Nearly 80% of well-differentiated in situ duct carcinomas (g1 DCIS) have been shown to be multice... more Nearly 80% of well-differentiated in situ duct carcinomas (g1 DCIS) have been shown to be multicentric (multilobar) lesions, while most in situ poorly differentiated duct carcinomas (g3 DCIS) were unifocal (unilobar) lesions. Here we present a clonality study of 15 cases of DCIS, all showing multiple foci. Twelve of these cases were associated with an invasive duct carcinoma. Fifteen cases of female breast cancer patients all showing multiple DCIS foci (5 g1 DCIS, 5 g2 DCIS, 5 g3 DCIS) were randomly selected and histologically studied using large histological sections. Care was taken to laser-microdissect DCIS foci that were most distantly located from one another in the same large section, and pertinent cells were genetically studied. Invasive duct carcinoma and ipsilateral lymph node metastases and/or contralateral lesions, whenever present, were additionally microdissected. DNA of neoplastic cells was purified, and the mtDNA D-loop region was sequenced. Genetic distance of differ...
Title: Clonality analysis in primary oral squamous cell carcinoma and related lymph-node metastas... more Title: Clonality analysis in primary oral squamous cell carcinoma and related lymph-node metastasis revealed by TP53 and mitochondrial DNA next generation sequencing analysis Article Type: Original Paper Abstract: The chance of developing a neck nodal metastasis after initial treatment of oral squamous cell carcinoma varies from 12.4% to 62%. Despite being the main reason of cancer-related mortality, nodal metastases are still rarely subjected to molecular analyses, and our knowledge of the clonal heterogeneity of multiple lesions within the same patient is limited. The aim of the present study was to evaluate the relationship between primary oral cancer and lymph-node metastasis in a series of patients with synchronous and metachronous metastases by two clonality tests: mt-DNA and TP53 sequence analysis.The study population consisted of 10 consecutive patients. Data identified in this study demonstrate that our assay based on next generation analysis of TP53 and mt-DNA is simple, reliable, it allows high throughput and it may be applied to retrospective cases. The combination of mt-DNA and TP53 data analysis helped us to evaluate more precisely and consistently the genetic relationship among different tumor clones.
Virchows Archiv : an international journal of pathology, 2001
TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. ... more TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. The present paper describes the histopathological features of a case of TT virus-related acute recurrent hepatitis. The patient is a 28-year-old woman with no history of drug or alcohol abuse, presenting with repeated episodes of hypertransaminasemia evidenced during the last 4 years. No other markers of viral or autoimmune disease were found. On histological analysis, the liver parenchyma showed a preserved architecture. The histological features were those of a mild acute hepatitis. The clinicopathological findings suggest th
The antigen (YH206 antigen) corresponding to the monoclonal antibody (MoAb) YH206 (IgM), which wa... more The antigen (YH206 antigen) corresponding to the monoclonal antibody (MoAb) YH206 (IgM), which was produced against a lung adenocarcinoma cell line A549, was found to be an extremely high-molecular-weight protein of over 330,000 daltons by means of SDS-PAGE and Western blot analysis. The immunohistological distribution of the antigenic determinant recognized by MoAb YH206 was found to be limited to adenocarcinoma tissues. It was shown by reversed passive hemagglutination assay (RPHA) that the antigen could be detected not only in the spent medium from human lung cancer cell line A549 but also in the sera from cancer patients. Only 3 out of 30 (10%) healthy donors and 4 of 31 (12.9%) patients with benign diseases had serum antigen levels of more than 1/64 dilution. In contrast, 42 of 87 (48.3%) patients with lung cancer and 29 of 50 (58.0%) patients with cancers of the digestive organs had elevated levels of the antigen. As regards the relation between antigen levels and clinical stages of lung cancer, values of more than 1/128 dilution were detected only in patients with stage III or IV disease.
