Presence Of Residual Tumor Cells Research Articles

Pathologic examination of specimen after vacuum-assisted biopsy (VAB) in patients with breast cancer after neoadjuvant systemic therapy (NST).

e12589 Background: VAB of the tumor bed in the breast has shown promising results as a minimally invasive method for determining pathologic complete response (pCR). A significant disadvantage of VAB is the fragmentation of the obtained material and the lack of methods for determining generally accepted predictive and prognostic factors such as RCB index in case if residual tumor is detected. Here we present a description of the accumulated experience of histological examination of specimens obtained using VAB in patients with breast cancer after NST. Methods: A single-center, prospective, non-randomized study included patients with unifocal breast cancer (cT1–2N0–1M0). Patients who achieved a complete clinical response (cCR) underwent VAB. VAB specimen intraoperatively was divided into «inner contour» (first 6-12 samples) and «outer contour» (latter 6-12 samples). Patients without signs of residual tumor (pCR, ypT0N0) did not undergo further surgical intervention. In case if residual tumor cells (RTC) were detected, standard breast surgery was performed. To assess an extent of tumor response to NST instead of RCB we used Miller-Payne system which has correlation with RCB. Results: 35 patients with a mean age of 48.3 (31–67) years were included in the analysis. Examination of VAB samples showed that 11 (31.4%) patients had a residual tumor, and in 24 (68.6%) patients no tumor cells were detected (ypT0N0). According to the Miller-Payne system, 28 patients had a complete pathological response, which corresponds to Miller-Payne = 5 and pathological stage ypT0/ypTis (24 patients ypT0N0, 3 patients ypTisN0 and 1 patient ypT0N1). In 7 patients with residual invasive tumor, the tumor response according to the Miller-Payne scale corresponded to grades 3 and 4. There was a statistically significant correlation between presence of RTC in the «outer contour» of VAB and presence of RTC in the postoperative histology after standard surgery (Х2 p=0.01, Fisher exact test p=0.048). In case when RTC were found in the «inner contour» no correlation with the presence of RTC in the postoperative histology after standard surgery was observed (Х2 p=0.292, Fisher exact test p=1.0). Radiologic-pathologic discordance was 25% for mammolymphoscintigraphy, 35.5% for US and 39.4% for mammography. In case if 3 of 3 studies after NST described cCR radiologic-pathologic discordance was 16.7%, in case if 2 of 3 studies described cCR it was 22.2% and in case if only 1 of 3 studies described cCR it was 27.3%. Conclusions: The method used to evaluate histological material allows us to obtain predictive and prognostic information necessary to clarify further treatment tactics in accordance with modern standards. It is necessary to conduct large-scale studies in this area to answer the question if this method can be used in routine clinical practice. Clinical trial information: NCT04293796 .

An NCDB analysis of the predictive factors associated with the receival of tumor resection in mucinous cystadenoma of the pancreas.

e16356 Background: Mucinous cystadenoma (MCN) of the pancreas is characterized by mucin-producing cystic tumors that may lead to pancreatic ductal obstruction. While many of these cystic lesions are benign, there exists a notable risk for malignancy. Presently, the standard approach to managing MCN involves surveillance. Surgical resection is considered after evaluating histological features, the patient's age, surgical risk, and tumor size. Previous studies have linked surgical resection to favorable overall outcomes. However, no studies have investigated the predictive factors correlated to receiving surgery in MCN patients. This study aims to utilize the National Cancer Database (NCDB) to analyze factors that determine receival of tumor resection in patients with MCN of the pancreas. Methods: The NCDB was used to identify patients diagnosed with MCN of the pancreas from 2004 to 2019 using the histology codes 8470 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Multilevel Logistic Regression were performed, and data were analyzed using SPSS version 27. Statistical significance was set at α = 0.05. Results: 827 patients with MCN of the pancreas formed the initial sample. 552 patients received a tumor resection whereas 274 patients did not receive surgery ( 66.7% vs 33.1%, respectively). Surgical patients experienced significantly longer overall survival than nonsurgical patients ( 111.2 months vs. 20.1 months, p < 0.001). Complete tumor resection with no residual tumor cells was associated with improved outcomes in MCN( p < 0.001). Metastasis to distant sites was associated with decreased likelihood of receiving surgery ( p < 0.001). Well and moderately differentiated disease, stage I, II, and II disease, treatment at an academic facility, and private insurance status were associated with increased likelihood of receiving tumor resection ( p < 0.001). Income status and race did not appear to impact overall survival of these patients. Adjuvant therapies did not appear to impact overall survival of these patients. Conclusions: The results of this research align with other studies, affirming that surgical resection yields superior outcomes in patients with MCN of the pancreas. Factors such as well or moderately differentiated disease, early-stage diagnosis, treatment at academic facilities, and private insurance status increased the likelihood of tumor resection. Distant metastasis reduced the likelihood of receiving surgery. Complete tumor removal without presence of residual tumor cells post-surgery is correlated with improved survival. Income status and race did not appear to impact overall survival, and adjuvant therapies showed no discernible effect. To improve current treatment protocols for patients with MCN of the pancreas, more research needs to be conducted on the predictive factors of receiving surgery.

