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Giovanni Ponti - Top 30 Publications

The value of fluorimetry (Qubit) and spectrophotometry (NanoDrop) in the quantification of cell-free DNA (cfDNA) in malignant melanoma and prostate cancer patients.

Circulating cell-free tumor DNA (cfDNA) is of crucial interest in oncology. cfDNA constitutes a potential prognostic and therapeutic marker for different solid tumors and can be used in the diagnostic and therapeutic management of cancer patients for which nowadays there are no valid laboratory markers. In the present study, the quality and quantity of the cfDNA were assessed by different quantification procedures, in order to identify the potential applications of these techniques in the preliminary cfDNA quantification.

PTCH1 Germline Mutations and the Basaloid Follicular Hamartoma Values in the Tumor Spectrum of Basal Cell Carcinoma Syndrome (NBCCS).

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominantly inherited disorder characterized by multiple basal cell carcinomas (BCC), odontogenic tumors and various skeletal anomalies. Basaloid follicular hamartomas (BFHs) constitute rare neoplasms that can be detected in sporadic and familial settings as in the Basaloid Follicular Hamartoma Syndrome (BFHS). Although BFHS shares clinical, histopathological and genetic overlapping with the NBCCS, they are still considered two distinctive entities. The aim of our single-institution study was the analysis of a cohort of PTCH1-mutated patients in order to define clinical and biomolecular relationship between NBCCS and BFHs.

BRAF, NRAS and C-KIT Advanced Melanoma: Clinico-pathological Features, Targeted-Therapy Strategies and Survival.

The mutational status of stage III and IV melanomas should be recognized in order to allow for targeted therapies. The aim of our study was the characterization of BRAF, NRAS and C-KIT melanoma patients, in order to define their optimal management.

Myopic Loss Aversion under Ambiguity and Gender Effects.

Experimental evidence suggests that the frequency with which individuals get feedback information on their investments has an effect on their risk-taking behavior. In particular, when they are given information sufficiently often, they take less risks compared with a situation in which they are informed less frequently. We find that this result still holds when subjects do not know the probabilities of the lotteries they are betting upon. We also detect significant gender effects, in that the frequency with which information is disclosed mostly affects male betting behavior, and that males become more risk-seeking after experiencing a loss.

Desmoplastic melanoma: a challenge for the oncologist.

To evaluate clinical, pathologic and genetic features of desmoplastic melanoma (DM).

Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report.

Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple cafè-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease.

Congenital Glioblastoma multiforme and eruptive disseminated Spitz nevi.

Glioblastoma multiforme (GBM) is the deadliest malignant primary brain tumor in adults. GBM develops primarily in the cerebral hemispheres but can develop in other parts of the central nervous system. Its congenital variant is a very rare disease with few cases described in literature.

Fibroepithelioma of Pinkus: Solitary tumor or sign of a complex gastrointestinal syndrome.

Fibroepithelioma of Pinkus (FEP), which is considered to be an uncommon variant of basal cell carcinoma, has been described in association with other systemic diseases. However, no specific studies are currently available on this subject. The aim of our study was to evaluate the clinical and morphological characteristics of FEP and investigate whether this rare tumor is a single entity or seen in the context of a more complex syndrome. We retrospectively analyzed 49 cases of FEP diagnosed and excised in a single academic institution from 1995 to 2011. The tumors were mainly located on the trunk (77.55%), followed by the lower extremities (12.20%) and the head and neck (10.20%). In 9 of the 49 cases (18%), FEP was associated with gastrointestinal tumors. The abovementioned cases are presented in an attempt to make clinicians more aware of a possible association between FEP and gastrointestinal cancer. Although a possible underlying common genetic background between FEP and gastrointestinal tumors was not provided, our study suggests that patients with FEP should be screened for the occurrence of gastrointestinal tumors.

Wall paintings facies and their possible genetic correlates in the ancient Pompeii: A bio-anthropologic message from the past?

