Biomedical subjects

Roland Moll

Publications and source records attributed to Roland Moll.

At least 19 recordsLinked to original sources

PubMed2007

CD34+ fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder.

CD34+ fibrocytes are constitutive elements of the connective tissue where they play a role in matrix synthesis and tumor-associated stromal remodeling. Secreted protein, acidic, and rich in cysteine (SPARC) is a pivotal mediator of stromal remodeling precipitated by invasive carcinomas. The present study was undertaken to investigate CD34+ fibrocytes in the stroma of the tumor-free urinary bladder, chronic cystitis, and urothelial carcinomas together with stromal expression of alpha-smooth muscle actin (alpha-SMA), CD117, and SPARC. In tumor-free urinary bladder and chronic cystitis, CD34+ fibrocytes were found in the deep lamina propria and tunica muscularis, whereas the superficial lamina propria disclosed a CD34-negative and alpha-SMA-positive fibrocyte-like cell. Invasive urothelial carcinomas revealed a complete loss of CD34+ fibrocytes and concomitant appearance of alpha-SMA-reactive myofibroblasts which showed strong expression of SPARC. CD117 expression of tumor-free and tumor-associated stroma revealed no differences. We in this study for the first time describe CD34+ fibrocytes in the urinary bladder and an up-to-now unknown population of alpha-SMA-positive fibrocytes exclusively occurring in the superficial lamina propria. Stromal remodeling associated with invasive carcinomas in the urinary bladder is characterized by a loss of CD34+ fibrocytes paralleled by a gain of alpha-SMA-positive myofibroblasts and increased expression of SPARC.

ADAM Proteins↗

PubMed2006

Cystadenocarcinoma of the gallbladder.

Biliary cystadenocarcinomas are a very rare set of neoplasms that occur in the liver, the extrahepatic bile duct system, and occasionally in the gallbladder. We report on a 75-year-old man with a cystadenocarcinoma of the gallbladder who presented with mild abdominal discomfort and a palpable mass in the right upper abdomen. The diagnostic workup included ultrasound, magnetic resonance tomography, and fine needle core biopsy and revealed a multicystic tumor 16 cm in diameter. The patient underwent multivisceral resection of the tumor with a resection of the right colon, a partial resection of the stomach and the liver, and a lymph node dissection. The resected specimen weighed 2500 g and the final histopatholical diagnosis was a primary, moderately differentiated cystadenocarcinoma of the gallbladder with two lymph node metastases and invasion of the right colon. The patient remains without evidence of recurrence 12 months after surgery. The clinical presentation, diagnosis, therapeutic options, and classification of hepatobiliary cystadenocarcinomas are discussed.

Aged↗

PubMed2006

The cardiac isoform of alpha-actin in regenerating and atrophic skeletal muscle, myopathies and rhabdomyomatous tumors: an immunohistochemical study using monoclonal antibodies.

The two sarcomeric isoforms of actins, cardiac and skeletal muscle alpha-actin, are highly homologous so that their immunohistochemical distinction is extremely difficult. Taking advantage of monoclonal antibodies distinguishing the two conservative amino acid exchanges near the aminoterminus, we have performed an extended immunohistochemical analysis of the cardiac alpha-actin (CAA) isoform in normal, regenerating, diseased and neoplastic human muscle tissues. Intense and uniform CAA staining is seen in fetal and adult myocardium and in fetal skeletal muscle while adult skeletal muscle is essentially negative, except for muscle spindle myocytes and a few scattered muscle fibres with overall reduced diameter. By contrast, CAA synthesis is markedly induced in regenerating skeletal muscle cells, in Duchenne muscular dystrophy and upon degenerative atrophy. CAA has also been detected in certain vascular and visceral smooth muscle cells. Among tumors, CAA has consistently been seen in rhabdomyosarcomas and rhabdomyomatous cells of nephroblastomas, whereas, smooth muscle tumors have shown only occasional staining. While the synthesis of this actin isoform is less restricted than previously thought, monoclonal antibodies against CAA provide a well-defined, reliable and sensitive diagnostic tool for the definition and detection of aberrant differentiation in diseased skeletal muscle and of striated muscle differentiation in rhabdomyosarcomas.

