CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.

Understanding the Pathological Basis of Neurological Diseases Through Diagnostic Platforms Based on Innovations in Biomedical Engineering: New Concepts and Theranostics Perspectives.

The pace of advancement of genomics and proteomics together with the recent understanding of the molecular basis behind rare diseases could lead in the near future to significant advances in the diagnosing and treating of many pathological conditions. Innovative diagnostic platforms based on biomedical engineering (microdialysis and proteomics, biochip analysis, non-invasive impedance spectroscopy, etc.) are introduced at a rapid speed in clinical practice: this article primarily aims to highlight how such platforms will advance our understanding of the pathological basis of neurological diseases. An overview of the clinical challenges and regulatory hurdles facing the introduction of such platforms in clinical practice, as well as their potential impact on patient management, will complement the discussion on foreseeable theranostic perspectives. Indeed, the techniques outlined in this article are revolutionizing how we (1) identify biomarkers that better define the diagnostic criteria of any given disease, (2) develop research models, and (3) exploit the externalities coming from innovative pharmacological protocols (i.e., those based on monoclonal antibodies, nanodrugs, etc.) meant to tackle the molecular cascade so far identified.

How Nanotechnology and Biomedical Engineering Are Supporting the Identification of Predictive Biomarkers in Neuro-Oncology.

The field of neuro-oncology is rapidly progressing and internalizing many of the recent discoveries coming from research conducted in basic science laboratories worldwide. This systematic review aims to summarize the impact of nanotechnology and biomedical engineering in defining clinically meaningful predictive biomarkers with a potential application in the management of patients with brain tumors. Data were collected through a review of the existing English literature performed on Scopus, MEDLINE, MEDLINE in Process, EMBASE, and/or Cochrane Central Register of Controlled Trials: all available basic science and clinical papers relevant to address the above-stated research question were included and analyzed in this study. Based on the results of this systematic review we can conclude that: (1) the advances in nanotechnology and bioengineering are supporting tremendous efforts in optimizing the methods for genomic, epigenomic and proteomic profiling; (2) a successful translational approach is attempting to identify a growing number of biomarkers, some of which appear to be promising candidates in many areas of neuro-oncology; (3) the designing of Randomized Controlled Trials will be warranted to better define the prognostic value of those biomarkers and biosignatures.

Current and Future Applications of Biomedical Engineering for Proteomic Profiling: Predictive Biomarkers in Neuro-Traumatology.

This systematic review aims to summarize the impact of nanotechnology and biomedical engineering in defining clinically meaningful predictive biomarkers in patients with traumatic brain injury (TBI), a critical worldwide health problem with an estimated 10 billion people affected annually worldwide. Data were collected through a review of the existing English literature performed on Scopus, MEDLINE, MEDLINE in Process, EMBASE, and/or Cochrane Central Register of Controlled Trials. Only experimental articles revolving around the management of TBI, in which the role of new devices based on innovative discoveries coming from the field of nanotechnology and biomedical engineering were highlighted, have been included and analyzed in this study. Based on theresults gathered from this research on innovative methods for genomics, epigenomics, and proteomics, their future application in this field seems promising. Despite the outstanding technical challenges of identifying reliable biosignatures for TBI and the mixed nature of studies herein described (single cells proteomics, biofilms, sensors, etc.), the clinical implementation of those discoveries will allow us to gain confidence in the use of advanced neuromonitoring modalities with a potential dramatic improvement in the management of those patients.

Enhancing contrast agents and radiotracers performance through hyaluronic acid-coating in neuroradiology and nuclear medicine.

The use of hyaluronic acid nanoshells has been proposed to encapsulate prodrugs and exploit the mechanisms of interactions between living cells, like endocytes or cancer cells and hyaluronic acid, which is a natural component of the extracellular matrix. In this review we describe the potential and the limits of this promising research trend and discuss the theoretical advantages of such an engineering approach. Is it a possible scalability to increase the efficacy and biodegradability of molecules like contrast media and radiotracers especially for neuroradiology and nuclear medicine studies.

Immunoreactivity pattern of calretinin in the developing human cerebellar cortex.