Minimal residual disease analysis in multiple myeloma: A single-center experience

BACKGROUND: Over the years, with changes in treatment approaches, it has been possible to achieve higher complete response (CR) rates with chemotherapies or chemoimmunotherapies in multiple myeloma (MM). However, a subset of patients in CR still relapse owing to the presence of residual tumor cells in the bone marrow not detectable by conventional methods. Residual disease detection by flow cytometry (FCM) has been proven to be highly sensitive and prognostically significant in a number of clinical studies. AIMS AND OBJECTIVES: In this study, we compared FCM minimal residual disease (FCM MRD) in MM cases post-chemotherapy/autologous stem cell transplant with morphology and biochemical methods. We also tried to correlate the pre-therapy stage of the disease and cytogenetics with MRD. MATERIALS AND METHODS: Twenty eight samples from 26 patients were evaluated for MRD on 6 color 3 tube panel over the period of 2 years. RESULTS: MRD was detectable in 19 samples (67.9%). FCM had a sensitivity of 95% compared to immunohistochemistry (IHC). 100% of cases with MRD positivity had abnormalities in at least three surface antigens. The high risk cytogenetics and high risk stage groups had a higher frequency of MRD positivity compared to the low risk groups. CONCLUSION: FCM MRD analysis is able to risk stratify the patients in CR and stringent CR. Routine use of FCM to detect residual disease posttherapy in MM should be implemented.

Progression Patterns in Non-Contrast-Enhancing Gliomas Support Brain Tumor Responsiveness to Surgical Lesions.

Purpose: The overall benefit of surgical treatments for patients with glioma is undisputed. We have shown preclinically that brain tumor cells form a network that is capable of detecting damage to the tumor, and repair itself. The aim of this study was to determine whether a similar mechanism might contribute to local recurrence in the clinical setting. Methods: We evaluated tumor progression patterns of 24 initially non-contrast-enhancing gliomas that were partially resected or biopsied. We measured the distance between the new contrast enhancement developing over time, and prior surgical lesioning, and evaluated tumor network changes in response to sequential resections by quantifying tumor cells and tumor networks with specific stainings against IDH1-R132H. Results: We found that new contrast enhancement appeared within the residual, non-enhancing tumor mass in 21/24 patients (87.5%). The location of new contrast enhancement within the residual tumor region was non-random; it occurred adjacent to the wall of the resection cavity in 12/21 patients (57.1%). Interestingly, the density of the glioma cell network increased in all patient tumors between initial resection or biopsy and recurrence. In line with the histological and radiological malignization, Ki67 expression increased from initial to final resections in 14/17 cases. Conclusion: The non-random distribution of glioma malignization in patients and unidirectional increase of anatomical tumor networks after surgical procedures provides evidence that surgical lesions, in the presence of residual tumor cells, can stimulate local tumor progression and tumor cell network formation. This argues for the development of intraoperative treatments increasing the benefits from surgical resection by specifically disrupting the mechanisms of local recurrence, particularly tumor cell network functionality.