Actins↗

PubMed2006

Comparative genomic hybridization analysis on male breast cancer.

The spectrum of genetic alterations in primary male breast cancer is not well established. We analyzed chromosomal imbalances in 39 tumor samples from primary male breast cancer by comparative genomic hybridization (CGH) and correlated CGH findings with clinicopathological factors. Chromosomal gains were most frequent at 1q (46%), 8q (46%), 16p (36%), 17q (36%), Xq (28%), 20q (26%) and Xp (18%). Losses were most commonly observed at 8p (36%), 16q (28%), 13q (28%), 6q (18%), 11q (18%) and 22q (18%). Gains at 16p, 20q and Xq and losses at 13q correlated significantly with higher degree of cytogenetic complexity. Significant associations with clinicopathological factors were observed for +8q and -16q with larger tumor size and -16q with lower proliferative activity and lower grade of malignancy. A comparison with reported CGH data from female breast cancer showed a similar pattern of chromosomal imbalances, including +1q, -8p, +8q, -13q, +16p, -16q, +17q and +20q. Our results indicate that male breast cancer shares a common pattern of imbalances with female breast cancer, suggesting that similar genetic events may underlie the development and progression of male and female breast cancer.

Adult↗

PubMed2006

Differential expression of desmosomal plakophilins in various types of carcinomas: correlation with cell type and differentiation.

Plakophilins (PKPs) are a set of 3 constitutive armadillo repeat proteins of the desmosomal plaque, termed PKP 1, PKP 2, and PKP 3, which have been shown to be functionally relevant for desmosomal adhesion. We have performed a systematic immunohistochemical study of the 3 PKPs in oral and pharyngeal squamous cell carcinomas (SqCCs; n = 40); colorectal, pancreatic, and prostate adenocarcinomas (n = 31), and hepatocellular carcinomas (HCCs; n = 8). In SqCCs, PKP 1 and PKP 3 revealed common desmosome-type immunostaining, their expression level being inversely correlated with the degree of malignancy. Instead, staining for PKP 2 was limited. In contrast, all adenocarcinomas contained PKP 2 and-often abundantly-PKP 3 in desmosome-typical pattern, whereas PKP 1 was expressed only in prostate tumors. The presence of PKP 3 in adenocarcinomas was confirmed by immunoblotting. In HCCs, only PKP 2 was detected. Under certain staining conditions, focal nuclear immunoreactivity for PKP 1 was observed in some SqCCs and HCCs. Our results, which are inconsistent with previously published data to some extent, indicate a principal preservation of the cell type and differentiation-related expression patterns of PKPs in normal epithelia. For PKP 1, a suppressor function of malignant behavior seems conceivable, whereas the putative functional significance of its occurrence in tumor cell nuclei requires further studies.

Adenocarcinoma↗

PubMed2005

The complexus adhaerens of mammalian lymphatic endothelia revisited: a junction even more complex than hitherto thought.

The significance of a special kind of VE-cadherin-based, desmoplakin- and plakoglobin-containing adhering junction, originally identified in certain endothelial cells of the mammalian lymphatic system (notably the retothelial cells of the lymph node sinus and a subtype of lining endothelial cells of peripheral lymphatic vessels), has been widely confirmed and its importance in the formation of blood and lymph vessels has been demonstrated in vivo and in vitro. We have recently extended the molecular and structural characterization of the complexus adhaerens and can now report that it represents a rare and special combination of components known from three other major types of cell junction. It comprises zonula adhaerens proteins (VE-cadherin, alpha- and beta-catenin, protein p120(ctn), and afadin), desmosomal plaque components (desmoplakin and plakoglobin), and tight-junction proteins (claudin-5 and ZO-1) and forms junctions that vary markedly in size and shape. The special character and the possible biological roles of the complexus adhaerens and its unique ensemble of molecules in angiogenesis, immunology, and oncology are discussed. The surprising finding of claudin-5 and protein ZO-1 in substructures of retothelial cell-cell bridges, i.e. structures that do not separate different tissues or cell layer compartments, suggests that such tight-junction molecules are involved in functions other than the "fence" and "barrier" roles of zonulae occludentes.

3T3 Cells↗

PubMed2005

Stromal remodeling and SPARC (secreted protein acid rich in cysteine) expression in invasive ductal carcinomas of the breast.