The immunohistochemical expression of the calcium-binding protein calretinin during human cerebellar development has been investigated in this study. Human cerebellum samples, obtained from 7 fetuses and newborns ranging from 11 to 38 weeks of gestation, were 10% formalin-fixed, routinely processed and paraffin-embedded. 3µm-tick sections were immunostained with an anti-calretinin antibody. Our study evidenced a different immunoreactivity for calretinin in Purkinje cells and in several cerebellar interneurons at different intrauterine developmental stages. Whereas at 11 weeks of gestation calretinin immunoreactivity was not detected in the developing cerebellum, from the 18th to the 24th week, calretinin expression was found in Purkinje cells migrating from the ventricular neuroepithelium and in migrating cerebellar interneurons. From the 30th to the 38th week, calretinin was expressed by most of Purkinje cells and by migrating cerebellar interneurons. Furthermore, granule cells in the internal granular layer were also immunoreactive for calretinin. Our data show that calretinin, other than for developing Purkinje cells, is a useful marker also for migrating cerebellar interneurons and for some neuronal elements related to the granular layer. Moreover, given the critical role of calcium in a great variety of neuronal processes in the central nervous system, our findings suggest that calretinin may play a pivotal role in the regulation of neuronal excitability during intrauterine cerebellar development.

Interstitial stromal progenitors during kidney development: here, there and everywhere.

In recent years, the renal interstitium has been identified as the site of multiple cell types, giving rise to multiple contiguous cellular networks with multiple fundamental structural and functional roles. Few studies have been carried out on the morphological and functional properties of the stromal/interstitial renal cells during the intrauterine life. This work was aimed at reviewing the peculiar features of renal interstitial stem/progenitor cells involved in kidney development. The origin of the renal interstitial progenitor cells remains unknown. During kidney development, besides the Six2 + cells of the cap mesenchyme, a self-renewing progenitor population, characterized by the expression of Foxd1, represents the first actor of the non-nephrogenic lineage. Foxd1 + interstitial progenitors originate the cortical and the renal medullary interstitial progenitors. Here, the most important stromal/interstitial compartments present in the developing human kidney will be analyzed: capsular stromal cells, cortical interstitial cells, medullary interstitial cells, the interstitium inside the renal stem cell niche, Hilar interstitial cells and Ureteric interstitial cells. Data reported here indicate that the different interstitial compartments of the developing kidney are formed by different cell types that characterize the different renal areas. Further studies are needed to better characterize the different pools of renal interstitial progenitors and their role in human nephrogenesis.

Overlapping between CYP3A4 and CYP3A7 expression in the fetal human liver during development.

OBJECTIVE: The cytochrome P450 (CYP450) superfamily is implicated in important life processes, including metabolism of many molecules. CYP3A account for the largest portion of CYP450 proteins in human, including CYP3A4, CYP3A5 and CYP3A7. The purpose of this study was to investigate the immunohistochemical expression of CYP3A4 and CYP3A7 in human liver at different post-conceptional (PC) ages. METHODS: Human liver samples from 30 fetuses and newborns were, clustered according with the PC age, routinely processed for immunohistochemical analysis of CYP3A4 and CYP3A7. RESULTS: CYP3A4 was positive in all but two cases, CYP3A7 was positive in all but one case, which was negative also for CYP3A4. CONCLUSIONS: Our data on immunohistochemical detection of CYP3A4 and CYP3A7 during development show that CYP3A4 expression is not restricted to the post-natal age, being the immunostaining for both CYP3A4 and CYP3A7 identical after 25 weeks of PC age, thus the relationship between these CYP450 isoforms should be considered much more complex than previous thought. A high interindividual variability was observed among subjects at all gestational age. The variable CYP3A expression suggests the existence of a marked interindividual variability in drug metabolism during the intrauterine life and in perinatal period.

Aluminum exposure and toxicity in neonates: a practical guide to halt aluminum overload in the prenatal and perinatal periods.

BACKGROUND: During the last years, human newborns have been overexposed to biologically reactive aluminum, with possible relevant consequences on their future health and on their susceptibility to a variety of diseases. Children, newborns and particularly preterm neonates are at an increased risk of aluminum toxicity because of their relative immaturity. DATA SOURCES: Based on recent original publications and classical data of the literatures, we reviewed the aluminum content in mother's food during the intrauterine life as well as in breast milk and infant formula during lactation. We also determined the possible role of aluminum in parenteral nutrition solutions, in adjuvants of vaccines and in pharmaceutical products. A special focus is placed on the relationship between aluminum overexposure and the insurgence of bone diseases. RESULTS: Practical points of management and prevention are suggested. Aluminum sources that infants may receive during the first 6 months of life are presented. In the context of prevention of possible adverse effects of aluminum overload in fetal tissues during development, simple suggestions to pregnant women are described. Finally, practical points of management and prevention are suggested. CONCLUSIONS: Pediatricians and neonatologists must be more concerned about aluminum content in all products our newborns are exposed to, starting from monitoring aluminum concentrations in milk- and soy-based formulas in which, on the basis of recent studies, there is still too much aluminum.

