Preoperative chemoradiotherapy induces multiple pathways related to anti-tumour immunity in rectal cancer.

BACKGROUND: Rectal cancer treated with preoperative radiotherapy (RT) provides an interesting model to study changes induced on cancer cell immuno-phenotype that could be exploited by immunotherapy interventions to improve prognosis. MATERIALS AND METHODS: We assessed the expression of HLA-class-I, ß2-microglobulin, TAP1, PD-L1 and STING/IFNß in preoperative biopsies and respective post-RT surgical specimens from patients with rectal cancer (n = 27). The effect of radiation was further investigated in colorectal adenocarcinoma cell lines HT-29 and Caco-2. RESULTS: Rectal carcinomas exhibited extensive loss of expression of HLA-Class-I related molecules, which was restored in post-irradiation surgical specimens (P < 0.0001). RT induced the expression of IFNß and STING in cancer cells and tumour-infiltrating lymphocytes (P < 0.0001). In in vitro experiments, irradiation with 4 Gy or 10 Gy induced the expression of HLA-class-I protein (P < 0.001). PD-L1 levels were transiently induced for two days (P < 0.001). cGAS, STING, IFNß and the downstream genes (MX1, MX2, UBE2L6v2, IFI6v2 and IFI44) mRNA levels significantly increased after 3 × 8 Gy or 1 × 20 Gy irradiation (P < 0.001). TREX1 mRNA levels remained unaltered. CONCLUSIONS: RT induces the IFN-type-I pathway and the expression of HLA-class-I molecules on rectal carcinoma. The transient induction of PD-L1 expression suggests that long-course daily RT may sustain increased PD-L1 levels. Anti-PD-L1/PD-1 immunotherapy could block this immunosuppressive pathway.

Predicting Complicated Appendicitis in Children: Pros and Cons of a New Score Combining Clinical Signs, Laboratory Values, and Ultrasound Images (CLU Score).

BACKGROUND: This retrospective study aimed to combine the clinical signs, laboratory values, and ultrasound images of 199 children with acute appendicitis in order to create a new predictive score for complicated appendicitis in children. METHODS: The study included children who had clinical examination of abdominal pain (description of pain, anorexia, body temperature, nausea or vomiting, duration of symptoms), laboratory findings on admission (white blood cell, platelets, neutrophils, C-reactive protein), preoperative abdominal ultrasound, and histopathological report after an operation for appendicitis in their records during the period from January 2016 to February 2022. RESULTS: According to the statistical analysis of the values using multivariate logistic regression models, the patients with appendiceal diameter ≥ 8.45 mm, no target sign appearance, appendicolith, abscess, peritonitis, neutrophils ≥ 78.95%, C-reactive protein ≥ 1.99 mg/dL, body temperature ≥ 38 °C, pain migration to right lower quadrant, and duration of symptoms < 24 h were more likely to suffer from complicated appendicitis. The new score was comprised of the 10 variables that were found statistically significant in the multivariate logistic model. Each of these variables was assigned a score of 1 due to the values that were associated with complicated appendicitis. CONCLUSIONS: A cutoff value of ≥4 has been a good indicator of the final score. The sensitivity with the usage of this score is 81.1%, the specificity 82.4%, the PPV 73.2%, the NPV approaches 88% and finally the accuracy is 81.9%. Also, the pros and cons of this score are discussed in this study.

Ovarian Morphometric and Histologic Characteristics and Correlation with Clinical Factors: A Cross-Sectional Study.

