Impact of COVID-19 on birth rate trends in the Italian Metropolitan Cities of Milan, Genoa and Turin.

OBJECTIVES: The COVID-19 pandemic has led to major changes in the lives of people worldwide, including changes in personal and social habits. Faced with this global health emergency, governments have imposed strict mitigation measures. Within this context, and considering data from previous epidemics, it has been proposed that birth rates may have been negatively impacted. This study aimed to assess the trends in birth rates in three main industrial cities in Northern Italy during the COVID-19 pandemic. STUDY DESIGN: This was a retrospective and observational study. METHODS: Data on birth rates were collected and compared for the cities of Milan, Genoa and Turin from November 2019 to January 2020 (i.e. before the COVID-19 pandemic) and during the same period of the following year (i.e. during the COVID-19 pandemic). RESULTS: Birth rates in the cities of Milan, Genoa and Turin decreased by 55%, 12% and 33%, respectively. CONCLUSIONS: The decrease in birth rates during the COVID-19 pandemic in these three industrialised cities is in line with the demographic effects of previous pandemics. The negative impact of COVID-19 on conception may be a result of various underlying factors. Further studies are required to verify how social and demographic factors may influence birth rates during pandemics.

The FXR agonist obeticholic acid inhibits the cancerogenic potential of human cholangiocarcinoma.

Cholangiocarcinoma (CCA) is an aggressive cancer with high resistance to chemotherapeutics. CCA is enriched in cancer stem cells, which correlate with aggressiveness and prognosis. FXR, a member of the metabolic nuclear receptor family, is markedly down-regulated in human CCA. Our aim was to evaluate, in primary cultures of human intrahepatic CCA (iCCA), the effects of the FXR agonist obeticholic acid (OCA), a semisynthetic bile acid derivative, on their cancerogenic potential. Primary human iCCA cell cultures were prepared from surgical specimens of mucinous or mixed iCCA subtypes. Increasing concentrations (0-2.5 µM) of OCA were added to culture media and, after 3-10 days, effects on proliferation (MTS assay, cell population doubling time), apoptosis (annexin V-FITC/propidium iodide), cell migration and invasion (wound healing response and Matrigel invasion assay), and cancerogenic potential (spheroid formation, clonogenic assay, colony formation capacity) were evaluated. Results: FXR gene expression was downregulated (RT-qPCR) in iCCA cells vs normal human biliary tree stem cells (p < 0.05) and in mucinous iCCA vs mixed iCCA cells (p < 0.05) but was upregulated by addition of OCA. OCA significantly (p < 0.05) inhibited proliferation of both mucinous and mixed iCCA cells, starting at a concentration as low as 0.05 µM. Also, CDCA (but not UDCA) inhibited cell proliferation, although to a much lower extent than OCA, consistent with its different affinity for FXR. OCA significantly induced apoptosis of both iCCA subtypes and decreased their in vitro cancerogenic potential, as evaluated by impairment of colony and spheroid formation capacity and delayed wound healing and Matrigel invasion. In general, these effects were more evident in mixed than mucinous iCCA cells. When tested together with Gemcitabine and Cisplatin, OCA potentiated the anti-proliferative and pro-apoptotic effects of these chemotherapeutics, but mainly in mixed iCCA cells. OCA abolished the capacity of both mucinous and mixed iCCA cells to form colonies when administered together with Gemcitabine and Cisplatin. In subcutaneous xenografts of mixed iCCA cells, OCA alone or combined with Gemcitabine or Cisplatin markedly reduced the tumor size after 5 weeks of treatment by inducing necrosis of tumor mass and inhibiting cell proliferation. In conclusion, FXR is down-regulated in iCCA cells, and its activation by OCA results in anti-cancerogenic effects against mucinous and mixed iCCA cells, both in vitro and in vivo. The effects of OCA predominated in mixed iCCA cells, consistent with the lower aggressiveness and the higher FXR expression in this CCA subtype. These results, showing the FXR-mediated capacity of OCA to inhibit cholangiocarcinogenesis, represent the basis for testing OCA in clinical trials of CCA patients.

