Giuseppe Sammarco

Background: Almost 30% of patients with rectal cancer (RC) who submit to comprehensive treatment experience relapse. Surveillance plays a leading role in early detection. The landmark approach provides a more flexible and dynamic framework for survival prediction. Objective: This large retrospective study aims to develop a machine learning algorithm to profile the patient prognosis, especially the risk and the onset of RC relapse after curative resection. Methods: A cohort of 2450 RC patients were analyzed using landmark analysis. Model A applied a classical cause-specific Cox approach with a landmarking approach, while Model B implemented a landmarking-based RSF (random survival forest) competing risk algorithm. The two models were compared in terms of predictive and interpretative ability. A bootstrapped validation strategy was employed to validate the model’s performance and prevent overfitting. The best-performing hyperparameters were selected systematically, ensuring the model’s robustness within the landmark approach. The study assessed these factors’ importance and interactions using RSF and compared the predictive accuracy to that of the classical Cox model. Results: Model B outperformed Model A (mean C-index 0.95 vs. 0.78), capturing complex interactions and providing dynamic, individualized relapse predictions. Clinical factors influencing survival outcomes were identified across time with the landmark approach allowing for more accurate and timely predictions. Conclusions: The landmark approach offers an improvement over traditional methods in survival analysis. By accommodating time-dependent variables and the evolving nature of patient data, this approach provides a precise tool for profiling RC survival, thereby supporting more informed and dynamic clinical decision-making.

Colorectal cancer (CRC) is a genetically, anatomically, and transcriptionally heterogeneous disease. The prognosis for a CRC patient depends on the stage of the tumor at diagnosis and widely differs accordingly. The tumor microenvironment (TME) in CRC is an important factor affecting targeted cancer therapy. The TME has a dynamic composition including various cell types, such as cancer-associated fibroblasts, tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, as well as extracellular factors that surround cancer cells and have functional and structural roles under physiological and pathological conditions. Moreover, the TME can limit the efficacy of therapeutic agents through high interstitial pressure, fibrosis, and the degradation of the therapeutic agents by enzymatic activity. For this reason, the TME is a fertile ground for the discovery of new drugs. The aim of this narrative review is to present current knowledge and future perspectives regarding the TME composition based on strategies for patients with CRC.

Background: Pain is the most common complication after open excisional hemorrhoidectomy (OEH). We assessed the effectiveness of polycarbophil and Propionibacterium acnes lysate gel (Emorsan^®Gel) on pain control after OEH. Research design and methods: Fifty consecutive patients undergoing OEH were included. All patients received stool softeners and oral analgesia in the post-operative period. Emorsan^®Gel was also used topically by the last 25 patients (Emorsan^®Gel group (EG)) until Post-Operative Day 20 (POD 20). The primary outcome was the effectiveness of Emorsan^®Gel on pain relief using an 11-point visual analogue scale (VAS). Morbidity, wound healing (WH), and time to work were documented at POD 1, POD 10, POD 20, and POD 40. Results: Of the 50 patients enrolled, twenty-eight (56%) were males; median age, 49 (range, 28–73) years. The VAS score decreased over time in all patients, with significantly lower scores at POD 20 in the EG (1.44 (SD, 1.16) vs. 2.12 (0.93) in the control group (CG); p = 0.045). All patients in the EG achieved complete WH at last follow-up, compared to only 17 (68%) in the CG (p = 0.004). The likelihood of WH was 66% higher in the EG (OR, 1.66 [95%CI, 0.80–3.44; p = 0.172). Conclusions: Emorsan^®Gel is safe and effective at reducing pain after EOH, promoting earlier WH compared to standard care treatment.

Crohn’s Disease (CD) is a chronic inflammatory disorder that potentially involves the entire gastrointestinal tract. Perianal fistulizing CD (pCD) is a serious and frequent complication associated with significant morbidities and a heavy negative impact on quality of life. The aim of CD treatment is to induce and maintain disease remission and to promote mucosal repair. Unfortunately, even the best therapeutic regimens in pCD do not have long-term efficacy and cause a significant number of side effects. Therefore, it is mandatory to study new therapeutical options such as the use of mesenchymal stromal cells (MSCs). These cells promote tissue repair via the induction of immunomodulation. The present review aims to analyze the existing updated scientific literature on MSCs adoption in the treatment of pCD to evaluate its efficacy and safety and to compare the use of bone marrow and adipose tissue derived MSCs, type of administration, and dose required for recovery.

Colorectal cancer (CRC) is a heterogeneous disease, molecularly and anatomically, that develops in a multi-step process requiring the accumulation of several genetic or epigenetic mutations that lead to the gradual transformation of normal mucosa into cancer. In fact, tumorigenesis is extremely complex, with many immunologic and non-immunologic factors present in the tumor microenvironment that can influence tumorigenesis. In the last few years, a role for mast cells (MCs), microRNAs (miRNAs), Kirsten rat sarcoma (KRAS) and v-raf murine sarcoma viral oncogene homologue B (BRAF) in cancer development and progression has been suggested, and numerous efforts have been made to thoroughly assess their correlation with CRC to improve patient survival and quality of life. The identification of easily measurable, non-invasive and cost-effective biomarkers, the so-called “ideal biomarkers”, for CRC screening and treatment remains a high priority. The aim of this review is to discuss the emerging role of mast cells (MCs), microRNAs (miRNAs), KRAS and BRAF as diagnostic and prognostic biomarkers for CRC, evaluating their influence as potential therapy targets in the forthcoming era of precision medicine.