The figurative arts and precisely the ancient Pompeian wall paintings portraits can provide an additional source of information in supplementing bio-anthropological studies. There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to distinctive facial features. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant syndrome characterized by unusual skeletal changes, such as macrocephaly, facial asymmetry, hypertelorism, frontal and parietal bossing caused by germline mutations of the gene PTCH1. The Gorlin syndrome, clinically defined in 1963, existed during Dynastic Egyptian times, as revealed by a spectrum of skeletal findings compatible with the syndrome in mummies dating back to three thousand years ago and, most likely, in the ancient population of Pompeii. In the present research, we discuss the potential relationship between Pompeian wall paintings portrait and the cranio-metric bone changes revealed among the Pompeian skull collections assuming that the ancient portraits can constitute an important tool that should be strictly integrated with osteologic and biomolecular data in order to argue a syndromic diagnosis in ancient population.

Role of microsatellite instability, immunohistochemistry and mismatch repair germline aberrations in immunosuppressed transplant patients: a phenocopy dilemma in Muir-Torre syndrome.

Sebaceous tumours and keratoacanthomas are uncommon neoplasms that constitute important clinical criteria for Muir-Torre syndrome (MTS) diagnosis. In MTS patients, the increased risk of developing synchronous or metachronous visceral malignancies is characterised by autosomal dominant inheritance. However, there are further conditions, other than MTS, that increase the risk of sebaceous neoplasms, e.g. iatrogenic immunosuppression. In this latter scenario, the sebaceous tumours can present microsatellite instability (MSI) and loss of mismatch repair (MMR) proteins, characteristic of hereditary syndromes, even in the absence of MMR germline mutations. In this article, we examine transplant probands in which the immunosuppressive therapies unmask the MTS cutaneous phenotypes, showing MSI and loss of MMR protein expression, as demonstrated by immunohistochemistry (IHC). Furthermore, MMR genes sequencing analysis identified the presence of germline mutations in MTS-suspected individuals, in the absence of a visceral MTS phenotype. It is well known that immunosuppression plays a central role in the development of sebaceous tumours in both MTS and in non-syndromic settings. Sebaceous skin tumours' MSI status and IHC profiles can be influenced by epigenetic or iatrogenic factors; however, they constitute valuable tools and a cost-effective approach to screen individuals who otherways should undergo MMR genes direct sequencing in the context of immunosuppression. In this complex setting, the choice of the immunosuppressive drug becomes a critical decision for the management of both MTS and sporadic transplant patients, which may benefit from the administration of immunosuppressive drugs, resulting in a low impact on skin cancerogenesis.

Oral mucosal stigmata in hereditary-cancer syndromes: From germline mutations to distinctive clinical phenotypes and tailored therapies.

Numerous familial tumor syndromes are associated with distinctive oral mucosal findings, which may make possible an early diagnosis as an efficacious marker for the risk of developing visceral malignancies. In detail, Familial Adenomatous Polyposis (FAP), Gardner syndrome, Peutz-Jeghers syndrome, Cowden Syndrome, Gorlin Syndrome, Lynch/Muir-Torre Syndrome and Multiple Endocrine Neoplasia show specific lesions of the oral mucosa and other distinct clinical and molecular features. The common genetic background of the above mentioned syndromes involve germline mutations in tumor suppressor genes, such as APC, PTEN, PTCH1, STK11, RET, clearly implied in both ectodermal and mesodermal differentiation, being the oral mucosal and dental stigmata frequently associated in the specific clinical phenotypes. The oral and maxillofacial manifestations of these syndromes may become visible several years before the intestinal lesions, constituting a clinical marker that is predictive for the development of intestinal polyps and/or other visceral malignancies. A multidisciplinary approach is therefore necessary for both clinical diagnosis and management of the gene-carriers probands and their family members who have to be referred for genetic testing or have to be investigated for the presence of visceral cancers.

Skeletal stigmata as keys to access to the composite and ancient Gorlin-Goltz syndrome history: The Egypt, Pompeii and Herculaneum lessons.

There are several genetic diseases with a wide spectrum of congenital bone stigmata in association to cutaneous and visceral benign and malignant neoplasms. Gorlin-Goltz syndrome, also named nevoid basal cell carcinoma syndrome, is an autosomal dominant systemic disease with almost complete penetrance and high intra-familial phenotypic variability, caused by germline mutations of the gene PTCH1. The syndrome is characterized by unusual skeletal changes and high predisposition to the development of multiple basal cell carcinomas, odontogenic keratocysts tumors and other visceral tumors. The Gorlin syndrome, clinically defined as distinct syndrome in 1963, existed during Dynastic Egyptian times, as revealed by a costellation of skeletal findings compatible with the syndrome in mummies dating back to 3000years ago and, most likely, in the ancient population of Pompeii. These paleogenetic and historical evidences, together with the clinical and biomolecular modern evidences, confirm the quite benign behavior of the syndrome and the critical value of the multiple and synchronous skeletal anomalies in the recognition of these rare and complex genetic disease.