Transcriptomic analysis and mutational status of IDH1 in paired primary-recurrent intrahepatic cholangiocarcinoma.

BACKGROUND: Effective target therapies for intrahepatic cholangiocarcinoma (ICC) have not been identified so far. One of the reasons may be the genetic evolution from primary (PR) to recurrent (REC) tumors. We aim to identify peculiar characteristics and to select potential targets specific for recurrent tumors. Eighteen ICC paired PR and REC tumors were collected from 5 Italian Centers. Eleven pairs were analyzed for gene expression profiling and 16 for mutational status of IDH1. For one pair, deep mutational analysis by Next Generation Sequencing was also carried out. An independent cohort of patients was used for validation. RESULTS: Two class-paired comparison yielded 315 differentially expressed genes between REC and PR tumors. Up-regulated genes in RECs are involved in RNA/DNA processing, cell cycle, epithelial to mesenchymal transition (EMT), resistance to apoptosis, and cytoskeleton remodeling. Down-regulated genes participate to epithelial cell differentiation, proteolysis, apoptotic, immune response, and inflammatory processes. A 24 gene signature is able to discriminate RECs from PRs in an independent cohort; FANCG is statistically associated with survival in the chol-TCGA dataset. IDH1 was mutated in the RECs of five patients; 4 of them displayed the mutation only in RECs. Deep sequencing performed in one patient confirmed the IDH1 mutation in REC. CONCLUSIONS: RECs are enriched for genes involved in EMT, resistance to apoptosis, and cytoskeleton remodeling. Key players of these pathways might be considered druggable targets in RECs. IDH1 is mutated in 30% of RECs, becoming both a marker of progression and a target for therapy.

Clinical validity of tumor-infiltrating lymphocytes analysis in patients with triple-negative breast cancer.

BACKGROUND: Although tumor-infiltrating lymphocytes (TILs) have been associated with a favorable prognosis in triple-negative breast cancer (TNBC) patients, this marker is not currently considered robust enough for entering the clinical practice. In the present study, we assessed the clinical validity of the guidelines recently issued by the International TIL Working Group in a large retrospective series of well-annotated TNBC patients. PATIENTS AND METHODS: TILs were evaluated in all the full-face H&E sections from 897 consecutive TNBC (i.e. tumors with <1% of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification) patients diagnosed and treated at the European Institute of Oncology between 1995 and 2010 (median follow-up 8.2 years, range 6 months to 18 years). All mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor, reported as a percentage value and treated as a continuous variable in survival analysis. RESULTS: The median percentage of TILs was 20%, and 21.9% of the cases had ≥50% (lymphocyte predominant breast cancer, LPBC) TILs. At univariable survival analysis, TILs were a significant predictor of better disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P < 0.0001). Multivariable analysis confirmed that each 10% increase in TILs strongly predicted better survival, independent of patients' age, lymph node status, tumor size, histological grade, peritumoral vascular invasion and Ki-67 labeling index. Patients with LPBC had a 10-year survival rate of 71%, 84% and 96% for DFS, DDFS and OS, respectively. Stratified analysis revealed a positive correlation between TILs and OS across all the subgroups analyzed. CONCLUSION: Our data support the analytical validity of the recently issued TILs evaluation guidelines in the clinical practice.

Enhancement patterns of intrahepatic mass-forming cholangiocarcinoma at multiphasic computed tomography and magnetic resonance imaging and correlation with clinicopathologic features.