Reproductive lifespan is determined by the reserve of ovarian follicles; their quality and quality determine the fertility potential at a given point in time for a particular individual. Inter-individual variations related to morphometry, laterality, medical history, demographic characteristics and ethnicity may impact ovarian histology, which however, has not been extensively studied or documented. The present cross-sectional study aims to investigate the potential association of clinical factors (age, medical and obstetric history) with ovarian morphometry and histology in females of reproductive age in the local population. The sample included 31 specimens of whole human ovaries, obtained from surgical/autopsy procedures in reproductive-aged women, processed at the Pathology Department. Morphometric characteristics were assessed, including shape, color, length, width, thickness and gross ovarian pathology. Random samples of specific dimensions were histologically examined to determine follicular counts. The results were analyzed statistically in correlation to morphometric characteristics and medical history. The majority of the patients had oval-shaped ovaries (77.8% right; 92.3% left; p = 0.368) of whitish color (38.9% right; 46.2% left; p > 0.999). Right ovaries had significantly greater length, width and volume (p-values 0.018, 0.040 and 0.050, respectively). Thickness was equivalent, as well as follicular distribution of all classes. Age correlated inversely with ovarian volume and primordial/primary follicular count on histology. Women with a caesarian-section history yielded significantly lower primordial/primary follicular counts. As estimated by ovarian histology, macroscopic and clinical factors may be significantly associated with actual ovarian reserve.

Tumor-infiltrating lymphocytes, PD-L1, and MMR-deficiency combined characterization may identify subgroups of rectal cancer patients who would benefit from immunotherapy.

INTRODUCTION: Mismatch repair deficiency, immunological fertility, and PD-L1 expression status are key histopathological and molecular features defining tumor responsiveness to immunotherapy and, eventually, prognosis. These were investigated in a series of locally advanced rectal cancer patients treated with postoperative chemotherapy and radiotherapy. MATERIALS AND METHODS: Tumor-infiltrating lymphocyte (TIL) density was assessed in hematoxylin-eosin tissue sections. PD-L1 expression and the expression of MMR proteins (MLH1, PSM2, MSH2, and MSH6) were assessed with immunohistochemistry. Their association with histopathological variables (node involvement and tumor budding) and prognosis was assessed. RESULTS: The TIL-density was significantly higher in the invading tumor front and was inversely related to tumor budding and directly with better overall survival (OS) and distant metastasis-free survival (DMFS) (p = 0.02 and 0.02, respectively). Cancer cell PD-L1 expression was related to high TIL-density (p < 0.01) but not to prognosis, although its overexpression defined a trend for poorer OS in patients with high TIL-density. High PD-L1 expression by stroma infiltrating immune cells was linked with better OS and DMFS (p = 0.007 and 0.001, respectively. MMR deficiency was recorded in 26.2 % of cases, and this was linked with higher TIL-density, but not with prognosis. CONCLUSIONS: Dense intratumoral lymphocytic infiltration relates to a better prognosis in rectal cancer, although it is also linked with PD-L1 expression that may adversely modulate the anti-tumor effects of TILs. This latter subgroup of patients (high TIL-density/high cancer cell PD-L1 expression) could be an additional target for anti-PD-1/PD-L1 immunotherapy, along with the established subgroup of MMR deficient patients.

Safety and efficacy of ovarian tissue autotransplantation: A systematic literature review.

Ovarian tissue autotransplantation is an innovative fertility preservation technique that has provoked ongoing investigations. The purpose of the present study was to assess the safety and reproductive performance of ovarian tissue autotransplantation. This review is conducted according to PRISMA guidelines. Seven studies met the inclusion criteria. A total of 3427 patients underwent ovarian tissue cryopreservation and 205 received an autotransplantation. Tissue retrieval was mainly performed by laparoscopy and only one major complication occurred. Transplantations were predominantly performed by open procedures and data on safety were insufficient. A total of 295 autotransplantations were analyzed, resulting in 104 pregnancies. Sixty-five pregnancies led to live births, while nine were ongoing at that time. A pregnancy rate (PR) of 50.7% and a live-birth rate (LBR) of 32.7% were observed. Natural conception accounted for 46.3% of live births. No birth deficits were recorded. Ovarian tissue autotransplantation seems to be a safe procedure with acceptable pregnancy rates.

The Prognostic Value of Ultrasound Findings in Preoperatively Distinguishing between Uncomplicated and Complicated Types of Pediatric Acute Appendicitis Based on Correlation with Intraoperative and Histopathological Findings.

