Molecular Basis and Advances in Targeted Immunotherapy for Cancer.

Researchers have long attempted to stimulate the immune system of cancer patients as a therapeutic strategy [...].

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment.

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10-30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development.

Feasibility and safety of total laparoscopic hysterectomy for uteri weighing from 1.5 kg to 11.000 kg.

PURPOSE: To assess the feasibility and safety of total laparoscopic hysterectomy (TLH) for uteri ≥ 1.5 kg. METHODS: We prospectively evaluated all elective TLHs (with or without adnexectomy) performed for fibromatous uteri between August 2009 and August 2019 in the Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, and the Department of Gynecologic Oncology, Businco Hospital, Azienda Ospedaliera Brotzu, Cagliari. Patients with large myomatous uteri (uterine weight ≥ 1.5 kg on pathology reports) were included in the analysis. We examined all procedures and collected data about intra- and post-operative short-term and long-term complications, intraoperative blood loss, operative time, hospital stay, and time to achieve well-being. RESULTS: Seventy-eight patients were included. The median weight was 2,000 g (range 1,500-11,000 g), estimated blood loss was 100 mL (range 10-700 mL), operating time was 135 min (range 60-300 min), and hospital stay was 2 days (range 2-5 days). Conversion to laparotomy occurred in 4 patients (5.1%) with uterine weight ranging from 3 to 5.5 kg, due to severe adherence syndrome or inadequate visualization. As for intraoperative complications, 1 patient (who had the largest removed uterus weighing 11,000 g) experienced an intraoperative ureteral injury (grade III). No major postoperative complications occurred. CONCLUSIONS: This study provides the largest case series of TLH for fibromatous uteri > 1.5 kg and includes some of the largest uteri reported to date in the literature (weighing 5,320, 5,720, and 11,000 g, respectively). The study reaffirms the feasibility and safety of a minimally invasive hysterectomy even in the case of abnormally large uteri.

Laparoscopic splenectomy both for primary cytoreductive surgery for advanced ovarian cancer and for secondary surgery for isolated spleen recurrence: feasibility and technique.

BACKGROUND: This study investigated the feasibility and safety of laparoscopic splenectomy conducted in the contexts of both laparoscopic secondary surgery for isolated recurrence in the spleen and primary laparoscopic cytoreductive surgery for advanced ovarian cancer. METHODS: We performed a perspective observational study including all consecutive patients with ovarian cancer who underwent laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer or secondary surgery for isolated splenic recurrence between January 2016 and May 2020. RESULTS: We enrolled 13 consecutive patients, candidate to laparoscopic splenectomy as part of primary cytoreductive procedures for advanced stage ovarian cancer (6 patients) or secondary surgery for isolated splenic recurrence of platinum-sensitive ovarian cancer (7 patients). Median operative time (509 min [range, 200-845]) for primary cytoreductive surgery varied according to surgical complexity depending on the extensiveness of the disease. Median operative time for secondary surgery for isolated splenic metastasis was 253 min (90-380). Only 1 patient with isolated splenic recurrence required conversion to an open approach. No intraoperative complication occurred, and no intraoperative blood transfusions were required. Median hospital stay was 3 days (range, 2-5) for isolated recurrence and 9 days (7-18) for primary cytoreductive surgery. Complete tumor resection was achieved in all patients. Median time from surgery to adjuvant chemotherapy was 16 days (7-24). All six patients who underwent laparoscopic splenectomy during primary cytoreductive surgery remain alive, four of whom exhibit no evidence of disease (median follow-up 25 months [4-36]). Among patients who underwent laparoscopic splenectomy during secondary surgery for isolated splenic relapse, all patients are alive and only one had a central diaphragmatic relapse 2 years after surgery (median follow-up 17 months ([5-48 months]). CONCLUSIONS: The laparoscopic approach to splenectomy is feasible and safe both in patients undergoing primary cytoreductive surgery for advanced stage disease and those with isolated recurrence of ovarian cancer, without compromising survival and allowing early initiation of postoperative systemic chemotherapy.

