The Importance of Clinical Data for the Diagnosis of Breast Tumours in North Afghanistan.

BACKGROUND: This study was performed in knowledge of the increasing gap between breast disease treatment in countries with restricted resources and developed countries with increasingly sophisticated examination methods. METHODS: The authors present the analysis of a breast disease register consisting of diagnostic cases from Mazar e Sharif and Herat in 2018 and 2019. The study comprises a total of 567 cases, which were presented to experts via telemedicine for final diagnosis. 62 cases (10.9%) were excluded due to inacceptable data or insufficient image quality. These data provided by daily diagnostic classification were used for the built-up of a profile for each frequent breast disease and a breast cancer register. All images and cases were seen by at least 3 independent experts. The diagnoses were made in 60% of cases by cytology of fine needle aspiration and in 40% by histological images. RESULTS: For each entity of breast diseases (e.g., fibroadenoma), a profile of context variables was constructed allowing to assist medical decisions, as "wait and see," elective surgery or immediate surgical intervention with R0 (complete) resection. These "profiles" could be described for fibroadenoma, mastitis, galactocele, fibrous-cystic disease, and invasive breast cancer. CONCLUSIONS: The presented preliminary data set could serve as a cost-effective basis for a North Afghan breast cancer registry, with option to extent to a national model. These preliminary data are transformed in profiles of breast diseases, which are used by the local physicians in charge of breast disease patients. Each new case can be compared by the local treating physician with the profile of all preceded cases with the same diagnosis.

Re-evaluation of challenging telepathological diagnoses in support of a hospital in Tanzania.

Since 2007, a hospital in Tanzania has been supported with histopathological reports via telepathology (TP) by German pathologists. For this, the Internet-based platform iPath is used. The aim of this study was to analyse the rate of discrepancies in defined diagnostic groups. After shipment of paraffin-embedded tissue to Germany, specimens were processed according to recent diagnostic standards. All diagnoses were grouped into eight benign and 11 malignant main categories. The comparison comprised the following categories: 1, identical diagnosis; 2, mild discordance; 3, correct distinction between benign and malignant process, 4, false malignant; 5, false benign; and 6, no primary diagnosis possible. The cohort comprised 396 benign and 336 malignant diseases. Of the benign diseases, 62% were category 1, 23% category 2, 2% category 3, 6% category 4 and 7% category 6. Of the malignant diseases, 42% were category 1, 16% category 2, 12% category 3, 14% category 5 and 15% category 6. Exclusive support with static TP cannot meet all requirements of modern medical diagnostics. However, the project shows a approach for how pathologists in industrial countries can help low-income countries. In difficult cases, the opportunity for a final work-up using additional methods must be given for useful diagnostic purposes.

Different Incidence of Early-Onset Gastric Carcinoma Depending on Ethnicity: Preliminary Results of a Hospital in Liangshan.

BACKGROUND: In China, the incidence of cancer has significantly decreased over the last two decades. In contrast, the incidence of gastric carcinoma (GC) has risen in young patients. METHODS: We reevaluated the histopathological results of 4,353 endoscopic gastroscopies from the Department of Pathology at No 1 Hospital of Liangshan. The ethnic groups Han and Yi were almost equally distributed in this cohort. Over a five-year period, 1407 GC were diagnosed. RESULTS: In 171 of these cases (12%), the patients were ≤40 years old (early-onset GC, EOGC). Out of this cohort, 9 patients were aged ≤25 years. 54% of these patients were male and showed marked predominance (92%) of the Yi-minority. Using the classification of Lauren, 103 GC (60%) were of diffuse type, 27 (16%) of intestinal type, and 41 (24%) of mixed type. In the remaining 1,236 cases of patients ≥41 years (88%), 1,014 patients (82%) belonged to the Yi-minority. Helicobacter pylori (HP) were found in 46% of all cases. Familial clustering was found in 14 patients (18%; in first degree relatives, 12%, and in second degree relatives, 6%). Follow-up was not possible. CONCLUSION: This study demonstrates the unequal manifestation of EOGC within the two ethnic groups of Han and Yi. However, familial clustering was infrequent. Further investigations are necessary to discover relevant risk factors apart from hereditary predisposition.

Prognostic Potential of the Expression of Podoplanin (D2-40) Within Cells of Squamous Cell Carcinoma of the Larynx and Hypopharynx.

