Fungal association and root morphology shift stepwise during ontogenesis of orchid Cremastra appendiculata towards autotrophic nutrition.

The chlorophyllous, terrestrial orchid Cremastra appendiculata from East Asia is unique concerning its fungal mycorrhiza partners. The initially mycoheterotrophic protocorms exploit rather specialized non-rhizoctonia saprotrophic Psathyrellaceae. Adult individuals of this orchid species are either linked to Psathyrellaceae being partially mycoheterotrophic or form mycorrhiza with fungi of the ubiquitous saprotrophic rhizoctonia group. This study provides new insights on nutrition mode, subterranean morphology and fungal partners across different life stages of C. appendiculata. We compared different development stages of C. appendiculata to surrounding autotrophic reference plants based on multi-element natural abundance stable isotope analyses (δ13C, δ15N, δ2H, δ18O) and total N concentrations. Site- and sampling-time-independent enrichment factors of stable isotopes were used to reveal trophic strategies. We determined mycorrhizal fungi of C. appendiculata protocorm, seedling and adult samples using high-throughput DNA sequencing. We identified saprotrophic non-rhizoctonia Psathyrellaceae as dominant mycorrhizal fungi in protocorm and seedling rhizomes. In contrast, the roots of seedlings and mature C. appendiculata were mainly colonized with fungi belonging to the polyphyletic assembly of rhizoctonia (Ceratobasidium, Thanatephorus and Serendipitaceae). Mature C. appendiculata did not differ in isotopic signature from autotrophic reference plants suggesting a fully autotrophic nutrition mode. Characteristic of orchid specimens entirely relying on fungal nutrition, C. appendiculata protocorms were enriched in 15N, 13C and 2H compared to reference plants. Seedlings showed an intermediate isotopic signature, underpinning the differences in the fungal community depending on their subterranean morphology. In contrast to the suggestion that C. appendiculata is a partially mycoheterotrophic orchid species, we provide novel evidence that mature C. appendiculata with rhizoctonia mycobionts can be entirely autotrophic. Besides an environmentally driven variability among populations, we suggest high within-individual flexibility in nutrition and mycobionts of C. appendiculata, which is subject to the ontogenetic development stage.

Trastuzumab treatment of patients with early, HER2-positive breast cancer in 17 certified German breast cancer centers.

PURPOSE: Since 2008, guidelines recommend that patients with HER2-positive early breast cancer (BC) should receive adjuvant chemotherapy in combination with trastuzumab in Germany. However, recent studies highlight that a substantial share of patients do not receive trastuzumab. We investigate which patient characteristics are associated with a tumor board recommendation for trastuzumab in Breast Cancer Centers (BCC) certified by the German Cancer Society (DKG) and the German Society for Senology, and if the recommendation differs between BCCs. MATERIALS AND METHODS: Multi-level modeling was performed using quality assurance data based on 3052 HER2-positive, operated patients with a first diagnosis of early BC treated between 2006 and 2019 in 17 BCCs in Germany to investigate whether trastuzumab recommendation varies with patient sex, age, and disease characteristics, as well as over time and across BCCs. RESULTS: Tumor board recommendations for trastuzumab differ substantially between BCCs (intraclass correlation coefficient [ICC] null model: 0.11). Our final model (ICC 0.17, Akaike Information Criterion [AIC], 1328.0, R2 0.69) shows that physicians in BCCs more often recommend trastuzumab to patients who are younger than 60 years and those with a recommendation for any additional therapy (chemotherapy, radiation or endocrine therapy) (all p < 0.05). Furthermore, there is a significant time-dependent increase of trastuzumab recommendations (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.31-1.46, p < 0.05). CONCLUSION: In certified BCCs in Germany, guideline concordant trastuzumab recommendation is increasing since 2006 (positive cohort effect). Recommendation of trastuzumab for HER2-positive BC patients in BCCs is significantly associated with patients' age and the recommendations for other additional therapy strategies, apart from surgery. The quality assurance data analyzed do not include potentially relevant confounders, such as socioeconomic status or comorbidities.

Disseminated tumour cells from the bone marrow of early breast cancer patients: Results from an international pooled analysis.