BRAFp.V600E, p.V600K, and p.V600R Mutations in Malignant Melanoma: Do They Also Differ in Immunohistochemical Assessment and Clinical Features?

Although the detection of BRAF p.V600E mutation by immunohistochemistry was clearly described in melanoma, discordant evidences were reported for the detection of p.V600K and p.V600R mutations. The aim of the study was to evaluate the efficacy of BRAFp.V600E, p.V600K, and p.V600R detection by immunohistochemistry in melanoma.

Giuseppe Moscati: a man, a physician and a scientist.

The life of Giuseppe Moscati (1880-1927) as a man, as a physician and as a scientist may be framed within the cultural climate of Positivism, which spread over the last years of the 19th century and the beginning of the 20th Century. His activity contributed to patients' care improvement; in addition to meticulous drug regimens, he also prescribed a methodology of spiritual care, involving meditation and self-control as part of an holistic approach to healthcare. Our review deals with his published researches, highlighting the innovative findings on the juvenile diabetes treatment and extensive clinical changes consequent upon nephritis. This extraordinary man put considerable emphasis on primary care and holistic health in Italy, pioneering a new patient-centred, and holistic approach to medicine.

Social preferences and cognitive reflection: evidence from a dictator game experiment.

This paper provides experimental evidence on the relationship between social preferences and cognitive abilities, which we measure using the Cognitive Reflection Test (CRT). We elicit social preferences by way of 24 dictatorial situations, in which the Dictator's choice sets include (i) standard Dictator games, where increasing the Dictator's payoff yields a loss for the Recipient, (ii) efficient Dictator games, where increasing the Dictator's payoff also increases that the Recipient's; as well as other situations in which (iii) either the Dictator's or (iv) the Recipient's monetary payoff is held constant. We partition our subject pool into three groups: reflective (scoring 2 or more in the CRT), impulsive (opting twice or more for the "intuitive" but wrong answers in the CRT) and the remainder. We find that impulsive Dictators show a marked inequity aversion attitude, especially in standard Dictator Games. By contrast, reflective Dictators show lower distributional concerns, except for the situations in which the Dictators' payoff is held constant. In this case, reflective Dictators give significantly more.

Confocal microscopy characterization of BRAFV600E mutated melanomas.

Thanks to modern techniques, molecular signatures for melanoma are now identifiable and have opened new horizons in the treatment of metastatic disease with molecular-targeted therapies. We distinguish different melanoma subtypes on the basis of genetic mutations such as BRAFV600E and we can therefore hypothesize the existence of corresponding morphological patterns that might be detected in vivo by noninvasive diagnostic tools such as dermoscopy and confocal microscopy. Eight BRAFV600E mutated melanomas (six primary and two metastases) were collected, matched in terms of age, sex, and thickness wild-type controls, and analyzed. In this preliminary study, regression, corresponding to fibrosis and melanophages in the dermis, was the predominant pattern and was also observed confocally when dermoscopy showed no peppering. In particular, confocal microscopy could not only detect regression but also provided a semiquantitative analysis of its grade through the count of melanophages. Confocal microscopy can be proposed as a useful tool in the preliminary screening and characterization of BRAFV600E mutated melanomas, providing new insights for patients' screening and follow-up.

Gender differences in sleep deprivation effects on risk and inequality aversion: evidence from an economic experiment.

Excessive working hours--even at night--are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects' risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females' reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making.

The long road to the use of microscope in clinical medicine in vivo: from early pioneering proposals to the modern perspectives of optical biopsy.

For a long period the scientists did not recognized the potentialities of the compound microscope in medicine. Only few scientists recognized the potentialities of the microscope for the medicine; among them G. Campani who proposed the utilization of his microscope to investigate the skin lesions directly on the patient. The proposal was illustrated in a letter Acta Eruditorum of 1686. The recent development of optical techniques, capable of providing in-focus images of an object from different planes with high spatial resolution, significantly increased the diagnostic potential of the microscope directly on the patient.

Mismatch repair gene deficiency and genetic anticipation in Lynch syndrome: myth or reality?