Cachexia as Evidence of the Mechanisms of Resistance and Tolerance during the Evolution of Cancer Disease.

During its evolution, cancer induces changes in patients' energy metabolism that strongly affect the overall clinical state and are responsible for cancer-related cachexia syndrome. To better understand the mechanisms underlying cachexia and its metabolic derangements, research efforts should focus on the events that are driven by the immune system activation during the evolution of neoplastic disease and on the phenomena of "resistance" and "tolerance" typically involved in the human body response against stress, pathogens, or cancer. Indeed, in the case where resistance is not able to eliminate the cancer, tolerance mechanisms can utilize the symptoms of cachexia (anemia, anorexia, and fatigue) to counteract unregulated cancer growth. These notions are also sustained by the evidence that cancer cachexia may be reversible if the resistance and tolerance phases are supported by appropriate antineoplastic treatments. Accordingly, there is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cancer cachexia where, if harmoniously associated with effective antineoplastic therapies, they can contribute to preserve the quality of life and improve prognosis. Such anticachectic treatments should be based on targeting the complex immunological, inflammatory, and metabolic pathways involved in the complex pathogenesis of cachexia. Meanwhile, the role of the anticachectic therapies is very different in the stage of irreversible cachexia when the available antineoplastic treatments are not able to control the disease and the resistance mechanisms fail with the prevalence of the tolerance phenomena. At this stage, they can be useful only to improve the quality of life, allowing the patient and their family to get a better awareness of the final phases of life, thereby opening to the best spiritual remodulation of the final event, death.

Blocking inflammation to improve immunotherapy of advanced cancer.

The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T-cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

Laparoscopic removal of a very large uterus weighting 5320 g is feasible and safe: a case report.

BACKGROUND: Total laparoscopic hysterectomy (TLH) has demonstrated to be feasible and safe in the presence of very large uteri. However, it is currently difficult to establish the upper uterine weight limit for successful performance of a laparoscopic hysterectomy. CASE PRESENTATION: Here we report the case of a TLH performed for a very large fibromatous uteri weighing 5320 g in a 40-year-old Caucasian woman. The surgery had no complications with an operating time of approximately 220 min. The patient was discharged from the hospital on postoperative day 3 in very good condition. To our knowledge, the present paper is the only to describe a uterus of this size removed by laparoscopic hysterectomy. CONCLUSIONS: Our case demonstrates that uterine size is not a determinant for a final surgical decision to use laparoscopic hysterectomy. Therefore, if not contraindicated by the patient's comorbidities or peculiar anatomical conditions, we believe that laparoscopic hysterectomy could be performed in the presence of large uteri without hypothetical weight limits.

Long-Term Survival in a Patient With Abdominal Sarcomatosis From Uterine Leiomyosarcoma: Role of Repeated Laparoscopic Surgery in Treatment and Follow-Up.

Uterine leiomyosarcoma (LMS) in some cases may disseminate through the abdominal cavity, without extra-abdominal spreading, determining a condition of abdominal sarcomatosis, which represents a peculiar situation. Only radical surgical removal offers a chance of long-term survival in such cases of LMS. Here we describe a case of diffuse abdominal sarcomatosis from uterine LMS in a 51-year-old perimenopausal woman who underwent laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy, total pelvic peritonectomy, pelvic lymphadenectomy to the mesenteric inferior artery, and omentectomy. Then, given the high probability of disease recurrence, the patient underwent a close follow-up consisting of positron emission tomography (PET)/computed tomography every 3 months and diagnostic (and if necessary operative) laparoscopy every 6 months. To date, the patient had 11 laparoscopies; 5 of them were preceded by a PET indicative of the presence of disease with high metabolic activity, which was confirmed at surgery and each time completely removed laparoscopically with no evidence of residual disease. To date, 5 years from diagnosis the patient is alive and continues her follow-up. Our report brings to light the ability of laparoscopic surgery to obtain disease control in a case of LMS with abdominal dissemination. Moreover, laparoscopic surgery, as demonstrated in our case, may have an important role in the close follow-up of the disease and allow a timely and early radical surgical approach of relapses before they become extremely large and difficult to remove radically.