PURPOSE: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC. EXPERIMENTAL DESIGN: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients. RESULTS: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06-1.43, p = 0.006), 1.30 (95% CI: 1.12-1.52, p < 0.001) and 1.30 (95% CI: 1.08-1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68-2.16; p = 0.512). CONCLUSIONS: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy.

Use of social service counseling by cancer patients: an analysis of quality assurance data of 6339 breast cancer patients from 13 certified centers in Germany treated between 2015 and 2017.

BACKGROUND: Integrated social care may help to mitigate social risk factors in order to achieve more equitable health outcomes. In cancer centers certified according to the criteria set out by the German Cancer Society, every patient must be given low-threshold access to qualified social workers at the center for in-house social service counseling (SSC). Previous analyses have demonstrated large variation in the utilization of these services across individual centers. Therefore, this research aims at investigating whether SSC utilization varies regarding breast cancer patient characteristics and center characteristics presenting a unique approach of using routine data. METHODS: Multilevel modeling was performed using quality assurance data based on 6339 patients treated in 13 certified breast cancer centers in Germany in order to investigate whether SSC utilization varies with patient sex, age, and disease characteristics as well as over time and across centers. RESULTS: In the sample, 80.3% of the patients used SSC. SSC use varies substantially between centers for the unadjusted model (ICC = 0.24). Use was statistically significantly (P < .001) more likely in women, patients with invasive (in comparison to tumor in situ/ductal carcinoma in situ) diseases (P < .001), patients with both breasts affected (P = .03), patients who received a surgery (P < .001), patients who were diagnosed in 2015 or 2017 compared to 2016 (P < .001) and patients older than 84 years as compared to patients between 55 and 64 years old (P = .002). CONCLUSION: The analysis approach allows a unique insight into the reality of cancer care. Sociodemographic and disease-related patient characteristics were identified to explain SSC use to some extent.

Clinical relevance of circulating tumor cells in ovarian, fallopian tube and peritoneal cancer.

PURPOSE: Presence of circulating tumor cells (CTCs) is associated with impaired clinical outcome in several solid cancers. Limited data are available on the significance of CTCs in gynaecological malignancies. The aims of the present study were to evaluate the dynamics of CTCs in patients with ovarian, fallopian tube and peritoneal cancer during chemotherapy and to assess their clinical relevance. METHODS: 43 patients with ovarian, fallopian tube and peritoneal cancer were included into this prospective study. Patients received chemotherapy according to national guidelines. CTC analysis was performed using the CellSearch system prior to chemotherapy, after three and six cycles. RESULTS: In 26% of the patients, ≥ 1CTC per 7.5 ml of blood was detected at baseline (17% of patients with de novo disease, compared to 35% in recurrent patients). Presence of CTCs did not correlate with other factors. After three cycles of therapy, CTC positivity rate declined to 4.8%. After six cycles, no patient showed persistent CTCs. Patients with ≥ 1 CTC at baseline had significantly shorter overall survival and progression-free survival compared to CTC-negative patients (OS: median 3.1 months vs. not reached, p = 0.006, PFS: median 3.1 vs. 23.1 months, p = 0.005). When only the subgroup with newly diagnosed cancer was considered, the association between CTC status and survival was not significant (OS: mean 17.4 vs. 29.0 months, p = 0.192, PFS: 14.3 vs. 26.9 months, p = 0.085). Presence of ≥ 1 CTC after three cycles predicted shorter OS in the entire patient cohort (p < 0.001). CONCLUSIONS: Hematogenous tumor cell dissemination is a common phenomenon in ovarian, fallopian tube and peritoneal cancer. CTC status before start of systemic therapy correlates with clinical outcome. Chemotherapy leads to a rapid decline in CTC counts; further research is needed to evaluate the clinical value of CTC monitoring after therapy.

Non-pegylated liposomal doxorubicin for patients with recurrent ovarian cancer: A multicentric phase II trial.