Treatment options for glioblastoma (GBM) at recurrence have limited efficacy. Re-surgery has been... more Treatment options for glioblastoma (GBM) at recurrence have limited efficacy. Re-surgery has been used for confirmation of recurrent disease and to provide relief of symptoms but the real impact on survival is unknown. A retrospective analysis was performed for GBM patients followed between 01/2005 and 06/2010 at our Institution. Two hundred and thirty-two patients with recurrent GBM were evaluated. One hundred and two patients (44%) were treated with re-surgery followed by chemotherapy and 130 patients (56%) with chemotherapy alone. In multivariate analysis, no significant effect of re-surgery was found, with age (p=0.001), MGMT methylation (p=0.002) and PFS at 6 months (p=0.0001) being significant prognostic factors. Second surgery might have a limited impact in the clinical course of recurrent GBM patients.
As yet, no population-based prospective studies have been conducted to investigate the incidence ... more As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 2014
Frequencies as high as 60% of overexpressed p16(INK4) were recently reported in lichen planus (LP... more Frequencies as high as 60% of overexpressed p16(INK4) were recently reported in lichen planus (LP). Because p16(INK4) overexpression may be a feature of human papilloma virus (HPV)-induced cancer, it has been postulated that LP may be somehow related to HPV. The present study is the first to evaluate both high p16(INK4) expression and HPV in patients with LP. Thirty-five consecutive biopsy specimens from patients with LP constituted the basis of the present study. Level of p16(INK4A) expression was evaluated in each sample by immunohistochemical analysis, and the presence of HPV DNA was tested by real-time polymerase chain reaction (PCR). p16(INK4) expression was detected in 26 specimens, whereas HPV was found in 4 lesions: 3 low-risk HPV and 1 high-risk HPV. All HPV-positive lesions also indicated p16(INK4A) overexpression, whereas 22 cases of overexpressed p16(INK4A) were HPV negative (Chi square 2.6; ns). p16(INK4) overexpression is not correlated with HPV in patients with LP.
Oral surgery, oral medicine, oral pathology and oral radiology, 2014
Patients with head and neck squamous cell carcinoma (SCC) are at risk of developing additional tu... more Patients with head and neck squamous cell carcinoma (SCC) are at risk of developing additional tumors in the head and neck. The detection of a late lymph node metastasis poses a problem to the clinician: it could be a delayed regional metastasis or a new metastasis from a yet unknown second primary tumor. Differentiation between metastasis and recurrence of primary tumors versus second primary tumor may be difficult because all lesions have the histologic appearance of SCC. Differentiation between these possibilities, however, carries important differences in therapeutic and prognostic consequences. In the following case report we present an unusually late regional lymph node metastasis in a patient who was treated 4 years earlier for an SCC in the inferior alveolar ridge. The purpose of the present study was to apply mitochondrial DNA D-loop analysis to assess the clonal relationship between oral tumor and node metastasis.
Paget's carcinoma (PC) of the breast is characterized by neoplastic cells of "glandular" type loc... more Paget's carcinoma (PC) of the breast is characterized by neoplastic cells of "glandular" type located within the epidermis of the nipple-areolar complex, often associated with an underlying ductal carcinoma, either in situ or invasive. At present the origin of PC cells is controversial, although there is a widespread opinion that PC cells are "foreign" elements to the epidermis resulting from an epidermotropic migration of neoplastic elements from an underlying ductal carcinoma. An alternative view is that some cases result from neoplastic transformation of preexisting, innocent intraepidermal clear cells of the nipple-areolar complex (Toker cells) that migrate from nonneoplastic ducts. Consequently, 10 cases were studied using methods for clonality (
One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a r... more One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a risk factor or a precursor lesion of invasive lobular carcinoma (ILC). This is consequent to the fact that no conclusive data on the biology of LN exist. Molecular studies of LN and ILC are scanty, variable, and not consistent. Clonality of 12 cases of LN and ILC present simultaneously in the same block has been studied. Cells from both lesions were obtained by microdissection and were studied for mitochondrial DNA (mtDNA), D-loop sequencing, and neighbor-joining trees. Eight of the same cases were studied with comparative genomic hybridization (CGH) array to have additional data consistent with mtDNA. In all cases, loss of heterozygosity was studied for D16S496,locus 16q22.1 related to e-cadherin. It appears that no fewer than eight cases were genetically very similar (clonal) with mtDNA. Seven of these cases appeared also clonal with CGH array. It is concluded that in the present series, LN and ILC are genetically related lesions in the majority of cases and that LN might be the precursor of ILC.