Surgical outcome and complications of total laparoscopic hysterectomy for very large myomatous uteri in relation to uterine weight: a prospective study in a continuous series of 461 procedures.

PURPOSE: To analyze whether a large uterine size was associated with increased rate of intraoperative and postoperative surgical complications in patients who underwent total laparoscopic hysterectomy (TLH) for myomatous uteri. METHODS: We examined prospectively data from 461 consecutive TLHs performed by a single surgeon between August 2004 and August 2014 at the Department of Obstetrics and Gynecology, Sirai Hospital, Carbonia, and at the Department of Gynecologic Oncology, Businco Hospital, Cagliari, Italy. Demographic and surgical data were stratified by uterine weight (range 90-5500 g) into four groups: <300 g; from 300 to 500 g; from 500 to 800 g; and >800 g. Outcomes examined included blood loss, operative time, intraoperative and postoperative complications, and duration of hospital stay. A linear regression analysis was performed to identify whether uterine weight was an independent predictor affecting these outcomes. In addition, BMI, previous surgery with adhesiolysis, and endometriosis were tested as a predictor of surgical complications and outcomes. RESULTS: No significant difference was found in intraoperative and postoperative complications, as well as hospital stay, by uterine weight. Increased uterine size was significantly associated with longer operative time and increased blood loss. Beside uterine weight, prior surgery was predictive of postoperative complications. In contrast, higher BMI was not associated with increased complication rate. Independent predictors of longer operative time included previous surgery, endometriosis, and BMI. CONCLUSIONS: Our results showed that in experienced hands, TLH is feasible and safe also in presence of very large uteri. TLH results in a few complications and short hospital stay regardless of uterine weight.

The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study.

Anemia in oncology patients is often considered a side effect of cancer therapy; however, it may occur before any antineoplastic treatment (cancer-related anemia). This study was aimed to evaluate the prevalence of cancer-related anemia in a large cohort of oncology patients and whether inflammation and malnutrition were predictive of its development and severity. The present study included 888 patients with cancer at different sites between May 2011 and January 2014. Patients were assessed at diagnosis before any cancer treatment. The prevalence of anemia according to the main clinical factors (tumor site, stage and performance status) was analyzed. In each patient markers of inflammation, iron metabolism, malnutrition and oxidative stress as well as the modified Glasgow prognostic score, a combined index of malnutrition and inflammation, were assessed and their role in predicting hemoglobin level was evaluated. The percentage of anemic patients was 63% with the lowest hemoglobin levels being found in the patients with most advanced cancer and compromised performance status. Hemoglobin concentration differed by tumor site and was lowest in patients with ovarian cancer. Hemoglobin concentration was inversely correlated with inflammatory markers, hepcidin, ferritin, erythropoietin and reactive oxygen species, and positively correlated with leptin, albumin, cholesterol and antioxidant enzymes. In multivariate analysis, stage, interleukin-6 and leptin were independent predictors of hemoglobin concentration. Furthermore, hemoglobin was inversely dependent on modified Glasgow Prognostic Score. In conclusion, cancer-related anemia is a multifactorial problem with immune, nutritional and metabolic components that affect its severity. Only a detailed assessment of the pathogenesis of cancer-related anemia may enable clinicians to provide safe and effective individualized treatment.

Muscle wasting as main evidence of energy impairment in cancer cachexia: future therapeutic approaches.

The present review aimed at discussing the impact, pathogenesis and therapeutic approaches of muscle wasting, which is a major clinical feature of cancer-related cachexia syndrome. The pathogenesis of muscle wasting in cancer cachexia lies in a discrepancy between anabolic and catabolic pathways mediated by chronic inflammation. Effective interventions specifically aimed at hampering muscle loss and enhancing muscle function are still lacking. Promising agents include anti-inflammatory, orexigenic and anabolic drugs, alongside with nutritional supplements that influence the STAT3 and PI3K/Akt/mTOR pathways involved in muscle wasting. Personalized physical activity combined with pharmacological and nutritional support hold promise. A greater understanding of the pathogenetic processes of cancer cachexia-related muscle wasting will enable the development of an early and effective targeted mechanism-based multimodal approach.