Patients with non-platinum-sensitive recurrent ovarian cancer have a poor prognosis. Non-pegylated liposomal doxorubicin (Myocet®) is a promising drug that may be able to improve treatment for such patients. In the current study, patients with recurrent ovarian cancer relapsing within 12 months after primary treatment received non-pegylated liposomal doxorubicin at 75 mg/m2 d1q22 and 60 mg/m2 d1q22 after study dose modification, respectively. There were 29 patients enrolled in the trial, and 124 cycles of non-pegylated liposomal doxorubicin were administered in total. All 29 patients were evaluable for toxicity. The clinical benefit rate (defined as the proportion of patients with either complete remission or partial remission, or with stable disease for >6 months) was 50%. The predominant non-hematological toxicity was nausea and vomiting (18 patients, grade I/II), whilst no palmar plantar erythrodysesthesia was observed. In 3 patients, a grade III hematological toxicity occurred, and the treatment schedule was consequently modified to 60 mg/m2 d1q22. The findings suggest that non-pegylated liposomal doxorubicin administered in a schedule of 60 mg/m2 d1q22 is well-manageable and is associated with tolerable non-hematological toxicities (predominantly nausea).

Isolated subcutaneous implantation of a borderline ovarian tumor: A case report and review of the literature.

Laparoscopy-related tumor implantations of gynecological malignancies into the subcutaneous tissue are rarely diagnosed. We report an interesting case of a 46-year-old female who presented with an abdominal subcutaneous metastasis of a borderline ovarian tumor. The patient received a laparoscopic unilateral adnexectomy for a solid-cystic tumor of the right ovary. Histopathological workup showed a papillary borderline tumor of mucinous type. Nine days later she underwent a hysterectomy, left adnexectomy, appendectomy and omentectomy. Exploration of the peritoneum revealed no intraperitoneal implants. Further exploration showed a non-invasive implant of a borderline tumor in the subcutaneous tissue above the fascia that had no contact to the peritoneum. It is hypothesized that tumor cells may have been implanted during a previous laparoscopy, the most recent of which had been fourteen years prior to her current presentation. Various risk factors for port-site malignancies have been identified. Tumor manipulation and extraction of tumor tissue without a protective bag may contribute to development of trocar-site metastasis.

Magnetic resonance imaging of cervical carcinoma using an endorectal surface coil.

INTRODUCTION: The objective of this trial is to investigate the diagnostic value of magnetic resonance imaging (MRI) with an endorectal surface coil for precise local staging of patients with histologically proven cervical cancer by comparing the radiological, clinical, and histological results. MATERIALS AND METHODS: Women with cervical cancer were recruited for this trial between February 2007, and September 2010. All the patients were clinically staged according to the FIGO classification and underwent radiological staging by MRI that employed an endorectal surface coil. The staging results after surgery were compared to histopathology in all the operable patients. RESULTS: A total of 74 consecutive patients were included in the trial. Forty-four (59.5%) patients underwent primary surgery, whereas 30 (40.5%) patients were inoperable according to FIGO and underwent primary radiochemotherapy. The mean age of the patients was 50.6 years. In 11 out of the 44 patients concordant staging results were obtained by all three staging modalities. Thirty-two of the 44 patients were concordantly staged by FIGO and histopathological examination, while only 16 were concordantly staged by eMRI and histopathological examination. eMRI overstaged tumors in 14 cases and understaged them in 7 cases. CONCLUSIONS: eMRI is applicable in patients with cervical cancer, yet of no benefit than staging with FIGO or standard pelvic MRI. The most precise preoperative staging procedure still appears to be the clinical examination.

Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial.

BACKGROUND: The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068). METHODS: Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated. RESULTS: 86 patients could be included into survival analysis (median follow-up: 88 months, range: 8-108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011). CONCLUSIONS: Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].

The PACOVAR-trial: a phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer.

BACKGROUND: The prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC. METHODS/DESIGN: This study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject). DISCUSSION: The current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in combination with oral cyclophosphamide as salvage treatment in patients with recurrent, pretreated ovarian cancer.

Aesthetic and functional results after breast conserving surgery as correlates of quality of life measured by a German version of the Breast Cancer Treatment Outcome Scale (BCTOS).