BACKGROUND: Podoplanin (D2-20) stains immunohistochemically lymphatic vessels, regular mesothelium and tumor cells of different tumors, e.g. malignant mesothelioma or seminoma. In squamous cell carcinoma (SCC), the marker has been described as variously expressed. METHODS: This study has investigated the value of the immunohistochemical analysis for the prognostic relevance of the expression in 119 SCCs of the larynx and hypopharynx. The clinical data and documentation of follow-up for at least 5 years were available. RESULTS: The collective showed the expected distribution of patient age with accentuation of the male sex and a balanced spread of tumor stages including nodal status. The immunohistochemical stain intensity (negative, weak or strong) and the distribution (equal versus focal) were evaluated. In addition, the accentuation of the staining reaction was separately examined at the border of invasion. SCCs with a strong expression of podoplanin were associated with an unfavorable prognosis. A comparison of grouped cases showed a trend emerging with borderline results (negative to weakly positive, P = 0.51; negative to strongly positive, P = 0.054; weakly positive to strongly positive, P = 0.17). The staining at the border of invasion had no statistical effect on overall survival. Multivariate survival statistics however showed that lymphonodal metastasis and a reaction with podoplanin in tumor cells are associated with significant worse prognosis. CONCLUSION: In summary, regardless of the exact function of podoplanin in the process of cell migration and tumor progression, an immunohistochemical identification of expression in tumor cells of SCC of the larynx and hypopharynx can give additional information about the expectable prognosis.

Telepathological evaluation of paediatric histological specimens in support of a hospital in Tanzania.

BACKGROUND/OBJECTIVE: In a project of telepathology (TP) between German pathologists and a hospital in Tanzania, trained technical assistants have uploaded digital histological images onto the internet-based platform ipath. The diagnoses from 486 paediatric specimens were analysed. METHODS: The investigation included diagnoses, either primarily done via TP or secondarily after a further workup of the paraffin-embedded tissue, which was sent to Germany for cases which could not be solved via TP. In the latter, the initial TP-diagnoses were compared with the results after re-evaluation. RESULTS: The median age was 11 years. The cohort comprised 390 benign diseases (80.2%) and 96 malignant diseases (19.8%). For benign diseases, the most frequent anatomic sites were lymph nodes, skin, and soft tissue, breast, and head&-neck. Frequent diagnoses were non-specific inflammations and benign tumors. In malignant diseases, the most sites were lymph nodes, skin, soft tissue, head&neck, and ovary and the most frequent diseases sarcomas and lymphomas. The paraffin embedded tissue of 179 cases (36.3%) was shipped to Germany. With the concordance analysis, we could discover the mandatory necessity for the possibility of second opinion in difficult cases. CONCLUSION: An exclusively TP-support cannot meet all requirements of modern medical diagnostics. The education of local pathologists is imperative.

Diagnostic validity of static telepathology supporting hospitals without local pathologists in low-income countries.

INTRODUCTION: Static telepathology (TP) was used to support a hospital in Tanzania that cannot employ a resident pathologist but has a basic laboratory. Histological slides were prepared by the local technical staff and digital images were uploaded into an Internet-based system; consultant pathologists in Germany could give their opinion. The aim of the study was to examine the diagnostic validity of this project without local pathologists. METHODS: The set-up period for special training of local technical assistants was 10 weeks. Diagnoses of the first 545 cases that were processed via TP were compared with the results of a second opinion on the basis of routine slides created from the corresponding paraffin blocks, which were sent to Germany. RESULTS: Of all cases, 384 (70%) TP diagnoses were completely confirmed by the second opinion. Minor deviations (e.g. divergent subtypes of tumours or other aetiology of non-specific reactive processes) were documented in 76 cases (14%), so that overall, 84% of diagnoses were useful in the setting of the available therapeutic possibilities. The results were better in some subgroups of diseases (90-100% useful diagnoses) and suboptimal (minimum 63%) in a few subgroups with rare diseases. Thirty (5%) malignant diseases were primarily misinterpreted as being benign and 12 (2%) benign diseases as malignant. Forty-three (8%) cases were insufficient for diagnosis using TP and could not be provided with a primary assessment. DISCUSSION: Static TP can help support medical services in low-income countries in the absence of local pathologists with a potentially high diagnostic validity, especially for selected groups of diseases. The procedure can significantly improve the diagnostic procedures before commencement of therapy - a substantial contribution within a globalised world.

Strong Expression of Cancertestis Antigens CTAG1B and MAGEA3 Is Correlated with Unfavourable Histopathological Features and MAGEA3 Is Associated with Worse Progression-Free Survival in Urothelial Bladder Cancer.