Deeper sections reveal residual tumor cells in rectal cancer specimens diagnosed with pathological complete response following neoadjuvant treatment.

Guidelines and requirements for diagnosing pathological complete response (pCR) in rectal adenocarcinoma following neoadjuvant treatment vary, and there is currently no consensus on the appropriate number of sections to examine per formalin-fixed, paraffin-embedded (FFPE) tissue block. The consequences of systematic use of deeper sections on the diagnostic accuracy and prognosis for patients classified as ypT0 rectal cancer were investigated. In this retrospective study, 23 out of 155 patients who underwent neoadjuvant therapy and surgical resection between 2015 and 2020 were diagnosed with ypT0 rectal cancer. Three additional deeper sections were cut from each FFPE block from the primary tumor site and reviewed for presence of residual tumor cells. Additional sections revealed residual viable tumor cells in seven patients (30.4%), reducing the rate of pCR in the cohort from 14.8 to 10.3%. Of the seven patients, three patients later had local recurrence or distant metastasis during the follow-up period, compared with one patient with no residual tumor cells in deeper sections (p = 0.07). A nonsignificant reduction in disease-free survival (p = 0.08) was observed in the patients with residual tumor. Systematic use of deeper sections in evaluation of tumor regression in rectal cancer reveals the presence of residual tumor cells in a subset of patients originally diagnosed with pCR based on a single section per FFPE block. Although the results are not statistically significant, it cannot be excluded that accurately distinguishing complete from near-complete response may be clinically relevant for prognostic prediction.

Selection of surgical strategies for vulvar Paget's disease.

Selection of surgical strategies for vulvar Paget's disease.

Cell-Free Virus-Host Chimera DNA From Hepatitis B Virus Integration Sites as a Circulating Biomarker of Hepatocellular Cancer.

Early recurrence of hepatocellular carcinoma (HCC) after surgical resection compromises patient survival. Timely detection of HCC recurrence and its clonality is required to implement salvage therapies appropriately. This study examined the feasibility of virus-host chimera DNA (vh-DNA), generated from junctions of hepatitis B virus (HBV) integration in the HCC chromosome, as a circulating biomarker for this clinical setting. HBV integration in 50 patients with HBV-related HCC was determined by the Hybridization capture-based next-generation sequencing (NGS) platform. For individual HCC, the vh-DNA was quantified by specific droplet digital PCR (ddPCR) assay in plasma samples collected before and 2 months after surgery. HBV integrations were identified in 44 out of 50 patients with HBV-related HCC. Tumor-specific ddPCR was developed to measure the corresponding vh-DNA copy number in baseline plasma from each patient immediately before surgery. vh-DNA was detected in 43 patients (97.7%), and the levels correlated with the tumor sizes (detection limit at 1.5 cm). Among the plasma collected at 2 months after surgery, 10 cases (23.3%) still contained the same signature vh-DNA detected at baseline, indicating the presence of residual tumor cells. Nine of them (90%) experienced HCC recurrence within 1 year, supporting vh-DNA as an independent risk factor in predicting early recurrence. Analysis of circulating vh-DNA at recurrence further helped identify the clonal origin. A total of 81.8% of recurrences came from original HCC clones sharing the same plasma vh-DNA, whereas 18.2% were from de novo HCC. vh-DNA was shown to be a circulating biomarker for detecting the tumor load in majority of patients with HBV-related HCC and aided in monitoring residual tumor and recurrence clonality after tumor resection.

Rational Design of Conjugated Photosensitizers with Controllable Photoconversion for Dually Cooperative Phototherapy.