This prospective cohort study was carried out to develop a German version of the Breast Cancer Treatment Outcome Scale (BCTOS) and to examine the relations of aesthetic and functional outcome after breast conserving surgery with quality of life (QoL). The study included 189 patients with one-sided, early stage breast cancer. A factor analysis indicated three internally consistent scales of the German BCTOS: Aesthetic Status, Functional Status and Breast Sensitivity Status. QoL was measured by the EORTC Quality of Life Questionnaire C30-BR23 (EORTC). All BCTOS scales were correlated with scales of the EORTC. Correlation magnitudes ranged from 0.24 to 0.67 (p < 0.001). A multiple regression analyses confirmed these results. The analysis of relevant covariates demonstrated that younger patients revealed poorer status on all BCTOS scales. Aesthetic and functional outcome seems to be closely related to quality of Life. The German BCTOS demonstrated to be a useful instrument.

Prognostic impact of hemoglobin levels before and during carboplatin/taxane-based chemotherapy in patients with primary invasive epithelial ovarian cancer.

BACKGROUND: Carboplatin/taxane-based chemotherapy is the standard treatment for advanced primary ovarian cancer. Anemia is a frequent side effect of platinum-containing chemotherapy regimens. Furthermore, ovarian cancer is often associated with tumor anemia. The aim of this study was to evaluate the prognostic relevance of the mean hemoglobin level before and during carboplatin/taxane-based chemotherapy. MATERIAL/METHODS: We studied retrospectively 92 patients with primary invasive epithelial ovarian cancer (EOC) receiving carboplatin/taxane-based chemotherapy. Hemoglobin levels were determined before each cycle of therapy. Study objectives were progression-free survival time (PFS) and overall survival time (OS). Univariate analyses and Cox-regression studies were undertaken to evaluate the prognostic impact of hemoglobin levels before and throughout chemotherapy. In addition, sensitivity/specificity analyses and Kaplan-Meier-studies were performed to determine the cut-off level of prognostically relevant hemoglobin levels. RESULTS: In univariate analysis hemoglobin levels throughout chemotherapy showed prognostic relevance in terms of PFS (p<0.05). Sensitivity/specificity and Kaplan-Meier analyses found a hemoglobin level of 11.2 g/dL to be a prognostically relevant cut-off level in terms of PFS (p<0.05). There was a borderline significance for pretherapeutic hemoglobin levels to influence PFS (p=0.07), with a prognostically relevant cut-off level of 11.6 g/dL (p=0.06). CONCLUSIONS: Hemoglobin levels before and particularly throughout therapy seem to have prognostic relevance for patients with primary EOC undergoing carboplatin/taxane-based chemotherapy. Further trials are required to confirm these data in a prospective attempt and to evaluate the role of correcting anemia as standard supportive therapy in the treatment of patients with primary EOC.

hybseek: pathogen primer design tool for diagnostic multi-analyte assays.

Due to recent advances in genome sequencing, the detection of pathogens by DNA signatures, i.e. by oligonucleotide sequences that uniquely identify a specific genome, is becoming increasingly popular in modern clinical diagnostics. However, currently available screening methods, such as PCR and microarrays, lack multiplexing and sensitivity, respectively. Solid-phase amplification (SPA) is an emerging approach with the potential to overcome these limitations. SPA-based diagnostic assays require both pathogen-specific and compatible primer pairs for many, often closely related pathogens. Currently, none of the available tools supports an automated design of such primer sets, making it an iterative, labor-intensive, and often difficult procedure. Here we describe hybseek, a Web interface for efficient design of both pathogen-specific and compatible primer pairs for DNA-based diagnostic multi-analyte assays. hybseek achieves pathogen-specificity by selecting only candidates with unique 3(') subsequence, and the degree of this uniqueness is quantitatively expressed by a specificity score. qPCR experimental data confirm the feasibility of our design strategy. The service is freely available at https://www.hybseek.com.

Clinical Relevance of Disseminated Tumor Cells in the Bone Marrow and Circulating Tumor Cells in the Blood of Breast Cancer Patients.

Subclinical tumor cell spread, as the putative precursor stage of subsequent solid metastases, can be assessed in breast patients via the detection of disseminated tumor cells (DTC) in bone marrow aspirates or circulating tumor cells (CTC) in the peripheral blood with immunocytochemical and molecular techniques. In the context of a growing number of treatment strategies for cancer patients in the adjuvant setting as well as in the metastatic situation, markers predicting therapy efficacy are urgently needed. The detection of DTC or CTC may become one of the most interesting parameters not just for the prediction of survival or therapy monitoring but also for the characterization and specific targeting of residual tumor cells. Progress in this field now permits clinical studies that should lead to improvements in the treatment of breast cancer patients.