Synovial cysts of the lumbar spine--pathological considerations and surgical strategy.

Symptomatic lumbar synovial cysts (LSCs) are a rare cause of degenerative narrowing of the spinal canal, with thecal sac or nerve root compression. True synovial cysts have a thick wall lined by synovial cells, containing granulation tissue, numerous histiocytes, and giant cells. In contrast, pseudo-cysts lack specialized epithelium, have a collagenous capsule filled with myxoid material, and may be classified into ganglion cysts, originating from periarticular fibrous tissues, and ligamentous cysts, arising from the ligamentum flavum or even from the posterior longitudinal ligament. Here we present the surgical series of the Chair of Neurosurgery at the University of Cagliari (Italy) including a total of 17 LSCs. Surgical technique consisted of facet sparing excision of LSC, achieved by simple hemilaminectomy/laminectomy, and diagnosis was always confirmed by histological specimen examination, which detected the typical synovial epithelium, the intracystic presence of hemosiderin, histiocytes, and calcifications. Further immunohistochemical investigation revealed positive staining for cytokeratin: CK5, CK6, and AE1/AE3. Clinically, our cohort experienced rapid and complete resolution of symptoms, without perioperative complications, or recurrence of cysts or vertebral instability at a median follow up of 28 months, when the MacNab score was generally excellent. A review of the literature, retrieving articles published from 1973, collected a total of 101 articles concerning all the cases of LSC scientifically described to date. Both clinical and histological findings described in our study support the theory of degenerative microtraumatic pathogenesis of synovial cysts.

Rectus abdominis muscle endometriosis Report of two cases and review of the literature.

Endometriosis involving the rectus abdominis muscle is very rare; until now, only 19 such cases have been reported in the medical literature since it was first described in 1984 by Amato and Levitt; almost all were associated with previous abdominal surgery such as cesarean section or other operations. We report two additional cases of this very rare condition presenting with an abdominal mass which was surgically excised with an accompanying margin of normal tissue. Both patients are well and without recurrence. Endometriosis pain has generally been described as cyclical and this condition usually develops in an old surgical scar. Endometriosis has no pathognomonic imaging findings on CT, MRI or sonography, as its appearance depends on the phase of the menstrual cycle, the proportion of stromal and glandular elements, the amount of bleeding and the degree of surrounding inflammatory and fibrotic response. Surgery is the treatment of choice including 5-10 mm of surrounding healthy tissue as surgical margin, to prevent recurrence. Our experience is in agreement with the data of the literature. We suggest that endometriosis must be included in the differential diagnosis of a symptomatic mass in the abdominal wall in women with and without a surgical history. Key words: Endometriosis, Rectus abdominis muscle, Surgery.

Hepatic injury to the newborn liver due to drugs.

The result of the use of drugs in the newborn may be strongly influenced by the peculiar state of the neonate, characterized by the immaturity, at birth, of the processes controlling the absorption, distribution, metabolism and excretion of drugs. Additional important factors that may affect drugs' bioavailability and toxicity are gestational age, birth weight, intrauterine growth restriction, gender and, especially, liver function immaturity. Because of the high susceptibility to infections, antibiotics, in particular ampicillin and gentamicin, are the most widely used drugs in newborns. Erythromycin is often used for the therapy of gastrointestinal dismotility, while azithromycin has been proposed for the prevention of bronchopulmonary dysplasia. Prostaglandin synthesis inhibitors, like indomethacin, are administered on the first days of life to close the patent ductus arteriosus. All these drugs have been proved to can give rise to hepatotoxicity. The acute and chronic liver toxicity due to the most widely used drugs in the neonates will be here reviewed.

MUTYH-associated colon disease: adenomatous polyposis is only one of the possible phenotypes. A family report and literature review.

AIMS AND BACKGROUND: The MutY human homologue gene (MUTYH) is responsible for about a quarter of attenuated familial adenomatous polyposis. Occasionally, it has been associated with hyperplastic polyps and serrated adenoma. We report a family where the same MUTYH mutation determined four different phenotypes, including a case of hyperplastic polyposis syndrome. PATIENTS AND METHODS: A family with a history of right-sided colon cancer and multiple colonic polyposis was investigated. Genetic tests were correlated with clinical findings to define phenotypic manifestations of MUTYH mutations. The pertinent English-language literature was reviewed to evaluate the risk of malignancy of MUTYH and the role of prophylactic surgery. RESULTS: Three male siblings carried a biallelic MUTYH mutation (G382D-exon13), while the fourth was heterozygote. One developed an isolated cecal cancer at the age of 48. Another, aged 38, was diagnosed with numerous minute colonic and rectal polyps and underwent a proctocolectomy, with final pathology showing a picture of hyperplastic and lymphoid polyposis. The third biallelic brother, 46 years old, developed four hyperplastic lesions, while the heterozygote brother had a large flat serrated adenoma of the right colon removed at the age of 50. CONCLUSION: Many aspects of MUTYH mutation still need to be clarified and one of them regards the different phenotypic expressions. Although the majority of reported cases manifested attenuated adenomatous polyposis, hyperplastic polyps and serrated adenomas appear to be more common than expected. Presenting hyperplastic polyposis syndrome is very unusual and may represent a clinical dilemma for correct management. Current evidence suggests to handle MUTYH-associated polyposis as typical FAP.