The optimal end point for phase II studies for recurrent glioblastoma (GBM) is unclear and a matt... more The optimal end point for phase II studies for recurrent glioblastoma (GBM) is unclear and a matter of debate. Moreover, data about post-progression survival (PPS) after the first disease progression in GBM patients treated according to EORTC 26981/22981/NCIC CE.3 trial are limited. The aim of this study was to evaluate the PPS in GBM patients. The analysis was made with a database on 1,006 GBM patients followed prospectively between 06/2005 and 06/2010. Eligibility criteria for the study were: age ≥18 years; PS: 0-2; chemotherapy given at disease progression after RT/TMZ. 232 patients (mean age 52 years, range 18-77 years) were enrolled. The median PFS following second line chemotherapy (PFS2) was 2.5 months (95 % CI 2.1-2.9) and the rate of patients free of progression at 6 months (PFS2-6 mo), was 21.6 % (95 % CI 16.3-26.9 %). The median PPS was 8.6 months (95 % CI 7.4-9.8), PPS rates were: PPS-6: 66 % (95 % CI 60.3-72.9 %), PPS-9: 48.2 % (95 % CI 41.5-54.9 %) and PPS-12: 31.7 % (95 % CI 25.2-38.2 %). PPS in unselected patients treated with alkylating agents is about 8 months. PPS rates could be of interest as an end point in future studies in recurrent GBM.
Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear... more Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear to multinuclear cells and abundant, granular, eosinophilic cytoplasm. The cytoplasm of these same cells was filled by strongly immunoreactive mitochondria. At ultrastructure, numerous mitochondria, some of which were large, were evidenced in the cytoplasm of neoplastic cells. Finally, 9 of 10 of these cases had a significantly high mitochondrial DNA content compared with control tissue (P < .01). It seems that, for these tumors, the designation of oncocytic glioblastoma is appropriate. To the best of our knowledge, oncocytic changes have not been previously reported in such neoplasms. Oncocytic glioblastomas have to be added to the long list of various tumors that can manifest "unexpected" oncocytic changes in different organs. Albeit failing to show statistical significance (log-rank test, P = .597; Wilcoxon test, P = .233), we observed a trend for longer median survival in oncocytic glioblastomas, when compared with "ordinary" glioblastomas (median survival of 16 versus 8.7 months). Thus, it seems that the definition of neoplasms showing oncocytic changes, currently based on classic morphological parameters (ie, histology, ultrastructure, and immunohistochemistry), can be expanded by including the quantitative assessment of mitochondrial DNA content.
Thirty-nine glial tumours (28 glioblastomas (GB) and 11 low-grade gliomas) were investigated with... more Thirty-nine glial tumours (28 glioblastomas (GB) and 11 low-grade gliomas) were investigated with DNA microarrays to reveal a possible specific gene expression profile. Unsupervised classification through hierarchical cluster analysis identified two groups of tumours, the first composed of low-grade gliomas and the second mainly composed of GB. Nine genes were identified as most informative: seven were over-expressed in low-grade gliomas and under-expressed in GB; on the contrary, two genes, insulin-like growth factor binding protein 2 (IGFBP-2) and cell division cycle 20 homologue (CDC20), were over-expressed in GB and under-expressed in low-grade tumours. This same genetic profile was confirmed by reverse transcriptase polymerase chain reaction. Immunohistochemistry for IGFBP-2 was positive in 88.8% of the cases of GB and in only one low-grade glioma, whilst CDC20 immunostained 74.1% of the cases of GB and none low-grade glioma. This was confirmed in an additional series of cases studied with immunohistochemistry only. In conclusion, over-expression of mRNA levels of IGFBP-2 and CDC20 is highly related to GB, IGFBP-2 and CDC-20 gene and protein expressions are strongly correlated, and IGFBP-2 and CDC20 immunopositivity can be useful for the identification of GB in small biopsies.
TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. ... more TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. The present paper describes the histopathological features of a case of TT virus-related acute recurrent hepatitis. The patient is a 28-year-old woman with no history of drug or alcohol abuse, presenting with repeated episodes of hypertransaminasemia evidenced during the last 4 years. No other markers of viral or autoimmune disease were found. On histological analysis, the liver parenchyma showed a preserved architecture. The histological features were those of a mild acute hepatitis. The clinicopathological findings suggest that TT virus might be responsible for a mild form of liver disease.
Five cases of nasal seromucinous hamartoma were studied and their clinical, morphological, immuno... more Five cases of nasal seromucinous hamartoma were studied and their clinical, morphological, immunohistochemical and molecular data are reported. The patients, three females and two males, ranged in age from 49 to 66 years (mean 56 year, SD±7.91). All lesions were located in the nasal cavity. In four cases where follow-up was obtained, no recurrence was evident. In all cases, numerous small seromucinous tubules, embedded in a cellular stroma, were present in the lamina propria. Tubules were lined by one layer of cuboidal cells which displayed luminal phenotype positive for lysozyme and EMA in four, and S100 protein in all cases. Collagen IV and laminin positive basal lamina outlined the tubules which lacked basal cells. Stromal spindle cells present among tubules were immunoreactive for calponin in all cases and for alphasmooth muscle actin in four cases. DNA mutation analysis of mitochondrial D-loop region was performed by direct sequencing in order to verify the mutation rate of these lesions. The tubules of the five seromucinous hamartomas showed a higher mutation rate especially in heteroplasmy (0.52% homoplasmy, 2.02% heteroplasmy) in comparison to normal seromucinous glands which exhibited a lower mutation frequency (0.83%). This is considered a sign of a low cellular proliferation rate consistent with a benign process. It is concluded that nasal seromucinous hamartomas are benign glandular proliferations that may resemble microglandular adenosis of the breast. Their distinction from benign and malignant mimics is discussed.
Nearly 80% of well-differentiated in situ duct carcinomas (g1 DCIS) have been shown to be multice... more Nearly 80% of well-differentiated in situ duct carcinomas (g1 DCIS) have been shown to be multicentric (multilobar) lesions, while most in situ poorly differentiated duct carcinomas (g3 DCIS) were unifocal (unilobar) lesions. Here we present a clonality study of 15 cases of DCIS, all showing multiple foci. Twelve of these cases were associated with an invasive duct carcinoma. Fifteen cases of female breast cancer patients all showing multiple DCIS foci (5 g1 DCIS, 5 g2 DCIS, 5 g3 DCIS) were randomly selected and histologically studied using large histological sections. Care was taken to laser-microdissect DCIS foci that were most distantly located from one another in the same large section, and pertinent cells were genetically studied. Invasive duct carcinoma and ipsilateral lymph node metastases and/or contralateral lesions, whenever present, were additionally microdissected. DNA of neoplastic cells was purified, and the mtDNA D-loop region was sequenced. Genetic distance of differ...
Title: Clonality analysis in primary oral squamous cell carcinoma and related lymph-node metastas... more Title: Clonality analysis in primary oral squamous cell carcinoma and related lymph-node metastasis revealed by TP53 and mitochondrial DNA next generation sequencing analysis Article Type: Original Paper Abstract: The chance of developing a neck nodal metastasis after initial treatment of oral squamous cell carcinoma varies from 12.4% to 62%. Despite being the main reason of cancer-related mortality, nodal metastases are still rarely subjected to molecular analyses, and our knowledge of the clonal heterogeneity of multiple lesions within the same patient is limited. The aim of the present study was to evaluate the relationship between primary oral cancer and lymph-node metastasis in a series of patients with synchronous and metachronous metastases by two clonality tests: mt-DNA and TP53 sequence analysis.The study population consisted of 10 consecutive patients. Data identified in this study demonstrate that our assay based on next generation analysis of TP53 and mt-DNA is simple, reliable, it allows high throughput and it may be applied to retrospective cases. The combination of mt-DNA and TP53 data analysis helped us to evaluate more precisely and consistently the genetic relationship among different tumor clones.