Die subklinische Streuung von Tumorzellen als das Vorläuferstadium solider Metastasen kann bei Brustkrebspatienten durch die Detektion disseminierter Tumorzellen (DTC) in Knochenmarkaspiraten oder zirkulierender Tumorzellen (CTC) im periphären Blut mittels immunzytochemischer und molekularer Methoden beurteilt werden. Im Rahmen der stetig wachsenden Anzahl an Behandlungsstrategien für Krebspatienten sowohl im adjuvanten Setting als auch im metastasierten Stadium werden Marker zur Vorhersage der Behandlungseffizienz dringend benötigt. Die Detektion von DTC bzw. CTC könnte zu einem der interessantesten Parameter werden, sowohl für die Vorhersage des Überlebens und zum Zweck des Therapiemonitoring als auch für die Charakterisierung und das spezifische Targeting residueller Tumorzellen. Fortschritte auf diesem Gebiet lassen nunmehr klinische Studien zu, die zu Verbesserungen in der Behandlung von Brustkrebspatienten führen dürften.

On the way to specifically targeting minimal residual disease?

The target of all adjuvant systemic therapies after surgery in breast cancer is the eradication of a minimal subclinical residual disease. Although it is well known that tumor cell dissemination takes place already at an early stage of the disease, little is known about the tumorbiological parameters of these residual cells. Selection of patients eligible for adjuvant endocrine therapies is based on the analysis of receptor expression in the primary tumor - although the analysis is directed against disseminated tumor cells, these cells may vary in receptor expression in comparison with the primary tumor.

Extensive genital and gluteal epitheliolyses caused by locoregional lichen ruber two years after primary treatment of vulvar cancer.

BACKGROUND: Lichen ruber is a rare inflammatory mucocutaneous dermatosis with unknown etiology. Paraneoplastic manifestations of the disease are rare. Eruptions of lichen ruber subsequent to traumas such as surgery or radiotherapy are described as Köbner's phenomenon. PATIENTS AND METHODS: A 72-year-old woman presented at our institution because of increasing, extensive erosive epitheliolyses of the genital and gluteal area two years after surgery and radiotherapy because of vulvar cancer. RESULTS: Thorough clinical as well as histological examination revealed a localized lichen ruber reaction. All epitheliolyses healed well within weeks under topic treatment with steroids. CONCLUSION: Lichen ruber is a rare dermatologic reaction that can occur several months after surgery and radiotherapy and has to be taken into account on examination of patients with late-onset skin reactions after local cancer treatment.

Weekly paclitaxel and carboplatin (PC-W) for patients with primary advanced ovarian cancer: results of a multicenter phase-II study of the NOGGO.

OBJECTIVES: To study the toxicity and efficacy of weekly paclitaxel and carboplatin (PC-W) in women with primary ovarian cancer METHODS: This investigation extended a phase-I dose finding study and was approved by the institutional review boards of all participating institutions. Between 1999 and 2003, women with radically resected ovarian cancer of FIGO stages II B to IV were enrolled at 17 German centres. Patients received weekly paclitaxel at a dose of 100 mg/m2, followed by carboplatin AUC 2. After a first treatment block consisting of six cycles of chemotherapy, patients had a treatment-free interval of 14 days, followed by a second block of six cycles. Treatment was completed by a 28-days break and a final block of six cycles. RESULTS: Altogether, 129 women with a mean age of 59 +/- standard deviation 11 years entered the study. Most patients (82.9%) had serous papillary carcinoma of FIGO stage III (72.9%) and IV (20.9%). Participants received 1,851 cycles of chemotherapy; averaging 14.3 +/- 4.3 cycles each patient. PC-W produced low rates of peripheral neuropathy (grade 3: 2.3%, 95% confidence interval [CI] 0.5-6.6%), with rapid recovery after 3 months. However, 72 patients had grade III/IV anaemia (55.8%, 95% CI 46.8-64.5%). There were 36 events of grade III/IV leukopenia (27.9%, 95% CI 20.4-36.5%). One patient sustained neutropenic fever. CA-125- and objective response was noted in 73.9% (95% CI 64.7-81.8%) and 55.6% (95% CI 41.4-69.1%) of patients. Median progression free and overall survival was 21 and 43 months, respectively. CONCLUSIONS: PC-W is feasible; a randomized study is warranted to compare this new regimen with conventional 3-weekly treatment.