OBJECTIVE: This study compares the preoperative ultrasound findings of all children with a clinical picture of acute appendicitis on the basis of intraoperative and histopathological findings to assess the feasibility of this approach in preoperatively distinguishing between uncomplicated and complicated cases. METHODS: This retrospective study includes 224 pediatric patients who underwent ultrasound prior to appendectomy at our institution between January 2016 and February 2022. Logistic regression analysis was used to investigate the association between sonographic and intraoperative histopathological findings. RESULTS: Of the 224 participants, 61.1% were intraoperatively diagnosed with uncomplicated appendicitis (59.8% male). Multivariate logistic regression analysis revealed that patients with a higher appendiceal diameter, presence of appendicolith, and peritonitis were more likely to suffer from complicated appendicitis. Finally, the common anatomical position of the appendix and an appendiceal diameter greater than 6 mm had the highest sensitivity (94.6% and 94.5%, respectively) for predicting complicated appendicitis, with the most specific (99.3%) sonographic finding being the existence of an abscess. CONCLUSIONS: Preoperative abdominal ultrasound in children with a clinical diagnosis of acute appendicitis can distinguish between uncomplicated and complicated appendicitis in most cases of pediatric appendicitis. A higher appendiceal diameter, the presence of appendicolith, and peritonitis are parameters noted by ultrasound that strongly predict complicated appendicitis.

Primary Cervical Carcinosarcoma: Report of a Rare Case.

Background Carcinosarcomas are malignant mixed Müllerian tumors (MMMT), containing both epithelial and mesenchymal components. Carcinosarcomas of the uterine cervix comprise an extremely rare histopathological entity, with less than 150 cases reported in the literature to date. Materials and Methods A 79-year-old postmenopausal female patient was referred to our gynecological department due to a pelvic mass and vaginal bleeding. A cervical curettage was performed and the histological report revealed a malignant neoplasm with high cellularity consisting of two components; the first was a chondrosarcoma and the latter a adenocarcinoma. A diagnosis of MMMT was confirmed through immunohistochemical (IHC) staining. Neoadjuvant chemotherapy and radiotherapy were implemented, and a year later the patient underwent a radical hysterectomy and oncological pelvic lymph node dissection. She remains disease-free 12 months postoperatively. Conclusion Primary cervical carcinosarcomas are extremely rare tumors demonstrating a bipartite profile. Preoperative diagnosis with appropriate immunochemistry testing of this rare entity is crucial to decision making.

Cutaneous squamous-cell carcinoma of the head-neck area refractory to chemo-radiotherapy: benefit from anti-PD-1 immunotherapy.

OBJECTIVE: Radiotherapy provides excellent results in locally advanced cutaneous squamous-cell carcinoma of the head and neck area (cSCC-HN), with a 2-year local progression-free interval obtained for about 80% of patients. Overexpression of immune checkpoint co-inhibitory molecules, like PD-L1 (programmed death ligand 1), by cancer cells may define local immunosuppression, tumour escape from immune surveillance and reduced radiotherapy efficacy. METHODS: A 65-year-old female, with a large exophytic cSCC-HN invading adjacent soft tissues, was treated with hypofractionated accelerated chemo-radiotherapy. The patient received four bi-weekly cycles of chemotherapy concurrently with eight fractions of 5.5 Gy (two fractions per week). Two months after the end of chemo-radiotherapy, the tumour was stable in dimensions, without any signs of symptomatic relief. The patient was, after that, treated with anti-PD-1 immunotherapy (nivolumab). The tumour gradually regressed, reaching partial response after four cycles and complete response after 16 cycles of nivolumab. No side-effects related to immunotherapy were recorded. The patient is alive and without evidence of disease 28 months after radiotherapy. CONCLUSIONS: Treatment of patients with chemo- and radio-resistant cSCC-HN with immunotherapy may optimize the efficacy of radiotherapy by stimulating immunological tumour rejection mechanisms. cSCC-HN patients who fail to respond to chemo-radiotherapy completely are expected to benefit the most from immunotherapy because of the radio-vaccination effect expected from the preceded radiotherapy.