Virchows Archiv : an international journal of pathology, 2001
TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. ... more TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. The present paper describes the histopathological features of a case of TT virus-related acute recurrent hepatitis. The patient is a 28-year-old woman with no history of drug or alcohol abuse, presenting with repeated episodes of hypertransaminasemia evidenced during the last 4 years. No other markers of viral or autoimmune disease were found. On histological analysis, the liver parenchyma showed a preserved architecture. The histological features were those of a mild acute hepatitis. The clinicopathological findings suggest th
The antigen (YH206 antigen) corresponding to the monoclonal antibody (MoAb) YH206 (IgM), which wa... more The antigen (YH206 antigen) corresponding to the monoclonal antibody (MoAb) YH206 (IgM), which was produced against a lung adenocarcinoma cell line A549, was found to be an extremely high-molecular-weight protein of over 330,000 daltons by means of SDS-PAGE and Western blot analysis. The immunohistological distribution of the antigenic determinant recognized by MoAb YH206 was found to be limited to adenocarcinoma tissues. It was shown by reversed passive hemagglutination assay (RPHA) that the antigen could be detected not only in the spent medium from human lung cancer cell line A549 but also in the sera from cancer patients. Only 3 out of 30 (10%) healthy donors and 4 of 31 (12.9%) patients with benign diseases had serum antigen levels of more than 1/64 dilution. In contrast, 42 of 87 (48.3%) patients with lung cancer and 29 of 50 (58.0%) patients with cancers of the digestive organs had elevated levels of the antigen. As regards the relation between antigen levels and clinical stages of lung cancer, values of more than 1/128 dilution were detected only in patients with stage III or IV disease.
Treatment options for glioblastoma (GBM) at recurrence have limited efficacy. Re-surgery has been... more Treatment options for glioblastoma (GBM) at recurrence have limited efficacy. Re-surgery has been used for confirmation of recurrent disease and to provide relief of symptoms but the real impact on survival is unknown. A retrospective analysis was performed for GBM patients followed between 01/2005 and 06/2010 at our Institution. Two hundred and thirty-two patients with recurrent GBM were evaluated. One hundred and two patients (44%) were treated with re-surgery followed by chemotherapy and 130 patients (56%) with chemotherapy alone. In multivariate analysis, no significant effect of re-surgery was found, with age (p=0.001), MGMT methylation (p=0.002) and PFS at 6 months (p=0.0001) being significant prognostic factors. Second surgery might have a limited impact in the clinical course of recurrent GBM patients.
As yet, no population-based prospective studies have been conducted to investigate the incidence ... more As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients ≤aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged ≤70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor.
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, 2014
Frequencies as high as 60% of overexpressed p16(INK4) were recently reported in lichen planus (LP... more Frequencies as high as 60% of overexpressed p16(INK4) were recently reported in lichen planus (LP). Because p16(INK4) overexpression may be a feature of human papilloma virus (HPV)-induced cancer, it has been postulated that LP may be somehow related to HPV. The present study is the first to evaluate both high p16(INK4) expression and HPV in patients with LP. Thirty-five consecutive biopsy specimens from patients with LP constituted the basis of the present study. Level of p16(INK4A) expression was evaluated in each sample by immunohistochemical analysis, and the presence of HPV DNA was tested by real-time polymerase chain reaction (PCR). p16(INK4) expression was detected in 26 specimens, whereas HPV was found in 4 lesions: 3 low-risk HPV and 1 high-risk HPV. All HPV-positive lesions also indicated p16(INK4A) overexpression, whereas 22 cases of overexpressed p16(INK4A) were HPV negative (Chi square 2.6; ns). p16(INK4) overexpression is not correlated with HPV in patients with LP.
