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Importance: Measurable residual disease (MRD) is widely used as a therapy-stratification factor for acute myeloid leukemia (AML), but the association of dynamic MRD with postremission treatment (PRT) in patients with intermediate-risk AML (IR-AML) has not been well investigated., Objective: To investigate PRT choices based on dynamic MRD in patients with IR-AML., Design, Setting, and Participants: This cohort study examined 549 younger patients with de novo IR-AML in the South China Hematology Alliance database during the period from January 1, 2012, to June 30, 2016, including 154 who received chemotherapy, 116 who received an autologous stem cell transplant (auto-SCT), and 279 who received an allogeneic SCT (allo-SCT). Subgroup analyses were performed according to dynamic MRD after the first, second, and third courses of chemotherapy. The end point of the last follow-up was August 31, 2020. Statistical analysis was performed from December 1, 2019, to September 30, 2020., Exposures: Receipt of chemotherapy, auto-SCT, or allo-SCT., Main Outcomes and Measures: The primary end points were 5-year cumulative incidence of relapse and leukemia-free survival., Results: Subgroup analyses were performed for 549 participants (314 male participants [57.2%]; median age, 37 years [range, 14-60 years]) according to the dynamics of MRD after 1, 2, or 3 courses of chemotherapy. Comparable cumulative incidences of relapse, leukemia-free survival, and overall survival were observed among participants who had no MRD after 1, 2, or 3 courses of chemotherapy. Participants who underwent chemotherapy and those who underwent auto-SCT had better graft-vs-host disease-free, relapse-free survival (GRFS) than those who underwent allo-SCT (chemotherapy: hazard ratio [HR], 0.35 [95% CI, 0.14-0.90]; P = .03; auto-SCT: HR, 0.07 [95% CI, 0.01-0.58]; P = .01). Among participants with MRD after 1 course of chemotherapy but no MRD after 2 or 3 courses, those who underwent auto-SCT and allo-SCT showed lower cumulative incidence of relapse (auto-SCT: HR, 0.25 [95% CI, 0.08-0.78]; P = .01; allo-SCT: HR, 0.08 [95% CI, 0.02-0.24]; P < .001), better leukemia-free survival (auto-SCT: HR, 0.26 [95% CI, 0.10-0.64]; P = .004; allo-SCT: HR, 0.21 [95% CI, 0.09-0.46]; P < .001), and overall survival (auto-SCT: HR, 0.22 [95% CI, 0.08-0.64]; P = .005; allo-SCT: HR, 0.25 [95% CI, 0.11-0.59]; P = .001) vs chemotherapy. In addition, auto-SCT showed better GRFS than allo-SCT (HR, 0.45 [95% CI, 0.21-0.98]; P = .04) in this group. Among participants with MRD after 1 or 2 courses of chemotherapy but no MRD after 3 courses, allo-SCT had superior cumulative incidence of relapse (HR, 0.10 [95% CI, 0.06-0.94]; P = .04) and leukemia-free survival (HR, 0.18 [95% CI, 0.05-0.68]; P = .01) compared with chemotherapy, but no advantageous cumulative incidence of relapse (HR, 0.15 [95% CI, 0.02-1.42]; P = .10) and leukemia-free survival (HR, 0.23 [95% CI, 0.05-1.08]; P = .06) compared with auto-SCT. Among participants with MRD after 3 courses of chemotherapy, allo-SCT had superior cumulative incidences of relapse, leukemia-free survival, and overall survival compared with chemotherapy (relapse: HR, 0.16 [95% CI, 0.08-0.33]; P < .001; leukemia-free survival: HR, 0.19 [95% CI, 0.10-0.35]; P < .001; overall survival: HR, 0.29 [95% CI, 0.15-0.55]; P < .001) and auto-SCT (relapse: HR, 0.25 [95% CI, 0.12-0.53]; P < .001; leukemia-free survival: HR, 0.35 [95% CI, 0.18-0.73]; P = .004; overall survival: HR, 0.54 [95% CI, 0.26-0.94]; P = .04). Among participants with recurrent MRD, allo-SCT was also associated with advantageous cumulative incidence of relapse, leukemia-free survival, and overall survival compared with chemotherapy (relapse: HR, 0.12 [95% CI, 0.04-0.33]; P < .001; leukemia-free survival: HR, 0.24 [95% CI, 0.10-0.56]; P = .001; overall survival: HR, 0.31 [95% CI, 0.13-0.75]; P = .01) and auto-SCT (relapse: HR, 0.28 [95% CI, 0.09-0.81]; P = .02; leukemia-free survival: HR, 0.30 [95% CI, 0.12-0.76]; P = .01; overall survival: HR, 0.26 [95% CI, 0.10-0.70]; P = .007)., Conclusions and Relevance: This study suggests that clinical decisions based on dynamic MRD might be associated with improved therapy stratification and optimized PRT for patients with IR-AML. Prospective multicenter trials are needed to further validate these findings.