In the present study, we analyzed tumor associated stromal remodeling with special respect to SPARC (secreted protein acid rich in cysteine) expression. 25 invasive ductal carcinomas of the breast and corresponding tumor-free breast tissue were studied immunohistochemically (CD34, alpha-SMA, SPARC and TGFbeta-R1). Tumor associated stroma was characterized by a loss of CD34 expression, paralleled by a gain in alpha-SMA. While SPARC expression was virtually absent from normal stromal cells in the tumor stroma, strong cytoplasmic SPARC reactivity was found in the majority of stromal cells. The TGFbeta-R1 also showed stronger expression in the tumor stroma compared to that of the normal breast. Stromal response to antecedent core needle biopsy was similar to that observed in the tumor stroma. We conclude that SPARC overexpression is a constant and functionally important feature of invasive ductal carcinomas, since SPARC mediates stromal de-adhesion crucial for local tumor invasion and systemic spread, respectively. When considering changes of the stromal phenotype (normal: CD34+alpha-SMA-SPARC- vs. carcinoma: CD34-alpha-SMA+SPARC+) as a tool in distinguishing benign from malignant breast lesion one has to keep in mind that the phenotype of granulation tissue in areas of antecedent biopsy resembles that of tumor stroma.

Actins↗

PubMed2005

Urothelial umbrella cells of human ureter are heterogeneous with respect to their uroplakin composition: different degrees of urothelial maturity in ureter and bladder?

Urothelial umbrella cells are characterized by apical, rigid membrane plaques, which contain four major uroplakin proteins (UP Ia, Ib, II and III) forming UPIa/UPII and UPIb/UPIII pairs. These integral membrane proteins are thought to play an important role in maintaining the physical integrity and the permeability barrier function of the urothelium. We asked whether the four uroplakins always coexpress in the entire human lower urinary tract. We stained immunohistochemically (ABC-peroxidase method) paraffin sections of normal human ureter (n = 18) and urinary bladder (n = 10) using rabbit antibodies against UPIa, UPIb, UPII and UPIII; a recently raised mouse monoclonal antibody (MAb), AU1, and two new MAbs, AU2 and AU3, all against UPIII; and mouse MAbs against umbrella cell-associated cytokeratins CK18 and CK20. Immunoblotting showed that AU1, AU2 and AU3 antibodies all recognized the N-terminal extracellular domain of bovine UPIII. By immunohistochemistry, we found that in 15/18 cases of human ureter, but in only 2/10 cases of bladder, groups of normal-looking, CK18-positive umbrella cells lacked both UPIII and UPIb immunostaining. The UPIb/UPIII-negative cells showed either normal or reduced amounts of UPIa and UPII staining. These data were confirmed by double immunofluorescence microscopy. The distribution of the UPIb/UPIII-negative umbrella cells was not correlated with localized urothelial proliferation (Ki-67 staining) or with the distribution pattern of CK20. Similar heterogeneities were observed in bovine but not in mouse ureter. We provide the first evidence that urothelial umbrella cells are heterogeneous as some normal-looking umbrella cells can possess only one, instead of two, uroplakin pairs. This heterogeneity seems more prominent in the urothelium of human ureter than that of bladder. This finding may indicate that ureter urothelium is intrinsically different from bladder urothelium. Alternatively, a single lineage of urothelium may exhibit different phenotypes resulting from extrinsic modulations due to distinct mesenchymal influence and different degrees of pressure and stretch in bladder versus ureter. Additional studies are needed to distinguish these two possibilities and to elucidate the physiological and pathological significance of the observed urothelial and uroplakin heterogeneity.

Animals↗

PubMed2005

Identification of a stem cell candidate in the normal human prostate gland.