Oral surgery, oral medicine, oral pathology and oral radiology, 2014
Patients with head and neck squamous cell carcinoma (SCC) are at risk of developing additional tu... more Patients with head and neck squamous cell carcinoma (SCC) are at risk of developing additional tumors in the head and neck. The detection of a late lymph node metastasis poses a problem to the clinician: it could be a delayed regional metastasis or a new metastasis from a yet unknown second primary tumor. Differentiation between metastasis and recurrence of primary tumors versus second primary tumor may be difficult because all lesions have the histologic appearance of SCC. Differentiation between these possibilities, however, carries important differences in therapeutic and prognostic consequences. In the following case report we present an unusually late regional lymph node metastasis in a patient who was treated 4 years earlier for an SCC in the inferior alveolar ridge. The purpose of the present study was to apply mitochondrial DNA D-loop analysis to assess the clonal relationship between oral tumor and node metastasis.
Paget's carcinoma (PC) of the breast is characterized by neoplastic cells of "glandular" type loc... more Paget's carcinoma (PC) of the breast is characterized by neoplastic cells of "glandular" type located within the epidermis of the nipple-areolar complex, often associated with an underlying ductal carcinoma, either in situ or invasive. At present the origin of PC cells is controversial, although there is a widespread opinion that PC cells are "foreign" elements to the epidermis resulting from an epidermotropic migration of neoplastic elements from an underlying ductal carcinoma. An alternative view is that some cases result from neoplastic transformation of preexisting, innocent intraepidermal clear cells of the nipple-areolar complex (Toker cells) that migrate from nonneoplastic ducts. Consequently, 10 cases were studied using methods for clonality (
One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a r... more One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a risk factor or a precursor lesion of invasive lobular carcinoma (ILC). This is consequent to the fact that no conclusive data on the biology of LN exist. Molecular studies of LN and ILC are scanty, variable, and not consistent. Clonality of 12 cases of LN and ILC present simultaneously in the same block has been studied. Cells from both lesions were obtained by microdissection and were studied for mitochondrial DNA (mtDNA), D-loop sequencing, and neighbor-joining trees. Eight of the same cases were studied with comparative genomic hybridization (CGH) array to have additional data consistent with mtDNA. In all cases, loss of heterozygosity was studied for D16S496,locus 16q22.1 related to e-cadherin. It appears that no fewer than eight cases were genetically very similar (clonal) with mtDNA. Seven of these cases appeared also clonal with CGH array. It is concluded that in the present series, LN and ILC are genetically related lesions in the majority of cases and that LN might be the precursor of ILC.
The optimal end point for phase II studies for recurrent glioblastoma (GBM) is unclear and a matt... more The optimal end point for phase II studies for recurrent glioblastoma (GBM) is unclear and a matter of debate. Moreover, data about post-progression survival (PPS) after the first disease progression in GBM patients treated according to EORTC 26981/22981/NCIC CE.3 trial are limited. The aim of this study was to evaluate the PPS in GBM patients. The analysis was made with a database on 1,006 GBM patients followed prospectively between 06/2005 and 06/2010. Eligibility criteria for the study were: age ≥18 years; PS: 0-2; chemotherapy given at disease progression after RT/TMZ. 232 patients (mean age 52 years, range 18-77 years) were enrolled. The median PFS following second line chemotherapy (PFS2) was 2.5 months (95 % CI 2.1-2.9) and the rate of patients free of progression at 6 months (PFS2-6 mo), was 21.6 % (95 % CI 16.3-26.9 %). The median PPS was 8.6 months (95 % CI 7.4-9.8), PPS rates were: PPS-6: 66 % (95 % CI 60.3-72.9 %), PPS-9: 48.2 % (95 % CI 41.5-54.9 %) and PPS-12: 31.7 % (95 % CI 25.2-38.2 %). PPS in unselected patients treated with alkylating agents is about 8 months. PPS rates could be of interest as an end point in future studies in recurrent GBM.
Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear... more Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear to multinuclear cells and abundant, granular, eosinophilic cytoplasm. The cytoplasm of these same cells was filled by strongly immunoreactive mitochondria. At ultrastructure, numerous mitochondria, some of which were large, were evidenced in the cytoplasm of neoplastic cells. Finally, 9 of 10 of these cases had a significantly high mitochondrial DNA content compared with control tissue (P < .01). It seems that, for these tumors, the designation of oncocytic glioblastoma is appropriate. To the best of our knowledge, oncocytic changes have not been previously reported in such neoplasms. Oncocytic glioblastomas have to be added to the long list of various tumors that can manifest "unexpected" oncocytic changes in different organs. Albeit failing to show statistical significance (log-rank test, P = .597; Wilcoxon test, P = .233), we observed a trend for longer median survival in oncocytic glioblastomas, when compared with "ordinary" glioblastomas (median survival of 16 versus 8.7 months). Thus, it seems that the definition of neoplasms showing oncocytic changes, currently based on classic morphological parameters (ie, histology, ultrastructure, and immunohistochemistry), can be expanded by including the quantitative assessment of mitochondrial DNA content.
Thirty-nine glial tumours (28 glioblastomas (GB) and 11 low-grade gliomas) were investigated with... more Thirty-nine glial tumours (28 glioblastomas (GB) and 11 low-grade gliomas) were investigated with DNA microarrays to reveal a possible specific gene expression profile. Unsupervised classification through hierarchical cluster analysis identified two groups of tumours, the first composed of low-grade gliomas and the second mainly composed of GB. Nine genes were identified as most informative: seven were over-expressed in low-grade gliomas and under-expressed in GB; on the contrary, two genes, insulin-like growth factor binding protein 2 (IGFBP-2) and cell division cycle 20 homologue (CDC20), were over-expressed in GB and under-expressed in low-grade tumours. This same genetic profile was confirmed by reverse transcriptase polymerase chain reaction. Immunohistochemistry for IGFBP-2 was positive in 88.8% of the cases of GB and in only one low-grade glioma, whilst CDC20 immunostained 74.1% of the cases of GB and none low-grade glioma. This was confirmed in an additional series of cases studied with immunohistochemistry only. In conclusion, over-expression of mRNA levels of IGFBP-2 and CDC20 is highly related to GB, IGFBP-2 and CDC-20 gene and protein expressions are strongly correlated, and IGFBP-2 and CDC20 immunopositivity can be useful for the identification of GB in small biopsies.
TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. ... more TT virus is a recently discovered virus, of which the pathogenetic potential is still uncertain. The present paper describes the histopathological features of a case of TT virus-related acute recurrent hepatitis. The patient is a 28-year-old woman with no history of drug or alcohol abuse, presenting with repeated episodes of hypertransaminasemia evidenced during the last 4 years. No other markers of viral or autoimmune disease were found. On histological analysis, the liver parenchyma showed a preserved architecture. The histological features were those of a mild acute hepatitis. The clinicopathological findings suggest that TT virus might be responsible for a mild form of liver disease.
Five cases of nasal seromucinous hamartoma were studied and their clinical, morphological, immuno... more Five cases of nasal seromucinous hamartoma were studied and their clinical, morphological, immunohistochemical and molecular data are reported. The patients, three females and two males, ranged in age from 49 to 66 years (mean 56 year, SD±7.91). All lesions were located in the nasal cavity. In four cases where follow-up was obtained, no recurrence was evident. In all cases, numerous small seromucinous tubules, embedded in a cellular stroma, were present in the lamina propria. Tubules were lined by one layer of cuboidal cells which displayed luminal phenotype positive for lysozyme and EMA in four, and S100 protein in all cases. Collagen IV and laminin positive basal lamina outlined the tubules which lacked basal cells. Stromal spindle cells present among tubules were immunoreactive for calponin in all cases and for alphasmooth muscle actin in four cases. DNA mutation analysis of mitochondrial D-loop region was performed by direct sequencing in order to verify the mutation rate of these lesions. The tubules of the five seromucinous hamartomas showed a higher mutation rate especially in heteroplasmy (0.52% homoplasmy, 2.02% heteroplasmy) in comparison to normal seromucinous glands which exhibited a lower mutation frequency (0.83%). This is considered a sign of a low cellular proliferation rate consistent with a benign process. It is concluded that nasal seromucinous hamartomas are benign glandular proliferations that may resemble microglandular adenosis of the breast. Their distinction from benign and malignant mimics is discussed.
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Papers by Luca Morandi