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features., Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting., Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations., Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271 ., (©2020 American Association for Cancer Research.)

Background: Complete surgical resection affords the best prognosis at the time of interval debulking surgery. When complete surgical resection is unachievable, optimal residual disease is considered the next best alternative. Despite contradicting evidence on the survival benefit of interval debulking surgery if macroscopic residual disease remains, the current definition of "optimal" in patients undergoing interval debulking surgery is defined as largest diameter of disease measuring ≤1.0 cm, independent of the total volume of disease., Objective: To examine the relationship between volume and anatomic distribution of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing neoadjuvant chemotherapy then interval debulking surgery. For patients who did not undergo a complete surgical resection, a surrogate for volume of residual disease was used to assess oncologic outcomes., Study Design: Patient demographics, operative characteristics, anatomic site of residual disease, and outcome data were collected from medical records of patients with International Federation of Gynecology and Obstetrics stage IIIC and IV epithelial ovarian cancer undergoing interval debulking surgery from January 2010 to July 2015. Among patients who did not undergo complete surgical resection but had ≤1 cm of residual disease, the number of anatomic sites (single location vs multiple locations) with residual disease was used as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival and overall survival was evaluated., Results: Of 270 patients undergoing interval debulking surgery, 173 (64.1%) had complete surgical resection, 34 (12.6%) had ≤1 cm of residual disease in a single anatomic location, 47 (17.4%) had ≤1 cm of residual disease in multiple anatomic locations, and 16 (5.9%) were suboptimally debulked. Median progression-free survival for each group was 14, 12, 10, and 6 months, respectively (P<.001). Median overall survival for each group was: 58, 37, 26, and 33 months, respectively (P<.001)., Conclusion: Following interval debulking surgery, patients with complete surgical resection have the best prognosis, followed by patients with ≤1 cm single-anatomic location disease. In contrast, despite being considered "optimally debulked," patients with ≤1 cm multiple-anatomic location disease have a survival similar to suboptimally debulked patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The completeness of tumor removal is described in the residual tumor classification (R classification). The R category of a surgical specimen reflects the effects of treatment, influences further treatment decisions and is associated with patient survival. Thorough pathological examination of all resection planes, including the circumferential margin, is necessary for accurate classification.

Background: The residual tumor (R) classification describes the tumor status after therapy, which in patients with thyroid carcinomas is predominantly after surgical treatment. The aim of the R classification is to indicate the success of (surgical) therapy, which can influence further therapeutic procedures and allow relevant prognostic statements., Objective: Definition of R1 resection as well as minimally invasive extrathyroidal growth of thyroid carcinomas as the latter is a common prerequisite for R1 resected thyroid carcinoma., Results: Presentation of the pathological work-up and histopathological assessment. Proposal to supplement and extend the recently introduced 8th edition of the TNM classification in order to systematically classify minimally invasive extrathyroidal carcinomas., Conclusion: The presented definitions (e.g. R1, minimally invasive extrathyroidal invasion) in combination with the proposed extension of the TNM classification permit the prospective scientific assessment of the biological relevance of these two parameters.

