OBJECTIVE: Schwannomas of the sciatic nerve, which is the largest nerve of the human body, are very rare accounting for ≤ 1% of all schwannomas. They often may raise confusion with other more common causes of sciatica, such as lumbar degenerative and inflammatory diseases or spinal tumors, which may often lead to a late correct diagnosis. PATIENTS AND METHODS: We present two cases of sciatic nerve schwannomas that were recently treated at our Institution, and we review the pertinent English literature on this topic over the last 15 years, yielding twenty three cases to analyze. RESULTS: Even if sciatic nerve schwannomas are a rare occurrence, a thorough clinical and radiological evaluation of the sciatic nerve should be considered whenever a sciatic pain is not otherwise explained. A positive Tinel sign and a palpable mass along the course of the sciatic nerve may be strong clues to achieve the diagnosis. Combined morphological and advanced functional MRI imaging may help to differentiate benign from malignant peripheral nerve sheath tumors, avoiding unnecessary preoperative biopsy. CONCLUSIONS: A standard microsurgical technique guided by ultrasound and neurophysiologic monitoring, allows in most of the cases a safe removal of the tumor and very satisfactory post-operative results for the patients.

Outcome Evaluation after 2023 Nipple-Sparing Mastectomies: Our Experience.

BACKGROUND: Although quadrantectomy and lumpectomy help diminish the psychological and physical devastation inflicted, mastectomy is still elected in 20 to 30 percent of breast cancers. Although initially inciting controversy over heightened risk of local recurrences, recent studies maintain that nipple-sparing mastectomy can be used in any patient qualifying for total mastectomy and also improves aesthetic and psychologic outcomes. The manner in which mastectomy influences reconstructive implant outcomes has been documented by several groups. This report details the authors' experience performing nipple-sparing mastectomy with immediate implant-based breast reconstruction, focusing attention on patient characteristics and aspects of surgical mastectomy that influence reconstruction outcomes. The aim of the study was to examine various issues, such as surgical access, mode of tissue dissection, and flap thickness, clearly linked to development of complications and poor results. METHODS: A retrospective study was conducted, analyzing patients with breast cancer. An external three-surgeon panel served to generate average scores for predefined parameters. Based on total scores, outcomes were designated excellent, good, moderate, or poor. RESULTS: The authors' cohort included 1647 patients. Overall, 2023 nipple-sparing mastectomies were performed, including bilateral procedures in 376 patients. After a minimum follow-up period of 12 months, the authors' cohort was stratified by scored outcomes. Significant impact of body mass index, skin incision, flap thickness, and grade of ptosis has been demonstrated. CONCLUSIONS: The authors' data suggest that proper patient selection and well-executed operations are mandatory to limit complications. They also indicate that aesthetic outcome is clearly dependent on surgical proficiency and some patient characteristics. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reconstruction after musculoskeletal sarcomas: how to avoid a surgical trap.

BACKGROUND: Musculoskeletal sarcomas comprise 1% of all malignancies in adults. Unfortunately, sometimes they are addressed in non-appropriate way requiring a more invasive procedure to achieve radical surgery at a later date. Due to incomplete predictability of their extension, scheduled reconstruction cannot be performed at times, forcing plans to change or clogging up immediate reconstruction. In this paper, the authors provide an insight in the treatment of musculoskeletal sarcomas, particularly focusing on the preoperative planning of reconstructive strategies, which is crucial in order to prevent unpleasant surprises during reconstruction. METHODS: Fifty-six consecutive patients requiring reconstructive procedures following the extirpation of tumors were recruited. All data collected during the diagnostic phase were analyzed collectively during a multi-disciplinary meeting where the surgical procedure was planned. A score system was created and results were then classified into "excellent", "good", "sufficient" and "poor". RESULTS: After a minimum follow up of 12 months, we recorded the following results: excellent in 10 patients (17.9%), good in 28 patients (50%), sufficient in 12 cases (21.4%) and poor in 6 cases (10.7%). CONCLUSIONS: The improvement of treatment and the long-lasting survival in musculoskeletal sarcoma have shifted the goal of therapeutic protocol to obtaining radical tumor removal and maximum functional restoration. When facing unpredictable extension of the resections, reconstruction may be a challenging or even impossible task to fulfil. Only meticulous preoperative planning can prevent surgeons from falling into all sorts of surgical traps following wide resections.

Radiotherapy following surgery in keloid treatment: our protocol.