BACKGROUND: Cancer/testis antigens (CTA) are expressed in urothelial bladder cancer (UBC). Their therapeutical and prognostic relevance remains unclear. We studied the correlation of MAGEA3 and CTAG1B with histopathological factors in UBC and their prognostic value. METHODS: Retrospective analysis of 93 patients who underwent treatment for UBC was conducted. Besides clinical and histopathological parameters, the expression of MAGEA3 and CTAG1B was assessed by immunohistochemistry. RESULTS: Median follow-up was 75 months. Fifteen per cent of patients showed strong positive reaction to MAGEA3 staining. These tumours were statistically and significantly more often correlated with unfavourable World Health Organization (WHO) grading (G1: 0%, G2: 10.3%, G3: 23.4%, p = 0.048; low grade 0%, high grade 18.4%, p = 0.046 respectively). Correlation of CTAG1B with WHO grading was impressive with strong expression in no G1, 31.1% of G2 and 51.1% of G3 tumours (low grade 0%, high grade 43.4%, p = 0.001, respectively). Concomitant carcinoma in situ (Cis) was associated with strong CTAG1B expression (54.2% in concomitant Cis vs. 29% without concomitant Cis, p = 0.026). Kaplan-Meier analysis revealed statistically and significantly worse 5 years progression-free survival (PFS) associated with a strong expression of MAGEA3 (59 vs. 84%, p = 0.032). CONCLUSIONS: Strong CTA expression was correlated with unfavourable histopathological features. A strong expression of MAGEA3 was statistically and significantly associated with worse PFS across all stages of UBC.

Practical Consequences Resulting from the Analysis of a 21-Multigene Array in the Interdisciplinary Conference of a Breast Cancer Center.

During the multidisciplinary planning of postoperative therapy after breast cancer, borderline cases can arise with no clear rationale for or against adjuvant chemotherapy. In 50 hormone- receptor-positive, Her2neu-negative carcinomas of the breast with no or only minimal lymph node involvement (max. pT1a) we initiated an Oncotype DX® multigene assay in addition to the evaluation of usual parameters. In the oncology conference a vote for or against chemotherapy was taken on the basis of the conventional criteria for decision-making before the test results were available. The final recommendation was made after the multigene test. In 32 breast carcinomas (64%) a low recurrence score could be documented, while 26 (32%) showed an intermediate RS and 3 (6%) showed a high RS. In most cases the result of the test could validate the choice of therapy established using conventional criteria. In 5 cases the initial recommendation for adjuvant therapy was revised, and in 3 cases chemotherapy was secondarily recommended after evaluation of the test results. Conversely, in some cases a low or intermediate risk constellation did not argue against a recommendation for adjuvant chemotherapy. Altogether, the results of our study do not indicate that a multigene assay should be used as a routine diagnostic tool. Instead a thorough compilation and careful analysis of conventional parameters for therapeutic decision-making should take precedence, with special emphasis on histopathological and immunohistochemical results. In selected cases, however, a multigene assay can be a useful tool in the deliberation for or against a therapeutic pathway.

Clinicopathologic features of adult EBV-associated B-cell lymphoproliferative disease.

In the present study, 21 cases of adult/late-onset EBV-associated lymphoproliferative disease (AELPD) with an uncertain malignant potential were investigated with regard to their histomorphology, immunophenotype, clonal rearrangement of the heavy chain (IgH) and T-cell receptor (TCR) genes and clinical course. The cases were histomorphologically reevaluated and assigned to one of three morphological groups: mononucleosis-like, Hodgkin-like, or polymorphous. In addition, cases with or without detectable necrosis were investigated for differences in clinical outcome. Overall survival was highest in the group with Hodgkin-like morphology (4/4 patients), followed by patients with mononucleosis-like phenotype (4/5 patients surviving). Cases with polymorphous morphology showed the poorest survival rates with 7/12 patients dead of disease (58%). 4/6 patients with histologically detectable necrosis died (66%), but only 4/15 patients without necrosis (27%). 11/21 cases with AELPD showed clonal rearrangement for IgH (n = 4), TCR (n = 5) or IgH + TCR (n = 2). 5/11 patients with clonal rearrangement died (45%), and this percentage was similar in all of the three subgroups. In conclusion, the present study shows that polymorphous morphology and detection of necrosis in AELPD are frequently linked to a fatal clinical course, whereas Hodgkin-like morphology seems to be associated with a more favourable prognosis. Clonal rearrangement of IgH or TCR is frequent in AELPD, but prognosis is unpredictable from this feature.