Regulatory tumor-infiltrating lymphocytes prevail in endometrial tumors with low vascular survival ability.

INTRODUCTION: Angiogenic activity and vascular survival ability are two distinct vasculature related tumor features that can be assessed in tumor tissues. We examined their correlation with anti-tumor immunity in a series of endometrial carcinomas. MATERIAL AND METHODS: Thirty-three, stage I, endometrial carcinomas of endometrioid histology were analyzed with immunohistochemistry for the expression of CD31 pan-endothelial cell marker and CD25 and FOXP3 markers of regulatory T-cells. Angiogenic activity (AA) was assessed as the microvessel density in the invading tumor front (MVDt1). The vascular survival ability VSA was assessed by comparing the MVDt1 to the MVD in inner tumor areas (MVDt2 and MVDt3). The tumor-infiltrating lymphocyte TIL-density and the CD25+ and FOXP3+ TILD-density were assessed in the invading front and internal tumor areas. RESULTS: The AA and VSA varied 4-fold and 10-fold among tumors, respectively. Highly angiogenic tumors were more frequently related with high histological grade (p = 0.01) and low VSA (p < 0.05). Although TIL-density was not associated with MVDt1, a statistically significant inverse association was noted with MVDt3 and VSA (p = 0.0005 and p = 0.002, respectively). Similarly, we observed a statistically significant association between the density of regulatory CD25+ and FOXP3+ TILs with low MVDt3 and low VSA (p = 0.03 and p = 0.04, respectively). CONCLUSIONS: Low vascular survival ability relates to high accumulation of regulatory T-cells in inner tumor areas of endometrial carcinomas. The current data hypothesizes meaningful interactions between vascular survival, microenvironmental conditions, and immunosuppression in endometrial cancer.

Rectal cancer induces a regulatory lymphocytic phenotype in the tumor-draining lymph nodes to promote cancer cell installation.

Tumor-draining lymph nodes (TDLNs) are critical organs, where activation of B cells and T cells is orchestrated. Effector or regulatory anti-tumor immune responses are reflected by the composition of the lymphocytic and monocytic cell population of the node. Aside from the migratory cancer cell abilities, immune cell phenotypic changes in the TDLNs may define nodal invasion by cancer. We assessed the qualitative and quantitative differences between lymphocytic phenotypes in regional TDLNs, in 20 node-negative and 20 node-positive patients (involved and uninvolved nodes) with rectal adenocarcinomas. Benign reactive nodes were also analyzed. CD8+ cells, the main source of cytotoxic T cells, were increased in all TDLNs and, even stronger, in the involved nodes. The percentage of CD4+ cells were significantly increased in negative and uninvolved nodes, while the CD4/CD8 ratio was significantly lower in involved TDLNs. CD25+ and FOXP3+ regulatory lymphocytes, however, prevailed in involved nodes, while uninvolved and negative nodes had a low presence of these regulatory cells. CD20+ B cells were also more abundant in involved nodes. PD-1+ lymphocytes were localized in the germinal centers. A significantly lower percentage of PD-1+ lymphocytes were noted in involved nodes. The development of a regulatory lymphocytic phenotype in the TDLNs appears as an important mechanism that allows cancer cell installation into the nodal environment. As negative/uninvolved TDLNs had a less severe immunosuppression, it is postulated that secreted molecules by cancer cells gradually attenuate the anti-tumor defenses of the TDLNs allowing the subsequent intra-nodal growth of cancer.

iNOS Expression by Tumor-Infiltrating Lymphocytes, PD-L1 and Prognosis in Non-Small-Cell Lung Cancer.