Purpose: Outcome of childhood acute lymphoblastic leukemia (ALL) improved greatly by intensifying chemotherapy for all patients. Minimal residual disease (MRD) levels during the first months predict outcome and may select patients for therapy reduction or intensification., Methods: Patients 1 to 18 years old with ALL were stratified on the basis of MRD levels after the first and second course of chemotherapy. Thereafter, therapy was substantially reduced in patients with undetectable MRD (standard risk) and intensified in patients with intermediate (medium risk) and high (high risk) levels of MRD. Seven hundred seventy-eight consecutive patients were enrolled. The method of analysis was intention-to-treat. Outcome was compared with historical controls., Results: In MRD-based standard-risk patients, the 5-year event-free survival (EFS) rate was 93% (SE 2%), the 5-year survival rate was 99% (SE 1%), and the 5-year cumulative incidence of relapse rate was 6% (SE 2%). The safety upper limit of number of observation years was reached and therapy reduction was declared safe.MRD-based medium-risk patients had a significantly higher 5-year EFS rate (88%, SE 2%) with therapy intensification (including 30 weeks of asparaginase exposure and dexamethasone/vincristine pulses) compared with historical controls (76%, SE 6%). Intensive chemotherapy and stem cell transplantation in MRD-based high-risk patients resulted in a significantly better 5-year EFS rate (78%, SE 8% v 16%, SE 8% in controls). Overall outcome improved significantly (5-year EFS rate 87%, 5-year survival rate 92%, and 5-year cumulative incidence of relapse rate 8%) compared with preceding Dutch Childhood Oncology Group protocols., Conclusion: Chemotherapy was substantially reduced safely in one-quarter of children with ALL who were selected on the basis of undetectable MRD levels, without jeopardizing the survival rate. Outcomes of patients with intermediate and high levels of MRD improved with therapy intensification., (© 2016 by American Society of Clinical Oncology.)

The residual (R) tumor classification is an essential, even if facultative component of the TNM classification; however, it should alway be included in the pathology results of certified lung cancer centers. In discussions it becomes clear again and again that different hospitals and departments have different approaches and interpretations with respect to the R status after lung resection. We carried out a questionnaire-based survey of pathologists (with specialization in pulmonary pathology) and thoracic surgeons on the application of the R classification for lung tumors. The results of the survey revealed the different perceptions of the participating centers with respect to application and interpretation, which results in divergent decisions for adjuvant therapy and complicates the comparability of national and international studies. The results of the survey are especially valuable because all participants have a high level of expertise in the field of thoracic pathology and the data reflect the current practice in certified lung cancer centers. It appears to be necessary to examine the application and interpretation of the R classification for lung cancer more closely in an interdisciplinary exchange and to produce a catalogue of criteria to guarantee at least a better national standardization.

To establish a prognostic prediction system, we examined the relationships between prognosis and histological therapeutic effect or ypTNM classification in 258 breast cancer patients who received neoadjuvant chemotherapy. The case distribution according to therapeutic effect was nine patients (3.5%) with Grade 0, 169 (65.5%) with Grade 1, 58 (22.5%) with Grade 2, and 22 (8.5%) with Grade 3. The 5-year overall survival (OS) rate by therapeutic effect was 56% in Grade 0, 81% in Grade 1, 87% in Grade 2, and 96% in Grade 3. The higher the therapeutic effect the better the prognosis, with a significant difference among the groups (P = 0.008). The case distribution according to ypTNM classification was 20 patients (7.8%) with Stage 0, 83 (32.2%) with Stage I, 77 (29.8%) with Stage II, and 78 (30.2%) with Stage III. The 5-year OS rate by ypTNM classification was 95% in Stage 0, 94% in Stage I, 89% in Stage II, and 59% in Stage III. While prognosis was mostly comparable in Stages 0 and I, in the other stages it became significantly worse as residual cancer increased (P < 0.001). The prognosis of breast cancer patients with neoadjuvant chemotherapy can be predicted by histological therapeutic effect and staging classification of residual cancer., (© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

In the current German S3 guidelines for colorectal carcinoma (CRC), morphologically based tumor grading is extended by molecular grading for poorly differentiated and undifferentiated carcinomas, as well as for special morphological subtypes. These CRC are classified as low-grade when microsatellite instability (MSI) is found. In routine diagnostics, immunohistochemistry for hMLH1 and hMSH2, capturing MSI-CRC with high sensitivity and specificity, can be used as an inexpensive substitute for molecular MSI-testing. In patients with positive Bethesda criteria, a stepwise immunohistochemical and molecular diagnostic scheme is proposed. The detection of a BRAF mutation in tumors with hMLH1 loss allows distinguishing between sporadic and HNPCC-associated MSI-CRC. For rectal cancer the residual tumor classification (R-status) is completed by the circumferential resection margin classification (CRM).