Testicular Inflammatory Myofibroblastic Tumor: A Known Entity at a Very Rare Site.

Inflammatory myofibroblastic tumors (IMT) are distinctive lesions of unknown etiology, composed of myofibroblastic spindle cells with an associated inflammatory background. They can occur in a wide age range and at all anatomic sites, but most frequently they can be observed in the lung (especially in pediatric cases), abdomen, or retroperitoneum. The urinary bladder is one of the most common sites in urological cases. We present a very rare case of IMT of the testis. Clinically, a 40-year-old patient showed a palpable painless lesion of the right testis. Ultrasound examination showed two solid intratesticular foci. During surgical intervention, the intraoperative frozen section revealed mesenchymal tumors admixed with an uncommon inflammatory infiltrate, consistent with a reorganized abscess. Despite the benign result, orchiectomy was performed due to the multifocal presentation and the large size of 3 cm. The final diagnosis was IMT without ALK-rearrangement. Incomplete resection increases the risk of local relapses to 30%. In this case, a complete resection could be achieved and the patient is free of tumor 15 months later.

MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation.

Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC(+)). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC(+) rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC(-) DLBCL patients, the MYC(+) DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC(+) DLBCL patients than those in the MYC(-) DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC(+) DLBCL patients have a significant inferior prognosis than MYC(-) DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.

The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study.

PURPOSE: To evaluate the prognostic value of the cell of origin (COO) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBLC), prospectively treated by rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) versus rituximab, ifosfamide, carboplatin, and etoposide and followed by intensive therapy plus autologous stem-cell transplantation on the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) trial. PATIENTS AND METHODS: Among the 396 patients included on the trial, histologic material was available for a total of 249 patients at diagnosis (n = 189 patients) and/or at relapse (n = 147 patients), which included 87 matched pairs. The patient data were analyzed by immunochemistry for CD10, BCL6, MUM1, FOXP1, and BCL2 expression and by fluorescent in situ hybridization for BCL2, BCL6 and c-MYC breakpoints. The correlation with survival data was performed by using the log-rank test and the Cox model. RESULTS: Characteristics of immunophenotype and chromosomal abnormalities were statistically highly concordant in the matched biopsies. In univariate analysis, the presence of c-MYC gene rearrangement was the only parameter to be significantly correlated with a worse progression-free survival (PFS; P = .02) and a worse overall survival (P = .04). When treatment interaction was tested, the germinal center B (GCB) -like DLBCL that was based on the algorithm by Hans was significantly associated with a better PFS in the R-DHAP arm. In multivariate analysis, independent prognostic relevance was found for the GCB/non-GCB the Hans phenotype interaction treatment (P = .04), prior rituximab exposure (P = .0052), secondary age-adjusted International Prognostic Index (P = .039), and FoxP1 expression (P = .047). Confirmation was obtained by gene expression profiling in a subset of 39 patients. CONCLUSION: COO remains a major and independent factor in relapsed/refractory DLBCL, with a better response to R-DHAP in GCB-like DLBCL. This needs confirmation by a prospective study.

Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome.

Adrenocortical carcinoma is a rare but highly malignant neoplasm with still limited treatment options. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in many solid tumors, but its expression in adrenocortical carcinoma has been studied only in a limited number of cases. Therefore, we analyzed the expression of EGFR in 169 adrenocortical carcinoma samples and compared it with 31 adrenocortical adenomas. Additionally, in 30 cases of adrenocortical carcinoma, exons 18-21 of the EGFR gene were cloned and sequenced. EGFR expression was found in 128 of 169 adrenocortical carcinoma samples (76%), and in 60 of these samples (=36%) strong membrane staining was detected. However, there was no significant correlation with clinical outcome. In addition, all 30 sequenced cases revealed unmutated EGFR genes. In contrast, only 1 out of 31 adrenocortical adenomas weakly expressed the EGFR (3%). In summary, EGFR was overexpressed in more than three-quarters of adrenocortical carcinoma cases of this series. However, no mutations of the EGFR gene were found and EGFR expression was not of prognostic relevance. As EGFR is hardly expressed in adrenocortical adenomas, our results suggest that its expression in adrenocortical tumors indicates a malignant phenotype, which may be used in the differential diagnosis between adrenocortical adenomas and carcinomas.