BACKGROUND: Inducible Nitric Oxygen Synthase (iNOS) promotes the generation of NO in tissues. Its role in tumor progression and immune response is unclear. METHODS: The immunohistochemical expression patterns of iNOS were studied in a series of 98 tissue samples of non-small-cell lung carcinoma (NSCLC), in parallel with the expression of hypoxia and anaerobic metabolism markers, PD-L1 and tumor-infiltrating lymphocytes (TILs). RESULTS: iNOS is expressed by cancer cells in 19/98 (19.4%), while extensive expression by cancer-associated fibroblasts occurs in 8/98 (8.2%) cases. None of these patterns relate to stage or prognosis. Extensive infiltration of the tumor stroma by iNOS-expressing TILs (iNOS+TILs) occurs in 47/98 (48%) cases. This is related to low Hypoxia-Inducible Factor 1α (HIF1α), high PD-L1 expression and a better overall survival (p = 0.002). Expression of PD-L1, however, mitigates the beneficial effect of the presence of iNOS+TIL. CONCLUSIONS: Extensive expression of iNOS by TILs occurs in approximately 50% of NSCLCs, and this is significantly related to an improved overall survival. This brings forward the role of iNOS in anti-neoplastic lymphocyte biology, supporting iNOS+TILs as a putative marker of immune response. The value of this biomarker as a predictive and treatment-guiding tool for tumor immunotherapy demands further investigation.

A Novel Lipofuscin-detecting Marker of Senescence Relates With Hypoxia, Dysregulated Autophagy and With Poor Prognosis in Non-small-cell-lung Cancer.

BACKGROUND/AIM: The role of senescence in defining tumor aggressiveness at a clinical level remains obscure. A novel mixed histochemical/immunohistochemical method (SenTraGor™, STG) detecting lipofuscin accumulation allows the assessment of senescent cells in paraffin-embedded tissue material. MATERIALS AND METHODS: STG expression was quantified in 98 surgically resected primary non-small-cell-lung carcinomas (NSCLC). Data were analyzed in parallel with other immunohistochemical markers related to hypoxia and autophagy. RESULTS: Strong STG staining was noted in 36/98 cases (36.7%). High STG expression was significantly associated with high HIF1α expression and high expression of glucose (GLUT1) and monocarboxylate (MCT2) transporters, pointing to a link between senescence, hypoxia and glycolysis. High STG expression was also linked with high cytoplasmic accumulation of MAP1-LC3B, TFEB and LAMP2a, suggestive of a blockage of autophagy flux in tumors with intense senescence. Survival analysis showed a direct association with poor survival, independently of stage. CONCLUSION: SenTraGor™ provides a reliable methodology to detect lipofuscin accumulation in cancer cells in paraffin-embedded tissues, opening a new field for translational studies focused on senescence.

Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways.

AIMS: Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied. MATERIALS AND METHODS: We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted. RESULTS: CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels. CONCLUSION: Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.

P16 detection in benign, precursor epithelial lesions and carcinomas of head and neck.

BACKGROUND: Human papillomavirus (HPV) had recently been implicated in the pathogenesis of Head and Neck SCCs. The biological role of HPV in benign and pre-cancerous lesions is far less studied. p16 is a widely accepted marker to detect immonohistochemically the presence of HPV. METHODS: We evaluated, immunohistochemically, expression of p16 in 212 specimens: glottis, supraglottis, oropharynx, nasal/paranasal, with various diagnoses: hyperplasia, polyp/nodule, keratosis, papilloma, inverted papilloma, dysplasia, cancer (SCC). Analysis was completed according to location and disease. RESULTS: Hyperplasias/polyps were all negative for p16. A small percentage of papillomas was p16+ regardless of their location (12.5 %), the majority of inverted papillomas were p16+ (78.6 %) and statistically significant (p < 0.04). In carcinomas, 18/59 were p16+ (30.5 %): nasal/paranasal SCCs had a significantly higher percentage of p16+ cancer cells compared to glottis (p = 0.009), while tumours of the supraglottis/oropharynx had an intermediate score for p16+ cells (p = 0.07). Dysplasias were p16+ in 9/64 (14 %) regardless of grading (p = 0.03 compared to carcinomas). CONCLUSION: p16 was highly detected in inverted papillomas and in certain anatomic sites; however, it failed to be traced in benign lesions and only rarely encountered in dysplasias.

