Histopathologic changes following neoadjuvant chemotherapy in various malignancies

Sethi, Divya; Sen, Rajeev; Parshad, Sanjeev; Khetarpal, Sheena; Garg, Monika; Sen, Jyotsna

doi:10.4103/2229-516x.106353

Cited by 49 publications

(47 citation statements)

References 11 publications

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“…Differentiation after DNA-damaging therapies has been observed in diverse cancers [42, 43]. We show that the combination of genotoxic stress, functional p53 and impaired apoptosis is sufficient to induce abundant differentiation, as xRT provoked neural differentiation in tumors with intact p53 and Bax deletion.…”

Section: Discussionmentioning

confidence: 78%

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway

et al. 2016

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While treatments that induce DNA damage are commonly used as anti-cancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiation therapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine if the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that p53 was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies because they retain apoptosis competence.

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Section: Discussionmentioning

confidence: 78%

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway

et al. 2016

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“…More detectable changes in mean values of MBF, SI parametric maps were observed at week 8. These findings suggests that development of response in tumor cells is a gradual process which initially affects tissue micro-structure arrangement such as the spacing between lobules and later affects macro-structure such as lobule size, shape and their elastic properties and finally replaced with collagen and fibrotic deposition which reflect longer-term results of cell death process [ 33 ]. Ali et al [ 16 ] reported R and NR classification with the sensitivity 100% and specificity 100% early after NAC using combined mean QUS values and texture features.…”

Section: Discussionmentioning

confidence: 99%

Response monitoring of breast cancer patients receiving neoadjuvant chemotherapy using quantitative ultrasound, texture, and molecular features

et al. 2018

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BackgroundPathological response of breast cancer to chemotherapy is a prognostic indicator for long-term disease free and overall survival. Responses of locally advanced breast cancer in the neoadjuvant chemotherapy (NAC) settings are often variable, and the prediction of response is imperfect. The purpose of this study was to detect primary tumor responses early after the start of neoadjuvant chemotherapy using quantitative ultrasound (QUS), textural analysis and molecular features in patients with locally advanced breast cancer.MethodsThe study included ninety six patients treated with neoadjuvant chemotherapy. Breast tumors were scanned with a clinical ultrasound system prior to chemotherapy treatment, during the first, fourth and eighth week of treatment, and prior to surgery. Quantitative ultrasound parameters and scatterer-based features were calculated from ultrasound radio frequency (RF) data within tumor regions of interest. Additionally, texture features were extracted from QUS parametric maps. Prior to therapy, all patients underwent a core needle biopsy and histological subtypes and biomarker ER, PR, and HER2 status were determined. Patients were classified into three treatment response groups based on combination of clinical and pathological analyses: complete responders (CR), partial responders (PR), and non-responders (NR). Response classifications from QUS parameters, receptors status and pathological were compared. Discriminant analysis was performed on extracted parameters using a support vector machine classifier to categorize subjects into CR, PR, and NR groups at all scan times.ResultsOf the 96 patients, the number of CR, PR and NR patients were 21, 52, and 23, respectively. The best prediction of treatment response was achieved with the combination mean QUS values, texture and molecular features with accuracies of 78%, 86% and 83% at weeks 1, 4, and 8, after treatment respectively. Mean QUS parameters or clinical receptors status alone predicted the three response groups with accuracies less than 60% at all scan time points. Recurrence free survival (RFS) of response groups determined based on combined features followed similar trend as determined based on clinical and pathology.ConclusionsThis work demonstrates the potential of using QUS, texture and molecular features for predicting the response of primary breast tumors to chemotherapy early, and guiding the treatment planning of refractory patients.

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“…Previously, using SHG imaging, Wu et al demonstrated on ex vivo samples of patients' breast tissue that tumors underwent a fibrosis reaction, in which the tumor cells were replaced by collagen fibers post-chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (16). Sethi et al observed collagenization in the breast tumor stroma following neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, and 5-fluorouracil, or cyclophosphamide, epirubicin, and 5-fluorouracil), that significantly correlated to the pathological response and grade of tumor regression (31). Tumor replacement by loose fibrosis after neoadjuvant chemotherapy (cyclophosphamide, methotrexate, fluouracile) was identified in breast cancer in (32).…”

Section: Discussionmentioning

confidence: 99%

In vivo metabolic and SHG imaging for monitoring of tumor response to chemotherapy

et al. 2018

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Although chemotherapy remains one of the main types of treatment for cancer, treatment failure is a frequent occurrence, emphasizing the need for new approaches to the early assessment of tumor response. The aim of this study was to search for indicators based on optical imaging of cellular metabolism and of collagen in tumors in vivo that enable evaluation of their response to chemotherapy. The study was performed on a mouse colorectal cancer model with the use of cisplatin, paclitaxel, and irinotecan. The metabolic activity of the tumor cells was assessed using fluorescence lifetime imaging of the metabolic cofactor reduced nicotinamide adenine dinucleotide (phosphate), NAD(P)H. Second harmonic generation (SHG) imaging was used to analyze the extent and properties of collagen within the tumors. We detected an early decrease in the free/bound NAD(P)H ratio in all treated tumors, indicating a shift toward a more oxidative metabolism. Monitoring of collagen showed an early increase in the amount of collagen followed by an increase in the extent of its orientation in tumors treated with cisplatin and paclitaxel, and decrease in collagen content in the case of irinotecan. Our study suggests that changes in cellular metabolism and fibrotic stroma organization precede morphological alterations and tumor size reduction, and that this indicates that NAD(P)H and collagen can be considered as intrinsic indicators of the response to treatment. This is the first time that these parameters have been investigated in tumors in vivo in the course of chemotherapy with drugs having different mechanisms of action.COLORECTAL cancer is one of the most common cancers in the world. The current standard treatments for colorectal cancer include surgery, radiation therapy, and chemotherapy. Treatment options and recommendations depend on several factors, such as the type and stage of the cancer, possible side effects, and the patient's preferences and overall health.In standard clinical practice neoadjuvant chemotherapy is used for patients with stage II and III сolorectal cancer to facilitate resection of those tumors that were once considered unresectable. Adjuvant chemotherapy is recommended for Stage III colorectal cancer after resection to prevent tumor recurrence and the development of metastases (1). When resection of all known tumor sites is no longer possible or advisable, palliative care is offered. Current guidelines on the chemotherapy of сolorectal cancer prescribe the use of platinum drugs (oxaliplatin, cisplatin, or similar), or irinotecan in various combinations with a fluoropyrimidine (capecitabine or 5-fluorouracil). Additionally, paclitaxel can be used for chemotherapy of colorectal cancer in combination with 5-fluorouracil.

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Histopathologic changes following neoadjuvant chemotherapy in various malignancies

Cited by 49 publications

References 11 publications

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway

Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway

Response monitoring of breast cancer patients receiving neoadjuvant chemotherapy using quantitative ultrasound, texture, and molecular features

In vivo metabolic and SHG imaging for monitoring of tumor response to chemotherapy

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