Presence of apoptotic and nonapoptotic disseminated tumor cells reflects the response to neoadjuvant systemic therapy in breast cancer.

INTRODUCTION: Neoadjuvant systemic therapy (NST) is an established strategy to reduce tumor size in breast cancer patients prior to breast-conserving therapy. The effect of NST on tumor cell dissemination in these patients is not known. The aim of this study was to investigate the incidence of disseminated tumor cells (DTC), including apoptotic DTC, in breast cancer patients after NST, and to investigate the correlation of DTC status with therapy response. METHODS: Bone marrow aspiration was performed in 157 patients after NST. DTC were detected by immunocytochemistry using the A45-B/B3 anticytokeratin antibody. To detect apoptotic DTC the antibody M30 (Roche Diagnostics, Germany) was used, which detects a neo-epitope expressed only after caspase cleavage of cytokeratin 18 during early apoptosis. RESULTS: The incidence of DTC in breast cancer patients was 53% after completion of NST. Tumor dissemination was observed more frequently in patients with no change/progressive disease (69%) than in patients with partial remission or complete remission of the primary tumor (46%) (P < 0.05). Ten out of 24 patients with complete remission, however, were still bone marrow positive. Apoptotic DTC were present in 36 of 157 (23%) breast cancer patients. Apoptotic cells only were detected in 14% of the patients with partial remission or complete remission, but were detected in just 5% of the patients with stable disease. Apoptotic DTC were detectable in none of the patients with tumor progression. CONCLUSION: The pathological therapy response in breast cancer patients is reflected by the presence of apoptotic DTC. Patients with complete remission, however, may still have nonapoptotic DTC. These patients may also benefit from secondary adjuvant therapy.

A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation.

Numerous single-institutional studies and a large pooled analysis have demonstrated that the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) from patients with primary, nonmetastatic breast cancer (Stages I-III) is associated with impaired prognosis. To date, sampling of BM and assessment of DTCs is not considered a routine procedure in the clinical management of breast cancer patients; however, emerging data suggest a future role for risk stratification and monitoring of therapeutic efficacy. Because these clinical options need to be evaluated in trials to verify the principle of this concept in the clinical setting, agreement on the standardized detection of DTCs is necessary. Consequently, the German, Austrian, and Swiss Societies for Senology recently formed a panel 1) to review and discuss the existing methodologies, 2) to find a consensus for a standardized detection of DTCs, and 3) to explore the options for its clinical implementation.

Prediction of axillary lymph node status of breast cancer patients by tumorbiological factors of the primary tumor.

BACKGROUND AND PURPOSE: The increasing use of systemic adjuvant therapy even in lymph node-negative breast cancer patients and breast cancer screening programs detecting smaller tumors with less probability of metastatic lymph nodes questions the need for routine axillary lymph node dissection. Since morbidity of breast cancer surgery is predominantly related to axillary lymph node dissection, predictive models for lymph node involvement may provide a way to avoid lymph node surgery and its side effects in subgroups of patients. PATIENTS AND METHODS: Using a multivariate logistic regression model, tumorbiological parameters such as expression of estrogen and progesterone receptors, Ki-67, p53, cathepsin D, HER2, S-phase fraction, and ploidy were analyzed regarding their ability to predict axillary lymph node involvement in 655 breast cancer patients. RESULTS: The model correctly predicted axillary lymph node metastases in 58% of the patients by including expression of progesterone receptor, HER2, and Ki-67. In a subgroup of 200 patients predicted to be at extremely high or extremely low risk for axillary lymph node metastases, the accuracy of the prediction was 70%. CONCLUSION: With a model just based on tumorbiological parameters obtained in the primary tumor it is possible to predict axillary lymph node status. By including additional parameters it appears to be feasible to further improve the model in order to avoid axillary lymph node surgery in low-risk women.