Immunohistochemical detection of senescence markers in human sarcomas.

INTRODUCTION: Senescent cells in tumors are not inert cells but exert bystander effects by developing secretory phenotypes affecting the extracellular matrix and interfering the biological behavior of adjacent tumor cells. MATERIALS AND METHODS: We assessed putative senescent cell content in a series of human sarcomas, using in parallel markers related to cell proliferation (Ki67), DNA damage (γH2Ax), lipofuscin detection (SenTraGor®) and two cyclin-dependent kinase CDK-inhibitors (p16/INK4a and p21/cip/waf21). RESULTS: Necrosis was directly linked with the size of tumors (p = 0.02, r = 0.25), number of mitosis (p = 0.05, r = 0.21) and inversely with the expression of γH2Ax (p = 0.01, r = 0.28). Smaller tumors (less than 3 cm) had a higher p16 expression (p = 0.07); Moreover, in group analysis, tumors with lack of expression of p16 had significantly higher necrosis score (p = 0.03). Linear regression analysis showed that p21 expression was strongly and directly related with MIB1 (p < 0.0001, r = 0.44) and with Lipofuscin expression (p = 0.02, r = 0.26). CONCLUSION: Senescence markers are extensively expressed in human sarcomas and correlated with histopathological features. However, p16, p21 and Lipofuscin expression show different patterns, suggesting that these markers may detect different senescence phenotypes. In addition, our data suggest that the novel marker SenTraGor® may detect phenotypes of senescent cells involving p21 activation.

The Effect of Strontium Ranelate on Fracture Healing: An Animal Study.

BACKGROUND: Strontium ranelate (StR) is an antiosteoporotic agent previously utilized for the enhancement of fracture union. We investigated the effects of StR on fracture healing using a rabbit model. METHODS: Forty adult female rabbits were included in the study and were divided in 2 equal groups, according to StR treatment or untreated controls. All animals were subjected to osteotomy of the ulna, while the contralateral ulna remained intact and served as a control for the biomechanical assessment of fracture healing. Animals in the study group received 600 mg/kg/day of StR orally. All animals received ordinary food. At 2 and 4 weeks, all animals were euthanatized and the osteotomy sites were evaluated for healing through radiological, biomechanical, and histopathological studies. RESULTS: The treatment group presented statistically significant higher callus diameter, total callus area, percentage of fibrous tissue (p < 0.001), vessels/mm2, number of total vessels, and lower osteoclast number/mm2 (p < 0.05) than the control group at 2 weeks. Additionally, the treatment group presented significantly higher percentages of new trabecular bone, vessels/mm2, osteoclast number/mm2, and lower values for callus diameter, as well as total callus area (p < 0.05), than the control group at 4 weeks. At 4 weeks, in the treatment group, force applied (p = 0.003), energy at failure (p = 0.004), and load at failure (p = 0.003) were all significantly higher in the forearm specimens with the osteotomized ulnae compared to those without. Radiological bone union was demonstrated for animals receiving StR at 4 weeks compared with controls (p = 0.045). CONCLUSION: StR appears to enhance fracture healing but further studies are warranted in order to better elucidate the mechanisms and benefits of StR treatment.

Primary Malignant Melanoma of the Cervix: A Case Report and a Review of the Literature.