High-performance photosensitizers are highly desired for achieving selective tumor photoablation in the field of precise cancer therapy. However, photosensitizers frequently suffer from limited tumor suppression or unavoidable tumor regrowth due to the presence of residual tumor cells surviving in phototherapy. A major challenge still remains in exploring an efficient approach to promote dramatic photoconversions of photosensitizers for maximizing the anticancer efficiency. Here, a rational design of boron dipyrromethene (BDP)-based conjugated photosensitizers (CPs) that can induce dually cooperative phototherapy upon light exposure is demonstrated. The conjugated coupling of BDP monomers into dimeric BDP (di-BDP) or trimeric BDP (tri-BDP) induces photoconversions from fluorescence to singlet-to-triplet or nonradiative transitions, together with distinctly redshifted absorption into the near-infrared region. In particular, tri-BDP within nanoparticles shows preferable conversions into both primary thermal effect and minor singlet oxygen upon near-infrared light exposure, dramatically achieving tumor photoablation without any regrowth through their cooperative anticancer efficiency caused by their dominant late apoptosis and moderate early apoptosis. This rational design of CPs can serve as a valuable paradigm for cooperative cancer phototherapy in precision medicine.

MINIMAL RESIDUAL DISEASE ASSESMENT IN PATIENTS WITH ACUTE MYELOID LEUKEMIA BY MULTICOLOUR FLOW CYTOMETRY (LITERATURE REVIEW)

Patients with acute myeloid leukemia (AML) have a high risk of relapse. Determination of the presence of residual tumor cells during the remission of AML allows predicting the onset of relapse. Slow decrease of blast cells after induction courses is associated with a high probability of relapse. There are two most sensitive methods for determining minimal residual disease (MRD): molecular (polymerase chain reaction – PCR, droplet digital PCR, next generation sequencing – NGS) and immunophenotypic (multicolor flow cytometry – MFC). Both methods have advantages and disadvantages. The molecular diagnostic method is more sensitive, but it takes more time to get the result (from several days). Measurement of MRD by PCR is applicable in 40–50 % of AML patients, and by MFC – in 90 % of patients. The MFC method is based on the identification of antigens combination that is characteristic of tumor cells and is not found on normal hematopoietic cells. There are several drawbacks of the MFC method: the change of tumor clone immunophenotype during treatment, the inadequate difference in the antigen profiles of tumor cells and normal cells, difficulties in evaluating the MRD status in low cellularity bone marrow or blood sample. In AML patients the effect of MRD, measured by the MFC method, on long-term treatment outcomes was well-demonstrated. Evaluation of early MRD status shows tumor chemosensitivity and therapy efficacy. Despite the different approaches in MRD detection, thresholds and the combination of monoclonal antibodies, the lack of standardization, “positive” MRD values in early or later stages of therapy worsen the disease-free (DFS) and overall survival (OS) in AML patients. So far, the principles of MRD-directed therapy have not been developed, but protocols exist with the use of targeted drugs in combination with standard chemotherapy that help to reduce the MRD level. It is proved that the intensification of treatment does not affect the quantitative value of MRD and the long-term results of therapy. New prospective studies are needed to search for universal MRD markers, to create a standardized panel of monoclonal antibodies and to develop a specific therapy strategy in accordance with the MRD values.

DETECTION OF RESIDUAL LUNG CANCER CELLS BY PCR-BASED GENETIC TESTING FOR ROS1-TRANSLOCATION: CASE REPORT

A patient with lung cancer carrying ROS1 translocation was treated by crizotinib and then subjected to surgery. Morphological analysis revealed pathologic complete response in surgically removed tissues, while PCR test provided convincing evidence for the presence of residual tumor cells. PCR analysis of lung cancer specific gene translocations allows carrying out highly sensitive and reliable monitoring of tumor disease during the course of treatment.

Can "Indirect" Contact Laser Surgery be Used for Fluorescence-Image Guided Tumor Resections? Preliminary Results.