Role of inflammation and oxidative stress in post-menopausal oestrogen-dependent breast cancer.

Weight gain and obesity are among the most important risk factors for post-menopausal oestrogen-dependent breast cancer (EDBC). Weight gain is associated with oxidative stress, which in turn promotes breast cancer progression. We carried out a prospective study in 216 consecutive post-menopausal breast cancer patients aiming to examine the correlations between traditional prognostic factors (tumour size, T, nodal, N, grading, G, and metastasis status, M), and body mass index (BMI), leptin, pro-inflammatory cytokines (Interleukin, IL,-6 and tumour necrosis factor-alpha, TNF-α), and oxidative stress (reactive oxygen species, ROS, glutathione peroxidase, GPx, superoxide dismutase, SOD) among patients with oestrogen receptor (ER)+ and ER- breast cancers. Distribution of T, N and M categories did not differ between ER+ and ER- breast cancer patients. ER- patients showed a higher incidence of G3 tumours. Weight, BMI, leptin, IL-6 and ROS were higher in ER+ compared with ER- patients. Among ER+ patients, BMI, leptin, IL-6 and ROS correlated with T and M. Leptin, IL-6 and ROS were positively correlated also with N. Among ER- patients, BMI and leptin did not correlate with any of prognostic parameters, whereas a positive correlation between IL-6, ROS and M was found. Multivariate regression analysis showed that BMI, leptin, IL-6 and ROS were predictive for T, N and M in ER+ patients. Weight gain, inflammation and oxidative stress are involved in EDBC prognosis. Their modulation through antidiabetic, anti-inflammatory and antioxidants drugs combined with endocrine therapy may constitute a targeted approach in post-menopausal EDBC.

Large twisted ovarian fibroma associated with Meigs' syndrome, abdominal pain and severe anemia treated by laparoscopic surgery.

BACKGROUND: The Meigs' syndrome is a rare but well-known syndrome defined as the triad of benign solid ovarian tumor, ascites, and pleural effusion. Meigs' syndrome always requires surgical treatment. However, the optimal approach for its management has not been sufficiently investigated. CASE PRESENTATION: We report a patient with a large twisted ovarian fibroma associated with Meigs' syndrome, abdominal pain and severe hemolytic anemia that was treated by laparoscopic surgery. This case highlights the difficulties that may be encountered in the management of patients with Meigs' syndrome, including potential misdiagnosis of the tumor as a malignant ovarian neoplasm that may influence the medical and surgical approach and the adverse impact that Meigs' syndrome can have on the patient's condition, especially if it is associated with acute pain and severe anemia. Considering the patient's serious clinical condition and assuming that she had Meigs' syndrome with a twisted large ovarian mass and possible hemolytic anemia, we first concentrated on effective medical management of our patient and chose the most appropriate surgical treatment after laparoscopic examination. The main aim of our initial approach was preoperative management of the anemia. Blood transfusions and glucocorticoid therapy resulted in stabilization of the hemoglobin level and normalization of the bilirubin levels, which confirmed the appropriateness of this approach. Laparoscopic surgery 4 days after admission enabled definitive diagnosis of the tumor, confirmed torsion and removed the bulky ovarian fibroma, resulting in timely resolution of symptoms, short hospitalization, relatively low morbidity and a rapid return to her social and professional life. CONCLUSIONS: This case highlights the difficulties that may be encountered in the management of patients with Meigs' syndrome, including potential misdiagnosis of the tumor as a malignant ovarian neoplasm that may influence the medical and surgical approach, and the adverse impact that Meigs' syndrome can have on the patient's condition, especially if it is associated with acute pain and severe anemia. The present case suggests that laparoscopic surgery for potentially large malignant tumors is feasible and safe, but requires an appropriate medical and gynecological oncology expertise.