BACKGROUND: Gynecologic melanomas are extremely rare malignancies, and primary malignant melanoma of the cervix (PMMC) is the rarest among them all, with less than 100 cases reported so far. Although some conditions have been correlated with the pathogenesis of this entity, no specific risk factor has been yet identified, with vaginal bleeding being the most common symptoms. The diagnosis is based on physical examination with speculum assessment and cytologic and histopathologic findings accompanied with immunohistochemical staining of lesion's biopsies. Case Presentation. We report a case of PMMC in a 34-year-old para-2 patient, among the youngest cases of PMMC reported, that presented to our clinic for routine examination. Gynecologic examination demonstrated a dark, heavily fully pigmented cervical growth completely covering the entire external cervical os. Biopsy obtained and showed malignant melanoma. She underwent radical hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. The pathological diagnosis was FIGO stage IB1 PMMC. Despite 2 courses of anti-PD-1 antibody (Nivolumab) treatment, the patient passed away 13 months after diagnosis (12 months after surgery). CONCLUSIONS: Early diagnosis and subsequently early treatment are of high importance regarding patients' prognosis and survival. No standardized protocols or treatment guidelines specific for this rare cancer have been issued; thus, clinicians are called to assess each case individually. Current treatment options are based on surgical excision mostly with radical hysterectomy, but in advanced or recurrent state of the disease, other treatment modalities, such as chemotherapy, radiotherapy, and immunotherapy, can be employed. Prognosis for these patients is very poor, and survival rate remains extremely low, with the median OS reported being less than 2 years. Reporting and publishing of such cases are both of paramount importance for the better understanding of this uncommon cervical malignancy, and further biological and clinical investigations are required for more suitable and effective therapies to be determined. A new staging system, specific to PMMC, could be of great use for the better correlation of the disease's stage and prognosis of these patients.

Acute eosinophilic appendicitis after generalized skin reaction due to unknown cause in a child: Case report and literature review.

Acute eosinophilic appendicitis (AEA) is a rare variant of appendix inflammation possibly linked to allergy. Histopathological evidence of eosinophilic infiltration of the muscularis propria and edema separating the muscle fibers is the gold standard for the diagnosis. Here, we report a case of a young boy with AEA following a skin reaction of possible allergic origin. A 6-year-old male was presented to the emergency department with a two-day diffuse abdominal pain and tenderness in the right lower quadrant. A possible allergic reaction had occurred five days before as a pruritic rash. There was no history of allergy and the stool examination was negative for parasites. The initial diagnosis was acute appendicitis, and appendectomy was performed. The histopathological diagnosis was AEA. Further studies on the proper diagnostic and treatment approach of AEA before surgery are required.

Rheumatoid nodules in thyroid gland parenchyma as an expression of rheumatoid arthritis: a case report.

BACKGROUND: The rheumatoid nodule is the most common extra-articular manifestation of rheumatoid arthritis. When present, it is readily identified in conventional hematoxylin and eosin sections. CASE PRESENTATION: We report a case with several rheumatoid nodules in a thyroid gland of a 33-year-old Greek woman with a 3-year history of rheumatoid arthritis treated with methotrexate, after having total thyroidectomy for hypothyroidism. CONCLUSION: To the best of our knowledge, this is the first time that rheumatoid nodules have been encountered in the thyroid gland.

Angiogenic regeneration defines loco-regional recurrence following pre-operative radio-chemotherapy for rectal cancer: a pilot study.

Previous studies from our group have brought forward the concept of angiogenic regeneration during radiotherapy (RT), as a major cause of RT failure. This process was examined herein in rectal cancer patients undergoing preoperative chemo-radiotherapy. Out of 25 patients with stage II/III rectal adenocarcinoma, 15 had incomplete response (pIR) after preoperative chemo-radiotherapy. The MIB1 proliferation index, the vascular density (VD) assessed with the anti-CD31 antibody and the Hypoxia Inducible Factor HIF1α was assessed. High VD before RT was related with poor local relapse free survival LRFS (p = 0.04), in cases with pIR. Pre-RT values of MIB1 and of HIF1α were not related with LRFS. High MIB1 index and intensification of VD beyond pre-treatment levels in post-RT samples, features indicative of angiogenic regeneration, defined poor LRFS (p = 0.04 and p = 0.0008, respectively). Angiogenic regeneration is strongly related to failure of RT and surgery to control loco-regional disease in rectal cancer patients. Addition of anti-angiogenic agents in the preoperative chemo-radiotherapy regimens may prove beneficial in subgroups of patients.