High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors.

CONTEXT: No immunohistochemical marker has been established to reliably differentiate adrenocortical tumors from other adrenal masses. A panel of markers like melan-A and inhibin-α is currently used for this purpose but suffers from limited diagnostic accuracy. We hypothesized that expression of steroidogenic factor-1 (SF-1), a transcription factor involved in adrenal development, is of value for the differential diagnosis of adrenal masses and predicts prognosis in adrenocortical carcinoma (ACC). PATIENTS AND METHODS: SF-1 protein expression was assessed by immunohistochemistry on tissue samples from 167 ACC, 52 adrenocortical adenomas (ACA), six normal adrenal glands, six normal ovaries and 73 neoplastic nonsteroidogenic tissues. In an independent cohort of 33 ACC and 58 ACA, SF-1 mRNA expression was analyzed. SF-1 expression was correlated with clinical outcome in patients with ACC. RESULTS: SF-1 protein staining was detectable in 158 of 161 (98%) evaluable ACC samples including 49 (30%) with strong SF-1 staining and in all normal and benign steroidogenic tissues. In addition, SF-1 mRNA expression was present in all 91 analyzed adrenocortical tumors. In contrast, SF-1 expression was absent in all nonsteroidogenic tumors. Strong SF-1 protein expression significantly correlated with poor clinical outcome: tumor stage-adjusted hazard ratio for death 2.46 [95% confidence interval (CI) = 1.30-4.64] and for recurrence 3.91 (95% CI = 1.71-8.94). Similar results were obtained in the independent cohort using RNA analysis [tumor stage-adjusted hazard ratio for death 4.69 (95% CI = 1.44-15.30)]. CONCLUSION: SF-1 is a highly valuable immunohistochemical marker to determine the adrenocortical origin of an adrenal mass with high sensitivity and specificity. In addition, SF-1 expression is of stage-independent prognostic value in patients with ACC.

The expression of galectin-1 in vulvar neoplasia.

Vulvar cancer contributes to about 5% of all gynaecological cancers. Galectin-1, a member of an ubiquitous expressed beta-galactoside-binding family that comprises over 140 members to date, has been shown to be involved in many physiological and pathological processes, such as tumour progression, by promoting cancer cell invasion and metastasis, in apoptosis, embryogenesis and immunobiology. As the result of these findings, galectin-1 has been described as a potential marker for tumour progression in some malignancies. In this study, the expression pattern of galectin-1 was determined in 73 formalin-fixed, paraffin-embedded vulvar tissues by a standard immunohistochemical method: 12 benign vulvar specimen, 41 vulvar intraepithelial lesions (VIN), according to their differentiation were subdivided into VIN I, II and III and 20 invasive squamous cell carcinomas (ISCC). The immunohistochemical analyses showed that the intensity of galectin-1 expression on stromal cells next to the neoplastic cells steadily increased according to the pathological grade: benign vulvar tissue

The clinicopathological and prognostic relevance of pyruvate kinase M2 and pAkt expression in breast cancer.

BACKGROUND: Cancer cell growth has been described to depend on glucose utilization. Activation of Akt and up-regulation of pyruvate kinase M2 (M2-PK) are attributes of tumour glycolysis. PATIENTS AND METHODS: In order to evaluate the prognostic relevance of glycolytic markers in breast cancer, the expression of pAkt and M2PK was analysed in 160 tissue samples. The staining results were compared with clinicopathological characteristics and survival data. RESULTS: Overexpression of pAkt was detected in 58% and of M2PK in 70% of breast cancer samples. Increased pAkt-expression was accompanied with shorter survival time. In contrast, M2PK expression was significantly higher in patients surviving breast cancer for more than 13 years. CONCLUSION: Strong M2PK expression seems to be a favourable prognostic factor and its role in breast cancer progression should be further explored. Our data confirm previous observations of pAkt as a negative prognostic marker.

Nicotine and methyl methane sulfonate in mini organ cultures of human parotid gland tissue.