Stem cells of the human prostate gland have not yet been identified utilizing a structural biomarker. We have discovered a new prostatic epithelial cell phenotype-expressing cytokeratin 6a (Ck6a+ cells). The Ck6a+ cells are present within a specialized niche in the basal cell compartment in fetal, juvenile and adult prostate tissue, and within the stem cell-enriched urogenital sinus. In adult normal prostate tissue, the average abundance of Ck6a+ cells was 4.9%. With proliferative stimuli in the prostate organ culture model, in which the epithelial-stromal interaction was maintained, a remarkable increase of Ck6a expression was noticed to up to 64.9%. The difference in cytokeratin 6a expression between the normal adult prostate and the prostate organ culture model was statistically significant (p<0.0001). Within the prostate organ culture model the increase of cytokeratin 6a-expressing cells significantly correlated with increased proliferation index (r = 0.7616, p = 0.0467). The Ck6a+ cells were capable of differentiation as indicated by their expression of luminal cell markers such as ZO-1 and prostate specific antigen (PSA). Our data indicate that Ck6a+ cells represent a prostatic epithelial stem cell candidate possessing high potential for proliferation and differentiation. Since the development of benign prostatic hyperplasia and prostate carcinogenesis are disorders of proliferation and differentiation, the Ck6a+ cells may represent a major element in the development of these diseases.

Antibodies, Monoclonal↗

PubMed2005

Human Merkel cells--aspects of cell biology, distribution and functions.

Human Merkel cells were first described by Friedrich S. Merkel in 1875 and named "Tastzellen" (touch cells) assuming a sensory touch function within the skin. Only ultrastructural research revealed their characteristics such as dense-core granules, plasma membrane spines and dendrites as well as a loosely arranged cytoskeleton. Biochemical analysis identified the expression of very specific cytokeratins (most notably CK 20) allowing the immunohistochemical detection of Merkel cells. In humans, they occur within the basal epidermis, being concentrated in eccrine glandular ridges of glabrous skin and in Haarscheiben of hairy skin, within belt-like clusters of hair follicles, and in certain mucosal tissues. Within the human skin, the dense-core granules contain heterogeneously distributed neuropeptides, some of which might work as neurotransmitters through which Merkel cells and their associated nerves exert their classical function as slowly adapting mechanoreceptors type I. This is the case in the Haarscheiben, small sensory organs containing keratinocytes with a special program of differentiation that includes the expression of CK 17 and Ber-EP4. Other peptides may act as growth factors and thus might participate in growth, differentiation and homeostasis of cutaneous structures. It is not yet clear whether the Merkel cell carcinomas, aggressive skin carcinomas, indeed arise from Merkel cells. We summarize and discuss data on the distribution, function and heterogeneity of human Merkel cells in normal and diseased skin.

Adult↗

PubMed2005

Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial.

BACKGROUND & AIMS: The effect of octreotide plus interferon-alpha versus octreotide monotherapy on the primary study end points of time to treatment failure (progression, death, stop of study treatment) and long-term survival was investigated in patients with progressive metastatic neuroendocrine foregut (mainly pancreatic) and midgut tumors. METHODS: One hundred nine of 125 registered patients were randomized starting in January 1995, and 105 patients (51 monotherapy, 54 combination treatment) were finally analyzed in March 2000. Tumor growth was assessed at 3-month intervals by computed tomography or magnetic resonance imaging. Long-term survival was studied up to April 2004 in all analyzed patients and in 9 patients not randomized because of stable disease. RESULTS: Partial tumor regression occurred in 2.9%, 1.9%, and 5.7% and stabilization of tumor growth in 44.8%, 27.6%, and 15.2% at 3, 6, and 12 months, respectively, with no significant differences between both treatment arms. In March 2000, 9.5% of patients were in treatment. Time to treatment failure and long-term survival did not differ significantly between the 2 groups, with a median survival of 32 and 54 months for the octreotide and the combination groups, respectively. Survival was longer in patients not randomized because of stable disease (median, 68 months) and in those with low nuclear Ki-67. A trend toward longer survival was shown for patients with slow spontaneous tumor growth before randomization. Patients responding to treatment lived longer than unresponsive patients. CONCLUSIONS: Combination treatment was not superior to monotherapy concerning progression-free and long-term survival. Patients responding to treatment and those with slow spontaneous tumor growth had a survival advantage.

Adolescent↗

PubMed2004

Genetic pathways and new progression markers for prostate cancer suggested by microsatellite allelotyping.