OBJECTIVE: Incidence of intrahepatic mass-forming cholangiocarcinoma (IMCC) is increasing worldwide, especially in patients with chronic liver disease. The small and the histologically well-differentiated IMCCs in chronic liver disease could be arterially hypervascular lesions with/without washout on computed tomography (CT) and magnetic resonance imaging (MRI), mimicking typical hepatocellular carcinoma (HCC). The aim of this work is to evaluate contrast enhancement (CE) patterns of IMCCs at quadri-phasic multidetector CT (4-MDCT) and MRI, using imaging-clinicopathologic correlation. PATIENTS AND METHODS: The 4-MDCT and MR images of 56 histologically confirmed IMCCs were retrospectively evaluated for tumor morphology and enhancement features. Enhancement pattern was defined according to the behavior of the nodule in arterial (AP), portal venous (PVP) and equilibrium phases (EP), and dynamic pattern was described according to enhancement progression throughout the different phases. Arterial and dynamic enhancement patterns were correlated with chronic liver disease, tumor size and histological differentiation. RESULTS: Most of the nodules were peripherally hyperenhancing (50%) on AP, and partially hyperenhancing on PVP (67.9%) and EP (80.3%). Forty-six (82.1%) IMCCs showed progressive CE, 7 (12.5%) stable CE and 3 (5.4%) wash-out. In normal liver there were 34 nodules with progressive and 3 with stable CE, whereas in chronic liver disease there were 12 IMCCs with progressive, 4 with stable and 3 with washout pattern (p = 0.01); IMCCs with progressive CE were more differentiated than IMCCs with stable CE and wash-out (p = 0.02). CONCLUSIONS: The most prevalent enhancement pattern of IMCCs was arterial rim enhancement followed by progressive and concentric filling. The stable and the washout patterns were more frequent in poorly differentiated IMCCs. Contrast washout was observed only in IMCCs emerging in chronic liver disease with a risk of misdiagnosis with HCC.

Lymphoepithelial cyst of the pancreas: case report and review of the literature.

BACKGROUND AND STUDY AIMS: Lymphoepithelial cyst of the pancreas (LCP) is a rare, benign cyst mimicking pseudocyst or cystic neoplasm. Literature describing LCP is limited to case or brief series reports, and the natural history of this condition is largely unknown. A literature review was carried out in order to elucidate the clinical, pathological and biochemical features of LCP. The aim of this study was to define diagnostic criteria and treatment. METHODS: A Medline and Pubmed search was conducted by using the key-words "lymphoepithelial cyst" and "pancreas". The articles found were accurately examined and all details regarding clinical and pathological features were included in a data-base. Furthermore, a case recently observed in our unit was added to the review. RESULTS: Ninety-two cases of LCP were found in the worldwide literature, including the case that we observed. LCP occurs more frequently in males (M:F=5.5:1), its preferred site is the tail of the pancreas, and its size ranges between 2 and 10centimetres. Histologically, it is a true cyst delineated by a keratinizing squamous epithelium surrounded by lymphoid tissue. LCP is asymptomatic in the majority of cases and preoperative diagnosis is complicated by a lack of specific radiological features of the disease. An accurate preoperative diagnosis can only be made by obtaining cytological specimens and placing them in the hands of a pathologist who is familiar with the cytological appearances of the disease. CONCLUSIONS: LCP is a rare lesion worldwide, without any prevalence in different countries or in different ethnic groups. Understanding the features of LCP, making an accurate diagnosis and differentiating it from cystic neoplasm preoperatively is vital, as when it is diagnosed certainly, a conservative treatment is justified. Otherwise, radical surgery in the form of pancreatic resection is required to exclude the diagnosis of pancreatic cystic neoplasm.

Liver resection for intrahepatic stones in congenital bile duct dilatation.

OBJECTIVE: This study reports our clinical experience with liver resection for congenital dilatation of the intrahepatic bile duct and intrahepatic gallstones to evaluate results and define indications for treatment. PATIENTS AND METHODS: We studied the clinical data of patients who underwent hepatic resection for intrahepatic lithiasis from January 1992 to December 2008 and assessed the immediate and long-term results of these interventions. RESULTS: Of 49 treated patients, 47 underwent liver resection. In the majority of cases, the disease was limited to the left lobe and left hepatectomy was the most commonly performed surgical procedure. The operative mortality was zero with morbidity in 24.5% of patients. Cholangiocarcinoma was diagnosed in six cases (12.2%). In 91.6% of cases the long-term results were good or satisfactory. CONCLUSION: Treatment goals in all cases should be the elimination of intrahepatic stones, the prevention of recurrent lithiasis, and prevention or cure of cholangiocarcinoma. Surgical excision is the best possible treatment for symptomatic patients with localized disease and atrophy of the affected liver.