The aim was to demonstrate the applicability of using mini organ cultures (MOC) of the human parotid gland for indicating DNA damage by nicotine. Macroscopically healthy specimens of human parotid glands (1 mm3) were cultured for 7 d. Morphology was examined after HE and immunohistochemical staining of alpha-amylase. MOC were exposed to 2.0 mM nicotine or 100 microM methyl methane sulfonate (MMS) for 1, 2 and 3 h, followed by a regeneration period of 24 h. DNA damage was assessed by the comet assay. Histological findings demonstrated healthy acinar cells up to 8 days of culture and a strong expression pattern of alpha-amylase. Cells in the centre of mini organs showed a granular cytoplasm starting at day 3. 1-3 h nicotine exposure significantly increased DNA damage as determined by DNA in the tail (DT), with no significant differences with increasing exposure time and only a trend towards decreased values of DT after regeneration. MMS demonstrated a time-dependent increase in DNA damage and distinctly reduced DT values after regeneration. MOC may be used to study DNA damage and repair after repetitive exposure to xenobiotics. They provide additional information for in vitro studies of cells growing in an intact tissue structure.

Glycolytic phenotype in breast cancer: activation of Akt, up-regulation of GLUT1, TKTL1 and down-regulation of M2PK.

PURPOSE: Metabolic dependence on glucose utilisation has been described for different tumours characterised by activation of Akt, upregulation of GLUT1, M2PK and TKTL1. To date, however, little is known about glucose metabolism in breast cancer tissue. METHODS: We analysed 55 breast cancer specimens, 26 adjacent ductal carcinomas in situ (DCIS) and 23 adjacent normal breast tissues for expression of glycolytic markers by immunohistochemistry. RESULTS: We found expression of pAkt in 49%, GLUT1 in 25%, M2PK in 68% and TKTL1 in 31% of the tumours investigated. Expression of pAkt and Her2neu are positively correlated with borderline significance (P = 0.055). Expression of pAkt, GLUT1 and TKTL1 were higher in breast cancer and DCIS than in normal tissue. Surprisingly, M2PK expression was highest in normal breast tissue. CONCLUSIONS: We found a glycolytic phenotype in a high percentage of breast cancer samples. Inhibition of glycolysis might evolve as a future option for breast cancer therapy.

Expression of VEGFR-1 (Flt-1) in breast cancer is associated with VEGF expression and with node-negative tumour stage.

BACKGROUND: Vascular endothelial growth factor (VEGF) promotes breast cancer progression by inducing angiogenesis via VEGF receptors on endothelial cells but also signals directly through receptors such as VEGFR-1 (Flt-1) expressed on tumour cells. The impact of autocrine signalling loops on treatment with VEGF inhibitors is still unclear. MATERIALS AND METHODS: Six breast cancer cell lines were tested for expression of VEGFR-1 by RT-PCR and Western blot. To assess clinical significance, 93 breast cancer lesions were evaluated for expression of VEGF and VEGFR-1 by immunohistochemistry. RESULTS: VEGFR-1 mRNA was found in all 6 cell lines, while protein expression was found in 5 cell lines. VEGF was expressed in 60% and VEGFR-1 in 39% of breast cancer specimens. VEGFR-1 expression was associated with VEGF expression and with node-negative tumour stage. CONCLUSION: Our data suggest that analysis of VEGF/VEGFR-1 expression might be relevant in identifying patients with different response rates upon treatment with antiangiogenic agents.

Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides.

BACKGROUND: Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT). METHODS: Twenty-four female NMRI nude mice were injected subcutaneously with tumour cells of the gastric adenocarcinoma cell line 23132/87. The animals were then randomly split into two feeding groups and fed either a ketogenic diet (KD group; n = 12) or a standard diet (SD group; n = 12) ad libitum. Experiments were ended upon attainment of the target tumor volume of 600 mm3 to 700 mm3. The two diets were compared based on tumour growth and survival time (interval between tumour cell injection and attainment of target tumour volume). RESULTS: The ketogenic diet was well accepted by the KD mice. The tumour growth in the KD group was significantly delayed compared to that in the SD group. Tumours in the KD group reached the target tumour volume at 34.2 +/- 8.5 days versus only 23.3 +/- 3.9 days in the SD group. After day 20, tumours in the KD group grew faster although the differences in mean tumour growth continued significantly. Importantly, they revealed significantly larger necrotic areas than tumours of the SD group and the areas with vital tumour cells appear to have had fewer vessels than tumours of the SD group. Viable tumour cells in the border zone surrounding the necrotic areas of tumours of both groups exhibited a glycolytic phenotype with expression of glucose transporter-1 and transketolase-like 1 enzyme. CONCLUSION: Application of an unrestricted ketogenic diet enriched with omega-3 fatty acids and MCT delayed tumour growth in a mouse xenograft model. Further studies are needed to address the impact of this diet on other tumour-relevant functions such as invasive growth and metastasis.