Brain-derived neurotrophic factor (BDNF) and polysialylated-neural cell adhesion molecule (PSA-NCAM): codistribution in the human brainstem precerebellar nuclei from prenatal to adult age.

Occurrence and distribution of the neurotrophin brain-derived neurotrophic factor (BDNF) and polysialylated-neural cell adhesion molecule (PSA-NCAM), a neuroplasticity marker known to modulate BDNF signalling, were examined by immunohistochemistry in the human brainstem precerebellar nuclei at prenatal, perinatal and adult age. Western blot analysis performed in human brainstem showed for both molecules a single protein band compatible with the molecular weight of the dimeric form of mature BDNF and with that of PSA-NCAM. Detectability of both molecules up to 72h post-mortem was also assessed in rat brain. In neuronal perikarya, BDNF-like immunoreactivity (LI) appeared as intracytoplasmic granules, whereas PSA-NCAM-LI appeared mostly as peripheral staining, indicative of membrane labelling; immunoreactivity to both substances also labelled nerve fibres and terminals. BDNF- and PSA-NCAM-LI occurred in the external cuneate nucleus, perihypoglossal nuclei, inferior olive complex, arcuate nucleus, lateral reticular formation, vestibular nuclei, pontine reticulotegmental and paramedian reticular nuclei, and pontine basilar nuclei. With few exceptions, for both substances the distribution pattern detected at prenatal age persisted later on, though the immunoreactivity appeared often higher in pre- and full-term newborns than in adult specimens. The results obtained suggest that BDNF operates in the development, maturation, maintenance and plasticity of human brainstem precerebellar neuronal systems. They also imply a multiple origin for the BDNF-LI of the human cerebellum. The codistribution of BDNF- and PSA-NCAM-LI in analyzed regions suggests that PSA-NCAM may modulate the functional interaction between BDNF and its high and low affinity receptors, an issue worth further analysis, particularly in view of the possible clinical significance of neuronal trophism in cerebellar neurodegenerative disorders.

Deep fibrous histiocytoma with a clonal karyotypic alteration: molecular cytogenetic characterization of a t(16;17)(p13.3;q21.3).

Deep fibrous histiocytoma, a rare lesion occuring in deep soft tissues, has recently been formally characterized as a diagnostically distinguishable variant of the benign fibrous histiocytoma spectrum with distinct morphological features. Nevertheless, because of the small number of cases published, information on their clinical behavior, including propensity for local recurrence and metastasis, is quite limited, and no molecular genetic or cytogenetic data are available. We report a 46,XY,t(16;17)(p13.3;q21.3) karyotype in a deep fibrous histiocytoma. Fluorescence in situ hybridization using bacterial artificial chromosome (BAC) clones refined the translocation breakpoints within 119.9 kb at 16p13.3 and 214 kb at 17q21.3. Moreover, to ascertain whether they may be nonrandomly involved in changes in this rare tumor type, we designed two dual-color break-apart probes with BAC clones, mapping proximally and distally to the two breakpoints, to be tested in additional archival cases by interphase fluorescence in situ hybridization. No break-apart signals were observed in the six additional cases studied, indicating either that the translocation is sporadic or that it is rare in deep fibrous histiocytoma. In conclusion, our data show that chromosome aberrations may be found in deep fibrous histiocytoma and that, as with cutaneous lesions, they may have clonal, at present nonrecurrent, chromosome changes.

Rectal perforation from endometriosis in pregnancy: case report and literature review.