Despite total thyroidectomy (TT) is the most practiced procedure for a preoperatively diagnosed neoplastic lesion, according to the ATA guidelines, many surgeons perform completion thyroidectomy (CT) after hemithyroidectomy for patients with preoperative follicular proliferation/indeterminate cytology who are diagnosed with malignancy. CT has a higher complication rate than the primary procedure. The primary endpoint of our study is to compare the morbidity rate after CT with that after primary TT in patients with follicular proliferation/indeterminate cytology. We retrospectively reviewed 237 patients who underwent thyroid surgery from 2009 to 2018 at our institution. We recruited only patients with follicular proliferation/indeterminate cytology and excluded those undergoing lymphadenectomies and thyroidectomies for benign pathology and staged thyroidectomies after intraoperative documentation of a RLN lesion. One hundred eighty-six of these patients underwent TT, and fifty-one underwent CT for the detection of differentiated thyroid cancer at the histological exam. No differences were found in the total complication rates between the two groups (OR 0,76, 95% CI 0.35–1.65, P = 0.49). We did not find any significant differences in the subgroup analysis. In particular, no significant differences were identified for transient hypocalcaemia (OR 1.17, 95% CI 0.44–3.11; P = 0,74), permanent hypocalcaemia (OR 1.04, 95% CI 0.21–5.18; P = 0,95), transient unilateral recurrent laryngeal nerve palsy (OR 0.78, 95% CI 0.21–2.81; P = 0,16), permanent unilateral recurrent laryngeal nerve palsy (OR 1.48, 95% CI 0.28–7.85; P = 0,61), and haematoma (OR 1,84, 95% CI 0,16-20,71; P = 0,61). CT following hemithyroidectomy can be performed with acceptable morbidity in patients with thyroid nodules with preoperative indeterminate cytology/follicular proliferation.

Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.

Mast cells and macrophages can play a role in tumor angiogenesis by stimulating microvascular density (MVD). The density of mast cells positive to tryptase (MCDPT), tumor-associated macrophages (TAMs), and MVD were evaluated in a series of 86 gastric cancer (GC) tissue samples from patients who had undergone potential curative surgery. MCDPT, TAMs, and MVD were assessed in tumor tissue (TT) and in adjacent normal tissue (ANT) by immunohistochemistry and image analysis. Each of the above parameters was correlated with the others and, in particular for TT, with important clinico-pathological features. In TT, a significant correlation between MCDPT, TAMs, and MVD was found by Pearson t-test analysis (p ranged from 0.01 to 0.02). No correlation to the clinico-pathological features was found. A significant difference in terms of mean MCDPT, TAMs, and MVD between TT and ANT was found (p ranged from 0.001 to 0.002). Obtained data suggest MCDPT, TAMs, and MVD increased from ANT to TT. Interestingly, MCDPT and TAMs are linked in the tumor microenvironment and they play a role in GC angiogenesis in a synergistic manner. The assessment of the combination of MCDPT and TAMs could represent a surrogate marker of angiogenesis and could be evaluated as a target of novel anti-angiogenic therapies in GC patients.

Mast Cells (MCs) play a role in immune responses and more recently MCs have been involved in tumoral angiogenesis. In particular MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor via proteinase-activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase (MAPK) phosphorylation. MCs can release tryptase following c-Kit receptor activation. Nevertheless, no data are available concerning the relationship among MCs Density Positive to Tryptase (MCDPT) and Microvascular Density (MVD) in both primary gastric cancer tissue and loco-regional lymph node metastases. A series of 75 GC patients with stage T_2–3N_2–3M₀ (by AJCC for Gastric Cancer Seventh Edition) undergone to radical surgery were selected for the study. MCDPT and MVD were evaluated by immunohistochemistry and by image analysis system and results were correlated each to other in primary tumor tissue and in metastatic lymph nodes harvested. Furthermore, tissue parameters were correlated with important clinico-pathological features. A significant correlation between MCDPT and MVD was found in primary gastric cancer tissue and lymph node metastases. Pearson t-test analysis (r ranged from 0.74 to 0.79; p-value ranged from 0.001 to 0.003). These preliminary data suggest that MCDPT play a role in angiogenesis in both primary tumor and in lymph node metastases from GC. We suggest that MCs and tryptase could be further evaluated as novel targets for anti-angiogenic therapies.

CRC often arises from polyps: an early detection and resection are effective in decreasing both incidence and mortality rate. Relation between risk factors, adenomas and CRC have been showed, but there is little evidence for overweight association with preneoplastic lesions. This study analyzed the correlation between body mass index (BMI) and primitive site of polyps. We performed a retrospective study, in a period between January 2010 and October 2014. Subjects aged 50 years and older who underwent their first-time screening colonoscopy were included. Reports regarding characteristic of the polyps were collected. 142 patients were enrolled and they were divided into two groups: group I - patients with left sided colonic polyps, and group II - patients who right sided colonic polyps. The ANOVA test-one way, documents a difference between the BMI and the colon localization of polyps. Patients with overweight had a higher risk to develop lesions in the left colon compared to patients with normal weight. Despite the fact that Italian epidemiological studies have found a prevalence of polyps of 44-53% in rectal-sigmoid segment, 32-36% in transverse segment and of 14-20% in right segment, we showed an incidence of 26.05% for right sided polyps, which maybe related with the eating habits of the territory.