Gas in portal circulation and pneumatosis cystoides intestinalis during chemotherapy for advanced rectal cancer.

OBJECTIVES: Acute abdominal symptoms with CT scan evidence of intramural gas in bowel walls (pneumatosis cystoides intestinalis, PCI) and of gas in the portal venous blood (PBG) in patients undergoing chemotherapy may represent a worrisome picture, suggestive of bowel necrosis. This picture remains a major clinical clue and the reporting of new cases may help to share awareness and experience on management. We describe a patient with acute abdominal symptoms and evidence of PCI with PBG under cetuximab, oxaliplatin, tegafur-uracil and folinic acid chemotherapy for metastatic adenocarcinoma of the rectosigmoid junction. METHODS: After admission for mucositis with diarrhea and profound dehydration, and subsequent emergency laparotomy for derotation of an intestinal volvulus, on the tenth postoperative day the patient developed fever and abdominal pain, with CT scan evidence of PCI with PBG. The exam of the abdomen did not suggest major problems requiring emergency surgery, and antibiotic treatment with close monitoring were performed, followed by rapid improvement. RESULTS: Twelve days later, after resumption of oral diet, the patient unexpectedly suffered a spontaneous jejunal microperforation, requiring emergency laparotomy and bowel resection. Pathology showed that the perforation was within an area of ulceration involving the inner superficial layer of the bowel. Subsequently recovery was normal and at present, after 15 months, the patient is well and continuing chemotherapy. CONCLUSIONS: This is probably the first report of PCI with PBG related to intestinal toxicity during cetuximab, oxaliplatin, tegafur-uracil and folinic acid chemotherapy in a patient with advanced rectal carcinoma, followed by delayed small bowel perforation. It provides an example of the challenges involved in the management of this type of patient.

Total gastrectomy for type 1 gastric carcinoid: an unusual surgical indication?

Gastric carcinoid is a relatively rare neoplasm with peculiar features which differentiate it from the intestinal and pulmonary carcinoid and, obviously, from gastric adenocarcinoma. Gastric carcinoids are divided into three different types: Type 1, associated with gastric atrophy and megaloblastic anemia; Type 2, associated with Zollinger-Ellison syndrome within a type 1 multiple endocrine neoplasia (MEN); and Type 3, sporadic tumor not associated with other lesions, particularly invasive and with poor prognosis. Type 1 carcinoid is usually asymptomatic and casually detected at endoscopy due to aspecific symptoms or to screening in patients with atrophic gastritis. It is generally small, multifocal and located in the gastric fundus, has no tendency for vascular invasion and is associated with a benign course. Therefore, the recommended treatment, for lesions < 10 mm and in a number < 5, is endoscopic resection with strict follow-up. We report a case of a woman with a type 1 gastric carcinoid in which, for the presence of an extended micro-polyposis of the fundus a total gastrectomy was necessary for treatment. Pathology revealed vascular invasion at the level of the major lesion of 8 mm of diameter. In conclusion this finding, unknown before surgery, emphasizes the need for careful assessment also in the presence of apparently less important gastric carcinoid lesions.

Prulifloxacin versus ciprofloxacin in the treatment of adults with complicated urinary tract infections.