PURPOSE: At diagnosis, the biological behavior of prostate cancer is uncertain, making the choice of an adequate therapy option difficult. Performing microsatellite allelotyping on a large series of consecutive prostate cancers procured during radical prostatectomy at our institution, we sought to identify molecular markers associated with disease progression. EXPERIMENTAL DESIGN: A total of 156 consecutive fresh tumor samples was prospectively collected and macroscopically dissected from the whole prostatectomy specimen immediately after operation. Histologically 100 samples contained >75% tumor cells and were therefore enrolled in the microsatellite allelotyping, using a total of 24 polymorphic markers for the chromosomal regions 5p, 5q, 7q, 8p, 9p, 9q, 13q, 17p, 17q, and 18q. Fresh paired normal and tumor DNA was investigated in fluorescent microsatellite analysis with automated laser product detection. RESULTS: The incidence of tumor-DNA alterations [loss of heterozygosity or allelic imbalance (AI)] was highest for chromosomal regions 13q and 8p with 72 and 71%, respectively, followed by chromosomes 7q, 18q, 5q, and 17p with 57, 53, 41, and 39%, respectively. Alterations at chromosomes 8p, 9p, 13q, and 17p were significantly (P < 0.05) associated with advanced tumor stage, whereas AI at 8p and 17p was also associated with high Gleason score (P < 0.05). AI at 5q and 9p was associated with regional lymph node metastasis (P < 0.05). The combination of AI at 8p and 13q was strongly associated with advanced tumor stage (P < 0.0001). CONCLUSIONS: With the obtained results, we are able to postulate three distinct pathways in prostate carcinogenesis, and we identified microsatellite markers of prognostic value.

Alleles↗

PubMed2004

CD34+ fibrocytes, alpha-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx.

We investigated tumor-free mucosa and squamous cell carcinomas of the oral cavity, the pharynx, and larynx with respect to the presence of stromal CD34+ fibrocytes and alpha-smooth muscle antigen (SMA)-positive myofibroblasts. Additionally, stromal expression of CD117 was analyzed. A total of 39 squamous cell carcinomas were assessed immunohistochemically. In all cases investigated, CD34+ fibrocytes were found in the tumor-free stroma, whereas alpha-SMA-positive myofibroblasts were lacking. Areas of lymphocytic infiltration disclosed a focal reduction of CD34+ fibrocytes. CD117 expression was absent from the tumor-free stroma. Of 39 squamous cell carcinomas, 33 were free of stromal CD34+ fibrocytes, and, in 31 carcinomas, stromal alpha-SMA-positive myofibroblasts occurred at least focally. CD117-positive stromal spindle cells were found in 25 carcinomas. Compared with tumor-free mucosa, the number of tissue mast cells was significantly increased in carcinomas. We conclude that stromal remodeling induced by invasive carcinomas is characterized by a loss of CD34+ fibrocytes and subsequent gain of alpha-SMA-positive myofibroblasts. The diagnostic impact of this finding is, however, limited by the fact that chronic inflammation may also be accompanied by a focal loss of CD34+ fibrocytes.

Adult↗

PubMed2004

The sentinel node concept in head and neck cancer: solution for the controversies in the N0 neck?

BACKGROUND: The majority of patients with head and neck squamous cell carcinoma (HNSCC) who have a clinical N0 neck undergo neck dissection (ND) even though no lymph node metastases may be detected. With this background, our investigation critically analyzes the value of sentinel lymphadenectomy. METHODS: Ninety patients with HNSCC, all staged with an N0 neck, underwent intraoperative 99mTc-radiolabeled detection of up to three hot nodes (SN1-3) during elective ND and primary site resection. RESULTS: Sentinel lymphadenectomy (SN1-3) detected occult metastatic spread in 20 (22%) of 90 patients, whereas failure occurred in three of 90 patients. Metastatic spread was directed to level II in the majority (66.7%) of cases. If only the SN1 had been examined, the procedure would have failed in nine (39%) of 23 patients. CONCLUSION: Sentinel lymphadenectomy correctly identified the stage of metastatic disease in 97% of patients in cases in which up to three sentinel nodes were identified. If only the lymph node with the highest tracer activity had been excised, 39% of cancer-positive necks would have been missed. Selective ND identified metastatic disease in the additional 3% of patients.

Carcinoma, Squamous Cell↗

PubMed2004

Value of sentinel lymphadenectomy in head and neck cancer.