Ensuring the complete removal of tumor tissue is the main challenge during resection operations. Recently, a technique of “indirect” contact laser surgery has been developed. In this study we assess the possibility of using such surgery for fluorescence image-guided tumor resection. Mouse colon adenocarcinoma CT-26 cells stably expressing the fluorescent protein mKate-2 was used as the tumor model. Resections of the tumor nodes were performed with either a scalpel blade, a laser scalpel with a bare tip, or a laser scalpel with a strongly absorbing coating on the fiber tip. Tumor-positive resection margins were detected using an IVIS Spectrum fluorescence imaging system. After tumor resection with the scalpel blade over half of the animals needed one additional resection to remove residual tumor cells. Animals in this group showed tumor recurrence within 7 days. Fluorescence imaging of the tumor bed, performed after resection to assess the presence of tumor cell clusters, was sufficiently effective only with a bloodless resection. The laser scalpels both with the bare tip and with the strongly absorbing coating on the tip provided such bloodless tumor resection in contact mode. Fewer animals required additional resections when the bare tipped scalpel was used and this also resulted in a reduction in tumor recurrence. After resections were carried out with the laser scalpel with the strongly absorbing coating on the tip, fluorescence was detected in the operative field and this led to undertaking additional resections, although subsequent investigation suggested that this was “false” fluorescence, resulting from the effects of the scalpel rather than the presence of residual tumor cells. The method of laser resection with a strongly absorbing coating on the tip therefore did not appear to demonstrate definite advantages over laser resection with a bare tip when removing tumors.

A Case of Delayed Massive Hemothorax Caused by the Rupture of a Pulmonary Artery Pseudoaneurysm after Radiofrequency Ablation of Lung Tumors

Radiofrequency ablation has been applied as a minimally invasive therapy for the local control of lung tumors, including primary and metastatic neoplasms. Hemorrhagic complications after radiofrequency ablation can usually be treated conservatively, but such complications can be massive and fatal in some cases. In this paper, we report the rare case of delayed massive hemothorax caused by the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation that was treated using transcatheter coil embolization followed by a left lower lobectomy. A 75-year-old woman underwent radiofrequency ablation for the treatment of a metastatic lung tumor in the left lower lobe arising from a colorectal carcinoma located close to a branch of the pulmonary artery. Thirty-six hours later, hemothorax and hemorrhagic shock occurred as a result of a ruptured pulmonary artery pseudoaneurysm and radiofrequency ablation-induced damage to the interlobular pleura. After transcatheter coil embolization of the pulmonary artery pseudoaneurysm, she recovered from a state of shock and a left lower lobectomy was performed. Histological findings revealed the presence of residual tumor cells in the ablated lung tumor. The postoperative course was uneventful, and no evidence of recurrence of the primary disease was seen at 1 year after the surgery. Although hemothorax secondary to the rupture of a pulmonary artery pseudoaneurysm after lung radiofrequency ablation is a rare complication, it should be recognized as a serious potential complication of lung radiofrequency ablation for a tumor located close to the pulmonary artery branch.

Neoadjuvant Chemotherapy in Patients with Stage IV Colorectal Cancer: A Comparison of Histological Response in Liver Metastases, Primary Tumors, and Regional Lymph Nodes

We report the histopathological results of a novel "inversed" strategy designed to manage patients with colorectal cancer (CRC) who have synchronous liver metastases by using chemotherapy first, liver surgery second, and resection of the primary tumor as a final step. This study was designed to compare the response to chemotherapy in liver metastases, primary tumors, and locoregional lymph nodes. Twenty-nine patients with stage IV CRC received a combination of oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (OCFL) for 3-4months. Histological response to chemotherapy was assessed by using a tumor regression grading (TRG) score based on presence of residual tumor cells and extent of fibrosis. Median age of patients was 56 (range, 37-69) years. Primary tumor location was right colon (n=5), left colon (n=7), and rectum (n=17 patients). TRG scores correlated across disease sites (Spearman correlation coefficients for TRG in the primary tumor and lymph nodes was 0.59 [P=0.005]; for the primary tumor and metastases 0.44 [P=0.021]; and for lymph nodes and metastases 0.58 [P=0.006]). Complete absence or poor tumor response (TRG4/5) was significantly more frequent in primary tumors (35.7%) and locoregional lymph nodes (38%) than in liver metastases (6.9%; McNemar test, P=0.02). Two patients had a complete pathologic response (pT0N0M0). In patients with stage IV colorectal cancer, liver metastases exhibit a better histological response than primary tumors to OCFL neoadjuvant chemotherapy.