INTRODUCTION: The present study was performed to evaluate the efficacy and safety of a 10-day regimen of prulifloxacin 600 mg once daily as compared to ciprofloxacin 500 mg twice daily in the treatment of patients with complicated urinary tract infections (UTIs). MATERIALS AND METHODS: 257 patients (mean age +/- SD 62.3 +/- 16.5) were enrolled and orally treated with prulifloxacin (127 patients) or ciprofloxacin (130 patients). The study was designed as a randomized, double-blind, double-dummy, controlled clinical trial. The primary efficacy parameter was the eradication of infecting strains (<10(3) cfu/ml). The clinical outcome and tolerability were also assessed. RESULTS: At baseline, the most common infecting strains were Escherichia coli (62.8%), Proteus mirabilis (7.1%) and Klebsiella pneumoniae (4.1%). At the early follow-up, the rate of patients showing successful treatment was 90.8% in the prulifloxacin group, and 77.8% in the ciprofloxacin group (p = 0.008). A positive clinical outcome was observed in 94.8 and 93.3% of prulifloxacin- and ciprofloxacin-treated patients. Both drugs were well tolerated. Two patients dropped out for treatment-related adverse events. CONCLUSIONS: The high urinary concentrations of prulifloxacin, combined with a broad-spectrum antimicrobial activity, allow its use in the empiric therapy of UTIs.

Evaluation of sexual activity in patients treated with tadalafil: a randomized prospective placebo-controlled trial.

The chronological distribution of sexual intercourses in a group of patients treated with tadalafil versus placebo for 3 months was evaluated. In total, 120 patients with ED were randomized in two groups and treated, respectively, with one pill of tadalafil 20 mg or placebo on Tuesday and on Friday. After 3 months, we collected data using IIEF and SEP diaries. After 3 months, IIEF score and percentages of success SEP diaries increased in the tadalafil group (<0.01) versus placebo group. Considering all the successful intercourses of the 3 months of tadalafil assumption, the highest percentages were reported within 6-12 h range (35%) and 12-24 h range (28%). In tadalafil group, 41% of patients reported their first successful intercourse between 1 and 6 h and 78% of patients reported the recovery of spontaneous erections. In conclusion, after carrying out the first sexual attempt between 1 and 6 h, patients engaged in sexual activity between 6 and 24 h.

Combined oral therapy with sildenafil and doxazosin for the treatment of non-organic erectile dysfunction refractory to sildenafil monotherapy.

The purpose of this work was to investigate the efficacy and safety of sildenafil in combination with doxazosin for the treatment of non-organic erectile dysfunction in patients who did not respond to sildenafil. We enrolled 28 patients with non-organic erectile dysfunction, for whom 3 months of sildenafil monotherapy had failed. They were divided in two random and homogeneous groups: 14 were treated with doxazosin (4 mg daily) and sildenafil (100 mg 1 h before sexual intercourse); the other 14 patients received sildenafil and placebo. The results were assessed by means of the IIEF questionnaire before the beginning of the study, after 30 days of therapy and after 60 days. Of the 14 patients treated with doxazosin and sildenafil, 11 (78.6%) showed a statistically significant increase of IIEF; in the placebo group, only one patient (7.1%) recorded a significant IIEF increase. The differences observed in the two groups were statistically very significant (P=0.0016). Blood pressure did not show significant alterations. Side effects were minimal and even present during sildenafil monotherapy. The combination therapy with sildenafil and doxazosin resulted in the safe and effective treatment of men with non-organic erectile dysfunction for whom sildenafil alone had failed.

Arterial priapism and cycling: a new worrisome reality?

Arterial priapism is a rare condition caused by the traumatic formation of an arteriolacunar fistula. We report 2 cases of arterial priapism after cycling injuries. Both patients sustained a violent perineal trauma against the top tube on the bicycle. In both cases, penile detumescence was obtained by superselective arteriographic embolization of the fistula with gelatin sponge or microcoil. The fistula was monolateral in the first case and bilateral in the second. Cycling should be considered a possible risk factor for arterial priapism as it is for urethritis, prostatitis, hematuria, testicular torsion, scrotal and penile numbness, and erectile dysfunction.

[Priapism: decisional algorithm, our experience, and role of sildenafil in sexual rehabilitation]. / Priapismo: algoritmo decisionale, nostra esperienza e ruolo del sildenafil nella riabilitazione sessuale.