The increasing interest in the so-called sentinel node concept, which has recently been adapted to squamous cell carcinomas of the upper aerodigestive tract, can be explained by encouraging results in other tumor entities. Although the publications on this topic do not yet allow a final judgment on the significance of sentinel lymphadenectomy in head and neck squamous cell carcinoma, early results emphasize the importance of this new diagnostic and therapeutic concept. The basic prerequisite is a detailed knowledge of the existing method-specific limitations in this anatomic region. Critical and careful evaluation of the sentinel node concept is mandatory prior to its application to other tumor entities. Sentinel lymphadenectomy for head and neck cancer may prove helpful if the indications for its use are clearly defined.

Carcinoma, Squamous Cell↗

PubMed2004

Genetic pathways and new progression markers for prostate cancer defined by microsatellite allelotyping.

A prospective study was carried out on a large cohort of males undergoing radical retropubic prostatectomy in order to identify genetic marker regions significantly associated with tumor formation. By comprehensive allotyping of chromosomes known to be associated with prostate carcinogenesis, an algorithm could be formulated for the genetic pathway and a method of discrimination between aggressive and less aggressive forms could be identified.

Alleles↗

PubMed2004

Effectiveness of radiochemotherapy on lymph node metastases in patients with stage IV oropharyngeal cancer.

Radiochemotherapy plays a leading role in the treatment of patients with advanced squamous cell carcinomas (SCC) of the oropharynx. The aim of the present study was to estimate its effectiveness on lymph node (LN) metastases. Seventeen patients with advanced UICC stage IV oropharyngeal SCC (1xT2, 4xT3, 12xT4, 2xN1, 15xN2) were observed prospectively. They were treated with radiochemotherapy (total radiation doses 60-70.6 Gy). One to four months after neck dissection (ND) was performed. Specimens were histologically examined for metastases according to the neck levels obtained from. Local control was achieved in 14/17 (82.4%) patients and regional-in 10/17 (58.8%) patients. Of 566 LN studied, 29 exhibited signs of involvement. Two from 29 were found in neck level I, 20/29 in II, 6/29 in III and 1/29 in IV. In 13/29 LN the metastases had completely regressed under treatment whereas 16/29 LN (7 patients) contained vital tumoral tissue. The observed high incidence of vital LN metastases, which abide the radiochemotherapy, advocates further studies, concerning the value of planed ND after radiochemotherapy.

Adult↗

PubMed2004

Her-2/neu gene amplification and protein expression in primary male breast cancer.

The role of HER-2/ neu in male breast cancer is not well defined. The purpose of the current study was to measure the frequency of HER-2/ neu expression in primary male breast cancer, to demonstrate HER-2/ neu gene amplification in cases found to be positive for protein overexpression, and to correlate HER-2/ neu positivity with clinicopathological variables. Formalin-fixed, paraffin-embedded archival material from 99 primary male breast carcinomas was evaluated by immunohistochemistry (IHC) using the HercepTest (DAKO Corp., Hamburg, Germany). Scoring was performed according to established guidelines. All cases demonstrating HER-2/ neu staining by IHC (1+/2+ and 3+) were analyzed for HER-2/ neu gene amplification by fluorescence in situ hybridization (FISH) utilizing the PathVysion assay (Vysis Corp., Downers Grove, Illinois) to assess HER-2/ neu amplification status. The immunohistochemical staining of the HER-2/ neu protein revealed HER-2/ neu positivity in 15/99 (15.1%) cases, eight tumors showed 2+ and 7 tumors 3+ staining. HER-2/ neu gene amplification was observed in 11/99 cases (11,1%), and all of the 3+ and 4/8 from the 2+ cases were amplified. HER-2/ neu gene amplification/protein overexpression did not correlate with tumor state, histological grade or estrogen/progesterone receptor status nor the axillary lymph node status. This is the first comprehensive study of HER-2/ neu gene amplification by FISH analysis in primary male breast cancer. Compared to female primary breast cancer the percentage of HER-2/ neu positivity in our study was lower. Our data provide first evidence for HER-2/ neu gene amplification in male breast cancer. Further studies should be addressed on the potential application of the monoclonal rhuMAB HER-2/ neu antibody for treatment of HER-2/ neu positive male breast cancer.

Adult↗