Testicular tumors can be divided into germ cell tumors and sex cord stromal tumors. Malignant testicular germ cell tumors (TGCT) represent about 90-95 % of all testicular tumors and are the most common solid neoplasms in young men aged 20-40 years with an increasing incidence in industrialized countries. Treatment of TGCT is performed by an individual and risk-adapted approach taking primary tumor histology, histopathlogical and molecular prognostic risk factors, tumor stage and for metastasized tumors the response to systemic chemotherapy into consideration. Knowledge of the specific histopathology of the primary tumor and the prognostic factors is of utmost importance for the treating urologist and oncologist in order to avoid undertreatment or overtreatment. Established risk factors which have been validated in retrospective and prospective studies for clinical stage I non-seminomatous TGCT are the presence of vascular invasion and the percentage of embryonal carcinoma. In clinical stage I seminomas tumor size (> 4 cm) and presence of rete testis infiltration have been identified as risk factors in retrospective but not in prospective studies. Quantitative histopathology of the primary tumor is also important for the management of small residual masses following chemotherapy: if the masses are ≤ 1 cm, postchemotherapy retroperitoneal lymph node dissection is only indicated if the primary tumor contains ≥ 50 % teratoma. Quantitative pathohistology of the resected residual masses is of importance for the decision-making process of a consolidating chemotherapy which is only of benefit if the amount of vital cancer tissue is > 10 %. Resection of residual hepatic and thoracic masses is indispensable. For gonadal stromal tumors knowledge of atypical nuclear forms, increased rate of mitosis and increased growth fractions are important for therapy planning.

Background: Flow cytometry immunophenotyping (FCM) is an undispensable tool for the diagnosis and for the treatment stratification of childhood acute lymphoblastic leukemia. The correlation of the EGIL-classification with prognostically relevant parameters like age, prednisone response and risk group is analyzed., Patients: Between March 2000 and June 2009 12 patients less than 1 year of age, 1 836 patients with 1 to less than 6 years, 620 patients with 6 to less than 10 years, 615 patients with 10 to less than 15 years and 275 patients with 15 to less than 19 years were analyzed with a comprehensive 4-color antibody panel and classified according to the EGIL recommendations., Methods: Bone marrow or peripheral blood mononuclear cells were isolated by ficoll gradient centrifugation, washed and stained with fluorochrome-conjugated antigen-specific monoclonal antibodies. Cell preparations were acquired and analyzed on a flow cytometer., Results: Centralized FCM was performed for 2 775 patients (82.6%) with B-cell precursor acute lymphoblastic leukemia, 493 patients (14.7%) with T-cell acute lymphoblastic leukemia and 90 patients (2,7%) with biphenotypic acute leukemia. There was a slight overall predominance of male (56.1%) over female (43.9%) patients. Patients with B-cell precursor ALL had a slightly more favourable outcome with a 10 y pEFS of 78 ± 1.0%, compared to patients with a T-ALL or BAL (biphenotypic acute leukemia) phenotype with a 10 y pEFS of 74 ± 1.8% (n.s.) or 69 ± 9.0% (p<0.009), respectively., Conclusions: FCM according to the EGIL recommendations not only provides diagnostic lineage determination and subclassification but also enables an initial prognostic orientation before MRD (minimal residual disease)-based risk stratification becomes available., (© Georg Thieme Verlag KG Stuttgart · New York.)

The treatment of acute lymphoblastic leukemia (ALL) in childhood and adolescence achieves nowadays cure rates of more than 80%. The detection of minimal residual disease (MRD) via molecular genetic methods provides - in comparison with conventional clinical and biological parameters - much more sensitive approaches to monitor individual treatment response. Here we will discuss the molecular background and technical developments in the framework of the BFM-study group., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To screen the potential protein biomarkers in minimal residual disease (MRD) of the acute promyelocytic leukemia (APL) by comparison of differentially expressed serum protein between APL patients at diagnosis and after complete remission (CR) and healthy controls, and to establish and verify a diagnostic model., Methods: Serum proteins from 36 cases of primary APL, 29 cases of APL during complete remission and 32 healthy controls were purified by magnetic beads and then analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The spectra were analyzed statistically using FlexAnalysis(TM) and ClinProt(TM) software., Results: Two prediction model of primary APL/healthy control, primary APL/APL CR were developed. Thirty four statistically significant peptide peaks were obtained with the m/z value ranging from 1000 to 10 000 (P < 0.001) in primary APL/healthy control model. Seven statistically significant peptide peaks were obtained in primary APL/APL CR model (P < 0.001). Comparison of the protein profiles between the two models, three peptides with m/z 4642, 7764 and 9289 were considered as the protein biomarker of APL MRD. A diagnostic pattern for APL CR using m/z 4642 and 9289 was established. Blind validation yielded correct classification of 6 out of 8 cases., Conclusions: The MALDI-TOF MS analysis of APL patients serum protein can be used as a promising dynamic method for MRD detection and the two peptides with m/z 4642 and 9289 may be better biomarkers.