Non-Radical Diagnostic Biopsies Do Not Negatively Influence Melanoma Patient Survival

BackgroundIn fair-skinned Caucasian populations both the incidence and mortality rates of cutaneous melanoma have been increasing over the past decades. With adjuvant therapies still being under investigation, early detection is the only way to improve melanoma patient survival. The influence of incisional biopsies on melanoma patient survival has been discussed for many years. This study investigates both the influence of diagnostic biopsy type and the presence of residual tumor cells in the re-excision specimen on disease free and overall survival.MethodsAfter (partial) removal of a pigmented skin lesion 471 patients were diagnosed with stage I/II melanoma and underwent re-excision and a sentinel node biopsy. All patients were followed prospectively, mean follow up >5 years. Patients were divided according to their diagnostic biopsy type (wide excision biopsy, narrow excision biopsy, excision biopsy with positive margins and incisional biopsy) and the presence of residual tumor cells in their re-excision specimen. Survival analysis was done using Cox’s proportional hazard model adjusted for eight important confounders of melanoma patient survival.ResultsThe diagnostic biopsy was wide in 279 patients, narrow in 109 patients, 52 patients underwent an excision biopsy with positive margins and 31 patients an incisional biopsy. In 41 patients residual tumor cells were present in the re-excision specimen. Both the diagnostic biopsy type and the presence of tumor cells in the re-excision specimen did not influence disease free and overall survival of melanoma patients.ConclusionsNon-radical diagnostic biopsies do not negatively influence melanoma patient survival.

Detection of minimal residual disease

A high percentage of patients with leukemia, lymphoma, and solid tumors achieve a complete clinical remission after initial treatment, but the majority of these patients will finally relapse from residual tumor cells detectable in clinical remission only by the most sensitive methods. The in vitro amplification of tumor-specific DNA or RNA sequences by polymerase chain reaction (PCR) allows identification of a few neoplastic cells in 10(4) to 10(6) normal cells. Depending on the underlying malignant disease and therapeutic treatment, the presence of residual tumor cells in an individual patient may herald relapse, but a long-term stable situation or slowly vanishing tumor cells are also possible. Molecular monitoring of residual leukemia and lymphoma cells by quantitative PCR techniques has provided important information about the effectiveness of treatment and the risk of recurrent disease as shown by minimal residual disease (MRD) analysis in patients with various malignant diseases. Such diseases include childhood acute lymphoblastic leukemia, after induction therapy; acute promyelocytic leukemia, during and after chemotherapy; and chronic myelogenous leukemia, during treatment with alpha-interferon and after allogeneic bone marrow transplantation. Evaluation of the predictive value of the detection of MRD has to take into account its evolution and course, the pathogenesis, biology, and natural course of the underlying malignant disease, the molecular genetic lesion, and finally, the type of treatment. Quantification of minimal residual cells by the recently developed real-time quantitative PCR technique will surely have a major impact on our therapeutic strategies for patients with leukemia, lymphomas, and solid tumors. Based on quantitative PCR data, the terms molecular remission and molecular relapse have to be exactly defined and validated in prospective clinical trials to assess the biological and clinical significance of MRD in various types of malignancies.

High Dose Chemotherapy with Autologous Bone Marrow Transplantation for Limited Small Cell Lung Cancer

In 1980 we initiated a pilot study of high dose chemotherapy intensified with autologous bone marrow transplantation (ABMT) for seven patients with limited small cell lung cancer. Six patients were given the ABMT initially while one male patient received the ABMT late to intensify three courses of induction therapy. He further received radiotherapy and underwent a left pneumonectomy and adoptive immunotherapy, because the presence of residual tumor cells, and has maintained disease-free survival for over 117 weeks. Among the first six patients there were two with complete responses, two with partial responses and one who experienced no change, a total response rate of 80%. One patient died of cardiac tamponade at day 7 and could not be evaluated. The median survival time of 41 (range 34-108) weeks was not encouraging. an increased drug dose with ABMT to intensify the chemotherapy provided disappointing results both when the ABMT was used initially and when it was given late, after induction chemotherapy.