Complicated enterocele: timely resolution with bowel resection via a vaginal approach: case report.

Background: Enterocele is an uncommon, serious condition that requires accurate and early diagnosis to prevent complications such as intestinal obstruction, incarceration, and strangulation, with consequent intestinal ischemia, necrosis, and evisceration. We report a rare case of a patient with a voluminous enterocele and initial signs of intestinal ischemia who underwent urgent vaginal surgery. Case description: An 80-year-old woman presented with a voluminous mass protruding from the vagina, associated abdominopelvic pain, a 10-day history of bowel sub-occlusion, and numerous episodes of profuse vaginal bleeding. She was diagnosed with an enterocele with early signs of complications. Owing to her advanced clinical condition and comorbidities, we opted for an urgent vaginal procedure. Intestinal loops with initial signs of ischemia were resected via a transvaginal approach, leading to good clinical outcomes. She was discharged on postoperative day 5. Conclusions: This rare case highlights a surgical emergency that was managed with transvaginal resection of the intestine. Early identification of the initial signs of complications allowed for this less invasive approach, resulting in reduced morbidity and length of hospital stay.

Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.

Survival as a clinical outcome and its spiritual significance in a cohort of patients with advanced central pelvic neoplastic disease undergoing total pelvic evisceration: a poorly debated issue.

Background: Patients with either treatment-resistant or relapsing advanced central pelvic neoplastic disease present with a condition responsible for debilitating symptoms and consequently poor quality of life (QoL). For these patients, therapeutic strategies are very limited and total pelvic evisceration is the only option for relieving the symptoms and increasing survival. Of note, taking charge of these patients cannot be limited to increasing their lifespan but must also be aimed at improving the clinical, psychological, and spiritual conditions. This study aimed to prospectively evaluate the improvement in survival and QoL, focusing on spiritual wellbeing (SWB), in patients with poor life expectancy who underwent total pelvic evisceration for advanced gynecological cancers at our center. Patients and methods: The QoL and SWB were assessed using the European Organisation for Research and Treatment of Cancer QoL questionnaire (EORTC QLQ-C30), EORTC QLQ-SWB32, and SWB scale, which were repeatedly administered: 30 days before surgery, 7 days after the procedure, 1 and 3 months after surgery, and then every 3 months until death or the last follow-up assessment. Operative outcomes (blood loss, operative time, hospitalization, and incidence of complications) were evaluated as secondary endpoints. The patients and their families were included in a dedicated psycho-oncological and spiritual support protocol, which was managed by specifically trained and specialized personnel who accompanied them during all phases of the study. Results: A total of 20 consecutive patients from 2017 to 2022 were included in this study. Of these patients, 7 underwent total pelvic evisceration by laparotomy and 13 underwent laparoscopy. The median survival was 24 months (range: 1-61 months). After a median follow-up of 24 months, 16 (80%) and 10 patients (50%) were alive at 1 year and 2 years after surgery, respectively. The EORTC-QLQ-C30 scores significantly improved yet at 7 days and at 1, 3, 6, and 12 months, as compared with the preoperative values. In particular, an early improvement in pain, overall QoL, and physical and emotional functions was observed. With respect to the SWB, the global SWB item score of the EORTC QLQ-SWB32 questionnaire significantly increased after 1 month and 3 months, as compared with preoperative values (p = 0.0153 and p = 0.0018, respectively), and remained stable thereafter. The mean SWB scale score was 53.3, with a sense of low overall SWB in 10 patients, a sense of moderate SWB in eight patients, and a sense of high SWB in two patients. The SWB scale score significantly increased after 7 days, 1 month, and 3 months, as compared with the preoperative value (p = 0202, p = 0.0171, and p = 0.0255, respectively), and remained stable thereafter. Conclusion: Total pelvic evisceration is a valid approach for improving both survival and QoL in selected patients with advanced pelvic neoplasms and poor life expectancy. Our results particularly underline the importance of accompanying the patients and their families during the journey with dedicated psychological and spiritual support protocols.