In order to guarantee a unified application of the R classification, the S3 guidelines were amended. With the introduction of the so-called CRM concept the special situation of ductal adenocarcinoma of the pancreas head can be taken into account. In contrast to the R classification, in the CRM concept lymph node metastases, lymph vessel and perineural sheath infiltration are taken into consideration. The distance of the tumor from the resection margins is particularly documented. Because of the prognostic significance of tumor-free lymph nodes, in future the lymph node ratio should be given. This is defined as the relationship of lymph node metastases to the total number of lymph nodes removed/examined.

Objective: To define a subset of patients with early-stage cervical cancer at low risk for parametrial invasion through pathologic parameters of loop electrosurgical excision procedure (LEEP)., Materials and Methods: A retrospective analysis of data from 131 patients who underwent LEEP before radical hysterectomy or radical trachelectomy for stage IA2 to IB1 cervical cancer was performed. Subgroup analysis was performed to define a group of patients at the lowest risk for parametrial invasion based on LEEP findings., Results: Overall, 7 (5.3%) of 131 patients showed parametrial involvement, all of whom had residual tumors in hysterectomy specimens. Risk factors for residual disease included a tumor width greater than 30 mm and a positive endocervical or deep resection margin. A subgroup analysis demonstrated that LEEP parameters, including a depth of invasion of 5 mm or less and a negative endocervical resection margin, were able to define the subgroup of patients at low risk for parametrial invasion. In 24 patients (18.3%) who met these criteria, there was no evidence of parametrial spread as well as nodal metastasis., Conclusion: A subgroup of patients with early-stage cervical cancer selected by the 2 LEEP variables, depth of invasion of 5 mm or less and a negative endocervical resection margin, demonstrated no risk for parametrial invasion.

No consensus has been reached in the definitions of complete remission (CR) and minimal residual disease (MRD) on bone marrow biopsy specimens of patients with hairy cell leukemia (HCL). Large comparative studies correlating clinical outcome with detection of MRD by immunohistochemistry (IHC), flow cytometry, and molecular diagnostics are lacking. The presence of normal bone marrow B-lymphocytes and the lack of immunohistochemical stains that are both sensitive and specific can make it challenging to differentiate normal lymphocytes from hairy cells. The use of CD20 and/or DBA.44 immunohistochemical stains, in combination with either tartrate resistant acid phosphatase (TRAP), CD11c-5D11, or annexin A1, improve specificity and facilitate evaluation. The interobserver concordance in quantifying the percentage of residual hairy cells is poor. Performing cell counts in multiple fields improves reproducibility. The prolonged hematologic remissions of subsets of patients with MRD emphasize the need to define clinically relevant thresholds that correlate with long-term responses and clinical endpoints. The development of internationally accepted, reproducible, and clinically relevant CR, MRD, and relapse criteria are of paramount importance in evaluating and comparing clinical trials and in providing optimal patient care.

Background: Since the introduction of the TNM residual tumor (R) classification, the involvement of resection margins has been defined either as a microscopic (R1) or a macroscopic (R2) demonstration of tumor directly at the resection margin ("tumor transected")., Methods: The recognition of the importance of the circumferential resection margin (CRM) in patients with rectal cancer patients raises the need for an alternative definition of resection margin involvement, namely, the importance of delineating tumor with a minimal distance from the CRM of

Objective: It remains unknown whether the extent of surgical resection affects survival or disease progression in patients with supratentorial low-grade gliomas., Methods: We conducted a retrospective cohort study (n = 170) between 1996 and 2007 at a single institution to determine whether increasing extent of surgical resection was associated with improved progression-free survival (PFS) and overall survival (OS). Surgical resection of gliomas defined as gross total resection (GTR) (complete resection of the preoperative fluid-attenuated inversion recovery signal abnormality), near total resection (NTR) (<3-mm thin residual fluid-attenuated inversion recovery signal abnormality around the rim of the resection cavity only), or subtotal resection (STR) (residual nodular fluid-attenuated inversion recovery signal abnormality) based on magnetic resonance imaging performed less than 48 hours after surgery. Our main outcome measures were OS, PFS, and malignant degeneration-free survival (conversion to high-grade glioma)., Results: One hundred thirty-two primary and 38 revision resections were performed for low-grade astrocytomas (n = 93) or oligodendrogliomas (n = 77). GTR, NTR, and STR were achieved in 65 (38%), 39 (23%), and 66 (39%) cases, respectively. GTR versus STR was independently associated with increased OS (hazard ratio, 0.36; 95% confidence interval, 0.16-0.84; P = 0.017) and PFS (HR, 0.56; 95% confidence interval, 0.32-0.98; P = 0.043) and a trend of increased malignant degeneration-free survival (hazard ratio, 0.46; 95% confidence interval, 0.20-1.03; P = 0.060). NTR versus STR was not independently associated with improved OS, PFS, or malignant degeneration-free survival. Five-year OS after GTR, NTR, and STR was 95, 80, 70%, respectively, and 10-year OS was 76, 57, and 49%, respectively. After GTR, NTR, and STR, median time to tumor progression was 7.0, 4.0, and 3.5 years, respectively. Median time to malignant degeneration after GTR, NTR, and STR was 12.5, 5.8, and 7 years, respectively., Conclusion: GTR was associated with a delay in tumor progression and malignant degeneration as well as improved OS independent of age, degree of disability, histological subtype, or revision versus primary resection. GTR should be safely attempted when not limited by eloquent cortex.