OBJECTIVE: We report our experience in the management of priapism. MATERIALS AND METHODS: In a 2-year period we observed 7 patients of whom 4 presented with low flow and 3 with high flow priapism. RESULTS: In 2 of the patients with ischemic priapism, simple blood aspiration from the corpora allowed for a quick detumescence, while in the other 2 cases a derivative intervention (1 spongio cavernous and 1 glans cavernous) had to be performed. In all the 3 patients with high flow priapism we performed a superselective arteriography that obtained the visualisation of the arteriovenous fistula. These patients restarted their sexual activity after about three months. At six months a patient with low flow priapism restored sexual activity due to sildenafil 50 mg. CONCLUSION: The importance of distinguishing low and high flow priapism was confirmed.

Traumatic rupture of the corpora cavernosa: new physiopathologic acquisitions.

OBJECTIVES: To investigate the physiopathologic mechanisms of the rupture of the corpora cavernosa by means of a histologic study of the tunica albuginea. METHODS: In 6 patients (age range 28 to 49 years, mean 38) with traumatic penile rupture, samples of the tunica albuginea were taken during corrective surgery far from the site of the lesion. These specimens were analyzed with light microscopy by the same pathologist and compared with other samples of tunica albuginea taken from 7 patients who underwent penile surgery for other reasons. RESULTS: Five of the 6 patients with traumatic penile rupture had histologic anomalies of the tunica albuginea (fibrosclerosis in all 5 patients [83%] and phlogistic cellular infiltrations composed of lymphocytes or histiocytes in 3 patients [50%]). Only 1 patient (17%) with traumatic rupture of the corpus cavernosum had a completely healthy tunica albuginea. None of the control specimens revealed any histologic alterations. CONCLUSIONS: Structural anomalies could alter the mechanical properties of the tunica albuginea, representing a weakening factor of the corpora cavernosa and thus a predisposing factor for traumatic rupture of the penis. Therefore, patients with anomalous albuginea could undergo penile rupture even at intracavernous pressures inferior to pressures usually necessary to cause rupture in patients with healthy albuginea.

[Evaluation of the association between benign prostatic hyperplasia and sexual disorders]. / Valutazione dell'associazione tra iperplasia prostatica benigna e disturbi sessuali.

OBJECTIVE: The aim of this study was to determine the incidence of sexual dysfunction in patients with benign prostatic hyperplasia (BPH). METHODS: During the last 6 months 88 patients (mean age 65 years, range 55-78) suffering from BPH, without other chronic disease, were studied. RESULTS: Andrological evaluation enabled us to find erectile dysfunction in 52% of patients, ejaculation problems in 41% and decrease of libido in 54%. CONCLUSION: Due to the great impact of these disturbances in patients' quality of life, we believe that clinical and therapeutic approach in BPH patients should be global, with both urological and andrological assessment.

[Priapism: decisional algorithm. Our experience and role of sildenafil in sexual rehabilitation]. / Priapismo: algoritmo decisionale. Nostra esperienza e ruolo del sildenafil nella riabilitazione sessuale.

In this period we observed seven patients of whom four presented with low flow and three with high flow priapism. In two of the patients with ischemic priapism, simple blood aspiration from the corpora allowed for a quick detumescence, while in the other two cases a derivative intervention (one spongio cavernous and one glans cavernous) had to be performed. In all the three patients with high flow priapism we performed a superselective arteriography that obtained the visualisation of the arteriovenous fistula. These patients restarted their sexual activity after about three months. A six months a patient with low flow priapism restored sexual activity due to sildenafil 50 mg.

[Surgical approach in Peyronie's disease]. / Strategia chirurgica dell'induratio penis plastica.

The goal of surgical treatment of Induratio Penis Plastica should be the achievement of the best aesthetic and functional result with the lowest side-effects. During the last two years different techniques have been proposed for the cases with conserved erectile function, such as Nesbit's technique, excision or incision of the plaque followed by implants of autologous (dermal, saphena vein) or heterologous (dura madre, gore-tex) patches. The criteria for the choice of the most appropriated surgical technique include the curvature degree, the plaque dimension and the penis length. In our experience 6 months after the surgical correction a remaining curvature was observed in 4/38 patients (10%), only 1 of whom needed a new surgical treatment. One case of erectile disfunction occurred, treated by intra-cavernous injection of PgE1.