Hypomelanosis of Ito with a trisomy 2 mosaicism: a case report.

Hypomelanosis of Ito is a rare neurocutaneous disorder, characterized by streaks and swirls of hypopigmentation following the lines of Blaschko that may be associated to systemic abnormalities involving the central nervous system and musculoskeletal system. Despite the preponderance of reported sporadic hypomelanosis of Ito, few reports of familial hypomelanosis of Ito have been described.

Fordyce granules and hyperplastic mucosal sebaceous glands as distinctive stigmata in Muir-Torre syndrome patients: characterization with reflectance confocal microscopy.

The Muir-Torre syndrome (MTS), a variant of Lynch syndrome (LS), is characterized by the presence of sebaceous skin adenomas and/or carcinomas and keratoacanthomas associated with visceral malignancies. Fordyce granules (FGs) are oral mucosal lesions previously found in association with LS. The aim of this study was to analyze the specific frequency of FGs in sporadic individuals and gene carriers patients with MTS of known mismatch repair genes mutations. The secondary aim was to characterize FGs by means of reflectance confocal microscopy (RCM).

Skeletal and cranio-facial signs in Gorlin syndrome from ancient Egypt to the modern age: sphenoid asymmetry in a patient with a novel PTCH1 mutation.

Gorlin syndrome is an autosomal dominant disorder linked to PTCH1 mutation, identified by a collection of clinical and radiologic signs. We describe the case of a family in which father and son fulfilled clear cut diagnostic criteria for Gorlin syndrome including multiple basal cell carcinomas, keratocystic odontogenic tumors, atypical skeletal anomalies and a novel PTCH1 germline mutation (c.1041delAA). Craniofacial and other skeletal anomalies displayed at 3D and helical CT scan were: macrocephaly, positional plagiocephaly, skull base and sphenoid asymmetry, bifidity of multiple ribs and giant multilocular odontogenic jaw cysts. Extensive multilamellar calcifications were found in falx cerebri, tentorium, falx cerebelli and in the atlanto-occipital ligament. The inclusion of bifid ribs as a novel major criteri may be useful for the recognition and characterization of misdiagnosed cases.

NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies.

Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis.

High magnification digital dermoscopy of basal cell carcinoma: a single-centre study on 400 cases.

The aim of this study was to assess the frequency of classic dermoscopic basal cell carcinoma (BCC) features and the sensitivity of new descriptors, such as light brown nests (homogeneous and structured) only visible employing a high magnification digital videomicroscope. A retrospective analysis of 2,024 highly magnified digital images referring to 400 BCCs was performed by 3 independent observers, who assessed 11 classic BCC descriptors and the new ones. Light brown nests were detected in 40.5% of BCCs. Homogeneous ones were observable in 17.8%, and structured nests in 32.8%. Light brown nests were visible in 14.3% of non-pigmented lesions, whereas in the pigmented groups these were observed in 42-54% of the cases. We suggest that brown nests described in this study may improve early recognition of superficial BCCs and of non-pigmented or slightly pigmented ones that may lack classic dermoscopic patterns.

Multiple primary melanomas versus single melanoma of the head and neck: a comparison of genetic, diagnostic, and therapeutic implications.

Single primary and multiple primary melanomas (MPMs) of the head and neck region may be confused at first glance because of the common clinical and dermoscopic patterns. An inaccurate diagnosis may lead the clinician to a wrong diagnostic and therapeutic pathway because MPMs occurring in familial or sporadic settings are often involved in individual cancer susceptibility. We investigated the clinical, demographic, histological, and survival differences between MPMs and single melanoma occurring in the head and neck region. A retrospective analysis of medical and histologic records from 217 melanomas of the head and neck region was carried out. Malignant neoplasms affecting MPMs patients were also reported. Mutational analysis of specific genes was carried out when clinical data and family history were suggestive for a familial/hereditary setting. Two hundred and five out of 217 (94.5%) patients were affected by single primary melanoma and 12 (5.5%) by MPMs of the head and neck region. Individuals affected by MPMs were distinguished by a significantly higher mutation frequency and a higher prevalence of malignant neoplasms such as renal cancer. Genetic testing showed germline mutations affecting MITF E318K, CDKN2A genes. Our data highlight the importance of strict cancer surveillance in individuals with MPMs and the role of appropriate genetic counseling and testing in selected patients. Finally, personalized clinical and instrumental screening and follow-up strategies should also be based on mutational status. A heightened level of suspicion is required in the clinical management of mutation carriers.