Purpose: Several factors have been shown to correlate with prognosis of patients with breast carcinoma. Among the most useful are node involvement, tumor size, and pathologic grade. These factors retained their prognostic value when assessed after neoadjuvant chemotherapy., Methods: Previously we used a revised Nottingham prognostic index and defined 3 related indices (breast grading index, modified Nottingham prognostic index, and modified breast grading index) that were also significantly related to overall survival and disease-free survival. To assess the postchemotherapy risk globally, we have combined the 3 pathologic factors to design a specific classification to evaluate residual disease. This new classification includes 4 risk levels (levels 1-4) according to residual disease magnitude after neoadjuvant chemotherapy in 710 patients with operable breast cancer., Results: This classification resulted in significantly different results for overall survival (P < 10(-7)) and disease-free survival (P = 8.3 x 10(-7))., Conclusion: This classification should help us in the selection of subgroups of patients for further adjuvant treatment.

The completeness of tumor removal is described in the residual tumor classification. Residual tumor may be found in the area of primary tumor and its regional lymph nodes and/or at distant sites. The R classification reflects the effects of treatment and influences further treatment planning. Therefore very careful use is necessary, including thorough pathohistological examination of resection margins to ascertain an R0 resection or to prove an R1 situation.

Accurate reporting of the residual tumor size by pathologists after neoadjuvant chemotherapy is an important component of a breast cancer. Recent literature reported comparisons regarding the accuracy of clinical and radiological residual tumor size findings using the histopathology as a "gold standard". However, the histopathological methods of measuring the residual tumor size are not standardized. Most pathologists use the tumor size measured by the gross examination. We collected 32 patient samples and compared the residual tumor size by gross and microscopic pathologic examinations. Using microscopic tumor size as the gold standard, our study showed gross tumor size is overestimated in 25%, underestimated in 56% and correlated to the final microscopic tumor size in 19% of the cases after neoadjuvant chemotherapy. Determining accurate residual tumor size to estimate pathologic response to chemotherapy is essential. We attempted to provide guidelines for pathology reporting post-neoadjuvant chemotherapy on breast cancers.

The TNM system is the most important classification for describing the anatomical extent of tumors. The residual tumor classification describes the completeness of tumor removal. Although the definitions of both systems seem clear and precise, the daily work offers questions on how to use special situations. Despite the importance of the TNM- and residual tumor classification in planning clinical management before and after treatment, the misinterpretations and inconsistencies in application diminish or abrogate their clinical utility. Some of the questions and problems will be addressed in this contribution.

Background and Objectives: Competitive immunoglobulin/T-cell receptor polymerase-chain reaction (PCR) analysis with fluorescent detection is a rapid, cheap and reproducible method for quantifying minimal residual disease (MRD), which is well adapted to the recognition of high-risk childhood acute lymphoblastic leukemia (ALL). We aimed at defining whether flow cytometry (FC) techniques can bypass limitations of PCR for MRD determination., Design and Methods: We analyzed 140 remission samples from 91 patients using both competitive PCR amplification of antigen-receptor genes and four-color FC identification of leukemia immunophenotype. These methods were chosen with the aim of detecting at least 0.1% blasts., Results: MRD was measured using both PCR and FC methods in 123 samples and the two methods provided concordant results in 119 of them (97%). Moreover, three out of the four discordant results appeared minor since MRD was detectable by both methods, but at different levels. In 12 of 13 samples from nine patients, mainly infants with early CD10- and/or t(4;11) B-cell ALL and children with immature T-cell ALL, MRD could be determined using FC whereas PCR failed. Conversely, FC methods were unfeasible due to inappropriate leukemia immunophenotype in three additional children (including two with T-cell ALL) for whom PCR successfully provided MRD results., Interpretation and Conclusions: The MRD results provided by FC techniques were highly concordant with those of competitive PCR. Moreover, the applicability of FC appeared higher in certain ALL subsets, although the appropriateness of this technique in terms of outcome prediction remains to be demonstrated.