BACKGROUND: Despite the wide availability of literature on keloids, their onset is not completely understood. Several protocols have been described to treat keloids, but none are considered to be a gold standard. In this paper, we will report our experience treating recurrent keloids with surgical excision, followed by immediate postoperative radiotherapy, focusing on the irradiation protocol, to better define the treatment schedule, dose, and results. METHODS: From September 2009 to July 2012, 10 patients were referred to our department because of unresponsive keloids. All patients underwent 6-MeV electron beam radiotherapy, up to a total dose of 20 Gy, 24-48 hours after radical surgical keloid excision. RESULTS: Three patients had excellent results, while 5 patients had good results and 2 had moderate results; none of the cases had poor results. No major adverse events were observed. Small keloids can be treated with non-surgical therapy or radical excision, although followed by an adjuvant therapy. Radiotherapy seems to be a better adjuvant approach. The mechanism for the radiotherapeutic prevention of keloids is still poorly understood. It may act by controlling collagen synthesis through the elimination of abnormally-activated fibroblasts. CONCLUSIONS: From our results, postoperative electron radiotherapy is an effective and well-tolerated treatment to prevent keloid recurrence, especially in patients with bulky keloids or recurrent disease.

Skin-reducing mastectomy and immediate breast reconstruction in patients with macromastia.

INTRODUCTION: In women with macromastia, a type IV skin sparing mastectomy is often required to achieve an aesthetically pleasing reconstruction. The introduction of "skin-reducing mastectomy", which inserts a permanent prosthetic device into a large pouch made by the pectoralis major muscle and an inferior pedicle dermal flap, allows the surgeon to achieve a safe oncologic result plus a cosmetically satisfying reconstruction. OBJECTIVE: We report here our experience with the skin-reducing mastectomy with the aim of emphasizing the problems associated with the technique. MATERIALS AND METHOD: A study was conduced from April 2009 to November 2012, 74 patients with breast cancer were selected then received a skin-reducing mastectomy. The enrolled women satisfied the criteria of Nava. Statistical analysis was conduced to estimate the significance of the outcome results and complication rate. RESULT: A total of 88 SRMs were performed and the outcomes were as follows: excellent in 34 patients, good in 21, and poor in 8. We recorded 25 % of adverse events and statistic helped us to identify patient related factors whose can increase the complications onset. CONCLUSION: Skin-reducing mastectomy is an indispensable procedure to treat cancer in large and pendulous breasts. The correct patient selection is mandatory to reduce the not negligible complication risk. Skin reducing mastectomy when is well conduced allow to obtain good results with patient satisfaction but, like other breast-conserving surgeries, in some case is not the ultimate solution, because it may require some revisions to maintain the optimum results. To day it be consider relatively safe in selected patient and the gold standard in macormastia immediate reconstruction.

Intestinal Stenosis of Garré: An Old Problem Revisited.

BACKGROUND: Intestinal stenosis of Garré, first described in 1892, is a rare condition as a consequence of a complicated strangulated hernia. Preoperative diagnosis is challenging because of unspecific symptoms. Proper anamnesis, especially in terms of clinical and surgical history, as well as careful examination of both inguinal spaces is essential. CASE REPORT: We herein present a case of intestinal stenosis of Garré in a 70-year-old female. CONCLUSION: Intestinal stenosis of Garré should be considered in cases of occlusive symptoms occurring after a non-operative or surgical reduction of a strangulated hernia. A correct diagnosis and an adequate surgical treatment are necessary to solve this rare complication favorably.

Nerve growth factor expression in human dystrophic muscles.

Nerve growth factor (NGF) is a neurotrophin that is expressed during muscle development and is also capable of favoring muscle regeneration in experimental studies. The presence of NGF in muscular dystrophies, such as Duchenne and Becker muscular dystrophies, has never been fully explored. By means of immunohistochemistry, we show that regenerating muscle fibers from such patients consistently express NGF, as do myofibroblasts and mast cells. By contrast, rest fibers from dystrophic patients, as well as muscle fibers from healthy, control patients and even regenerative muscle fibers in polymyositis do not show NGF immunoreactivity. The paracrine effect of NGF on muscle regeneration, as well as its chemoattractant capacities for mast cells, may contribute to explaining why regenerating fibers most frequently occur in clusters and why mast cells are more numerous in dystrophic muscles. Moreover, being a mediator of wound healing and tissue fibrosis, NGF may contribute to long-term muscle regeneration impairment by tissue fibrosis in the muscular dystrophies.