Molecular targeted approaches for advanced BRAF V600, N-RAS, c-KIT, and GNAQ melanomas.

The introduction of a newly developed target therapy for metastatic melanomas poses the challenge to have a good molecular stratification of those patients who may benefit from this therapeutic option. Practically, BRAF mutation status (V600E) is commonly screened although other non-V600E mutations (i.e., K-R-M-D) could be found in some patients who respond to therapy equally to the patients harboring V600E mutations. Furthermore, other mutations, namely, N-RAS, KIT, and GNAQ, should be sequenced according to distinct melanoma specific subtypes and clinical aspects. In our report, a practical flow chart is described along with our experience in this field.

Giuseppe Moscati (1880-1927): a holistic approach to medicine.

Giuseppe Moscati was a physician, medical school professor and a pioneer in the field of biochemistry and Italian studies on diabetes. He was declared a Catholic saint in 1987. In order to respond better to both the physical and spiritual needs of his patients, he developed his own holistic approach to healthcare involving meticulous drug regimens, meditation and discipline.

Brooke-Spiegler syndrome tumor spectrum beyond the skin: a patient carrying germline R936X CYLD mutation and a somatic CYLD mutation in Brenner tumor.

Brooke-Spiegler syndrome is a hereditary disorder characterized by a predisposition to the development of skin appendage neoplasms and the major and minor salivary glands neoplasms. The role of the CYLD mutation in visceral neoplasms is still unclear, except for the parathyroid tumor. We report the case of a 46-year-old patient with multiple cylindromas and trichoepitheliomas, a Brenner tumor of the ovary and a negative family history for Brooke-Spiegler phenotype. Genetic analysis revealed R936X germline mutation in the proband, but not in the patient's relatives. The same somatic mutation was found in the Brenner tumor, together with a novel missense CYLD mutation (D889N), which has never been reported in the literature. A founder effect for R936X has been hypothesized due to its high prevalence; surprisingly, in our case, this mutation seems to be recognized as a de novo mutation. Future studies involving a greater number of cases, through the clinical analysis of the familial tumor spectrum and the associated molecular pathways, are necessary to understand possible genotype/phenotype correlations and the underlying molecular mechanisms.

Proteomic analysis of PTCH1+/- fibroblast lysate and conditioned culture media isolated from the skin of healthy subjects and nevoid basal cell carcinoma syndrome patients.

The pathogenesis underlying the increased predisposition to the development of basal cell carcinomas (BCCs) in the context of Gorlin-Goltz syndrome is linked to molecular mechanisms that differ from sporadic BCCs. Patients with Gorlin syndrome tend to develop multiple BCCs at an early age and present with tumors of non-sun-exposed skin. The aim of this study was to compare the proteomic profile of cultured fibroblast and fibroblast conditioned culture media of PTCH1+ and nonmutated fibroblasts.

Fluorescence in-situ hybridization and dermoscopy in the assessment of controversial melanocytic tumors.

Although the 'gold standard' for melanoma diagnosis remains histopathological analysis, presently dermoscopists play a significant role in the diagnostic process. However, even a combined approach may not allow a clear-cut judgment on equivocal melanocytic lesions. Fluorescence in-situ hybridization (FISH) can offer assistance in the evaluation of chromosome abnormalities associated with malignancies, and its role is emerging in melanoma diagnosis. The aim of this study was to evaluate the diagnostic role of the FISH in the assessment of controversial lesions, defined as those lesions showing discrepancies between dermatoscopic and histological evaluations. Twenty clinically and histologically ambiguous melanocytic lesions were selected. After the first histopathologic diagnosis, a second pathologist examined the specimens in a blinded review for a second opinion and to identify the most suitable areas to hybridize using probes specific to RREB1, MYB, and CCND1 genes and the centromere of chromosome 6. The first histopathological evaluation led to the diagnosis of melanoma in seven cases, whereas the second identified eight cases of malignant melanoma and was in agreement with the first in 65% of cases and with dermoscopy in 40% of cases. Cytogenetic abnormalities detected by FISH are markers of malignancy that can be useful in the characterization of difficult-to-diagnose melanocytic tumors, when the dermatologist and the pathologist have a different opinions.