Hematogenous distant metastasis is the leading cause of cancer-related death in breast cancer and other solid tumours. By applying sensitive immunocytochemical and molecular assays disseminated tumour cells (DTC) in bone marrow (BM) can be detected in 20-40% of cancer patients without any clinical or even histopathological signs of metastasis. The detection and characterisation of DTC in BM may lead to a better understanding of the biology initiating metastatic spread in cancer patients and will eventually contribute to the development of more effective strategies to eliminate DTC. In this review, we will therefore discuss the detection, characterisation and clinical relevance of DTC.

We assessed the incidence of circulating blasts occurring post-chemotherapy in 1000 consecutive pediatric blood samples. Blasts with myeloid morphology (<1-3%) were present in post-chemotherapy samples in 19 of 294 (6.4%) patients with acute leukemia in remission and in 11 of 361 (3.4%) patients with solid tumors, non-Hodgkin or Hodgkin lymphoma, and were associated with ANC>1.5x10(9)/l in 13 of 30 (43%) samples, and platelets >100x10(9)/l in 25 of 30 (83%) samples. Our findings suggest that the absence of circulating blasts may not be a prerequisite for remission in acute myeloid leukemia (AML).

Background: For cancer patients, prognosis is strongly influenced by the completeness of tumor removal at the time of cancer-directed surgery or disease remission after nonsurgical treatment with curative intent. These parameters define the relative success of definitive treatment and can be codified by an additional subclassification within the TNM system, the residual tumor (R) classification. Despite the importance of residual tumor status in designing clinical management after treatment, misinterpretation and inconsistent application of the R classification frequently occur that diminish or abrogate its clinical utility., Methods: An analysis of the relevant literature regarding the use and prognostic importance of the R classification was undertaken., Results: In the current study, the prognostic importance of the R classification for different kinds of tumors is discussed. Problems that arise in using the R classification are described. Special issues regarding the use of the R classification are addressed., Conclusions: The R classification is a strong indicator of prognosis and facilitates the comparison of treatment results if applied in a consistent manner. Uniform use and interpretation of this classification is essential for the standardization of posttreatment data collection., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10492)

Residual masses are frequently found in patients with aggressive lymphomas, following therapy. A study was undertaken to determine whether initial tumour size, changes during treatment, or size of the residual mass could provide prognostic information. Computed tomography (CT) examinations were carried out before, midway and after completion of chemotherapy in 37 patients with aggressive lymphoma with residual mass after treatment. The tumours were measured for both the greatest diameter sizes and area. The size of the residual mass correlated with the tumour size at diagnosis. Neither a large tumour size before treatment nor a large residual mass after treatment correlated with an increase in rate of relapse. The initial tumour reduction (measured after completion of half of the planned chemotherapy) was less pronounced in relapsing patients compared to relapse-free patients. Using a cut-off level of 70% tumour reduction (measured after completion of half of the planned chemotherapy), 66% of patients with a tumour reduction of < 70% relapsed, compared with 22% (p < 0.05) in those with more marked tumour regression.

Modern chemotherapy can place most patients with acute leukemia into remission. Unfortunately, many of these patients will subsequently relapse. The study of minimal residual disease focuses on the detection of patients destined to relapse despite appearing to be in clinical remission. In addition, the research has demonstrated that some patients appear to co-exist with their leukemia for years, and this suggests a need to re-examine what it means to be "cured" of leukemia. We await trials testing the intervention of "molecular relapse." Data appear to be sufficient to launch such trials in diseases such as pediatric acute lymphoblastic leukemia and the t(1 5;1 7) acute myeloid leukemia.