This case report describes a woman with spontaneous rectal perforation from decidualized endometriosis in pregnancy. A 37-year-old woman was admitted to our hospital at 30 wk of pregnancy with symptoms suggestive of pyelonephritis, which persisted until 33 wk of gestation when delivery of a premature male baby was performed through a cesarean section. On postoperative day 2, an abdominal computed tomography showed free air in the peritoneal cavity and a pelvic abscess. Explorative celiotomy revealed a diffuse severe fecaloid peritonitis that originated from a 3-cm wide rectal perforation. A Hartmann operation was then performed. Histopathological findings were consistent with decidualization of the rectal wall. Only 20 cases of intestinal perforation due to endometriosis have been reported in the literature. This report is believed to be the first case of spontaneous rectal perforation from endometriosis in pregnancy, and it shows the potential occurrence of serious and unexpected complications of the disease.

Agonist activity of N-desmethylclozapine at delta-opioid receptors of human frontal cortex.

The clozapine metabolite N-desmethylclozapine (NDMC) has been recently shown to act at different neurotransmitter receptors and to display both antagonist and agonist activities. We have previously reported that in cells over-expressing the recombinant delta-opioid receptor NDMC behaved as partial agonist with high intrinsic activity, but its action at the receptors naturally expressed in human brain remained to be investigated. In the present study, we examined whether NDMC was able to bind to and activate delta-opioid receptors in membranes of post-mortem human frontal cortex. In radioligand binding assays, NDMC competition curves displayed high- (K(i)=26 nM) and low-affinity (K(i)=3 microM) components, whose proportion was regulated by guanine nucleotides in an agonist-like fashion. In functional assays, NDMC stimulated [(35)S]GTPgammaS binding (EC(50)=905 nM) and inhibited cyclic AMP formation (EC(50)=590 nM) as effectively as delta-opioid agonists, whereas clozapine was much less potent and efficacious and clozapine N-oxide was completely inactive. The NDMC agonist activity was potently antagonized by the delta-opioid antagonist naltrindole, but not by the micro-opioid receptor antagonist CTAP (D-phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)) or the kappa-opioid antagonist nor-binaltorphimine. Moreover, blockade of either acetylcholine muscarinic, dopamine D(2) or serotonin 5HT(1A) receptors failed to affect NDMC agonist activity. These data demonstrate that at clinically relevant concentrations NDMC behaves as an efficacious agonist at delta-opioid receptors of human frontal cortex.

p16 ink4a and HPV L1 immunohistochemistry is helpful for estimating the behavior of low-grade dysplastic lesions of the cervix uteri.

As only a minority of low-grade dysplastic lesions of the cervix uteri will eventually progress to carcinoma, predicting the behavior of these lesions could be of high value in clinical practice. The aim of the study was to evaluate p16 ink4a and L1 as immunohistochemical markers of the biologic potentiality of low-grade dysplasia of the uterine cervix. The study included 38 conization specimens with coexisting cervical intraepithelial neoplasia grade 1 (CIN1) and 3 (CIN3) (group A) and 28 punch biopsies from women with CIN1 and proven spontaneous regression in the follow-up (group B). In group A, all CIN3 were p16 ink4a positive (p16+) and L1 negative (L1-). The CIN1 of this group were p16+L1- and p16+L1+ in 68.42% and 31.57%, respectively. No other expression pattern was found in this group. In group B, the p16+L1-, p16+L1+, p16-L1+, and p16-L1- patterns were found in 3.57%, 25%, 14.29%, and 57.14%, respectively. Overall, 96.29% p16+L1- CIN1 were found in group A, whereas all the p16-L1+ and p16-L1- CIN1 were found in group B. A significant difference between staining pattern distributions of group A and B was observed (P<0.0001). The results of the study show that p16 ink4a and L1 immunohistochemistry can be helpful for estimating the biologic potentiality of low-grade squamous cervical lesions. Particularly in cases in which the grade of the lesion is morphologically difficult to assess, the p16/L1 expression pattern could be useful for planning the clinical management of these women.

Complete pancreatic heterotopia of gallbladder with hypertrophic duct simulating an adenomyoma.

The gallbladder is an unusual location of pancreatic heterotopia, defined as the presence of pancreatic tissue lacking anatomical and vascular continuity with the main body of the gland. A 28-year-old man presented with anorexia, nausea and pain in the right upper abdomen. On physical examination, the abdomen was tender to palpation and Murphy sign was positive. The patient underwent a cholecystecomy. This case, in our opinion, is very interesting since it permits to consider a controversial issue in the pathology of the gallbladder. The histological appearance of ductal structure in pancreatic heterotopia resembles the histological picture of both Aschoff-Rokitansky (AR) sinuses and adenomyomas. This finding suggests that these lesions are linked by a common histogenetic origin. We suggest that the finding of an adenomyoma in the gallbladder should prompt an extensive sampling of the organ in order to verify the coexistence of pancreatic rests.