Background: Findings of isolated (disseminated or circulating) tumor cells (ITC) by immunocytochemistry and molecular pathology methods have led to varied interpretations and different applications of the TNM system., Methods: An analysis of the relevant literature was undertaken. In addition, optional proposals for the classification of ITC, micrometastasis, and cytologic results in pleural and peritoneal washings are presented., Results: Immunocytochemistry has a lower false-positive rate than nonmorphologic methods such as flow cytometry or the polymerase chain reaction; therefore the method(s) used always should be recorded. At the current time, the independent prognostic significance of ITC in regional lymph nodes and in the general circulation (blood, bone marrow, and other distant sites) is difficult to assess. To enable comparisons of treatment results and to avoid variation in staging, a finding of ITC should not be considered in the TNM and residual tumor (R) classifications, at least not at the current time. However, for future evaluation of their prognostic significance, the respective findings should be documented according to uniform criteria., Conclusions: ITC should be distinguished from micrometastasis. To investigate the independent prognostic significance of ITC and of positive lavage cytology, uniform data collection according to the proposed coding schema is recommended., (Copyright 1999 American Cancer Society.)

Objective: To determine the diagnostic value of obtaining an endocervical smear for cytologic examination immediately following cervical conization (by either the loop electrosurgical excision procedure or large loop excision of the transformation zone) in the detection of residual squamous dysplasia., Study Design: Thirty-eight cases were identified in which cervical conization was immediately followed by endocervical sampling (most commonly using a brush) and smear., Results: Twenty-one of the 38 postconization endocervical smears (55%) were either unsatisfactory or sub-optimal for evaluation due to cellular distortion (i.e., cautery artifact), degeneration or obscuring blood. Histologic in evaluation showed negative endocervical margins in 32 cases (84%) and positive endocervical margins in 6 cases (16%), including both low and high grade squamous intraepithelial lesions. The endocervical smears in the 32 cases with a negative surgical margin did not demonstrate evidence of dysplasia. However, in the six cases with histologically positive margins, postconization endocervical smears also failed to identify any evidence of dysplasia., Conclusion: Immediate postconization endocervical smears do not appear to be useful for the detection of residual disease in patients undergoing conization for squamous dysplasia of the cervix.

The anatomic extent of tumor (TNM, pTNM) and, in case of treatment, the residual tumor status following treatment (residual tumor, or R classification) are the strongest predictors for outcome of patients with gastrointestinal cancer. The results of the pTNM and the R classifications depend on the methods used. In particular, the pN classification correlates with the number of nodes examined. The findings of micrometastases or isolated tumor cells in bone marrow should be indicated, and such cases must be analyzed separately from other metastatic cases. The same applies to patients with positive cytology in ascites fluid or peritoneal washings without gross involvement of the peritoneum. For the R classification the additional descriptors (conv), for conventional methods used, and (soph), for sophisticated, are recommended to indicate the methods used for classification. In general, long-term survival can be expected only after R0 resection (resection without residual tumor). The observed 5-year survival after R0 resection is 15% to 40% for esophageal carcinoma, 40% to 75% for gastric carcinoma, and 55% to 60% for colorectal carcinoma; the respective figures for R1 and R2 resections are only about 5% each. In R1 and R2 cases prognosis is determined primarily by the absence or presence of distant metastases, and pT and pN are of minor significance. After R0 resection there is a wide spectrum of prognoses. Careful pTNM classification allows a good estimation of the prognosis and can be considered the gold standard for any analysis of treatment results.

We retrospectively analysed 13 patients (pts.) treated at the University of Tübingen from 1985 to 1993 to evaluate the results of radiation therapy (XRT) given as an adjuvant to totally or subtotally resected meningiomas. The overall survival was 38% at five years with a probability of relapse of 50% at this time. Reclassification of the tumours according to the new WHO-classification of brain tumours [14] revealed 10 grade-II-tumours (atypical meningioma) and 3 grade-III-tumours (anaplastic meningioma). Radiotherapy failed in all 3 pts. with macroscopically incomplete resection (Simpson's grade IV), who died with relapse between 4 and 51 months after radiotherapy. 5 out of 10 pts. with grade-II-tumours relapsed. All 3 pts. with grade-III-tumours died with relapse between 6 and 21 months after XRT. Morbidity was seen in 2 pts. after irradiation with 60 GY (ICRU dose specification). Complete surgical exstirpation offers the best possibility of tumour control. Grade-III-tumours should be irradiated whatever the extent of the primary surgery was. Our results might indicate a possible indication for XRT in pts. with atypical grade-II-tumours especially when radical surgery must be in doubt. Prospective multicentre trials are warranted to prove the prognostic value of the new WHO-classification for atypical and anaplastic meningiomas and to define the ultimate role of radiotherapy in this setting.