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| ID | Type | Description | Link |
|---|---|---|---|
| P30CA036727 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
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RATIONALE: Drugs used in chemotherapy, such as paclitaxel, cyclophosphamide, and doxorubicin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Injecting the patient's dendritic cells directly into the tumor may stimulate the immune system and stop tumor cells from growing. Radiation therapy uses high-energy x-rays to kill tumor cells. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving combination chemotherapy together with autologous dendritic cells before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving radiation therapy and hormone therapy after surgery may kill any tumor cells that remain after surgery.
PURPOSE: This phase II trial is studying the side effects and how well giving paclitaxel together with cyclophosphamide and doxorubicin followed by autologous dendritic cells and surgery with or without radiation therapy and/or hormone therapy works in treating women with stage II or stage III breast cancer.
OBJECTIVES:
OUTLINE: This is an open-label study.
Beginning 2 weeks after completion of paclitaxel chemotherapy, patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1 and G-CSF SC on days 4-14 or pegfilgrastim SC on day 2. Treatment repeats every 2 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
Peripheral blood samples are obtained during each DC injection, at staging/biopsy, and then periodically for up to 2 years. Blood samples are analyzed by ELISPOT and ELISA assays for evaluation of immune response.
Tumor tissue is obtained by core biopsy of the breast primary and/or palpable axillary lymph node at baseline and again after completion of paclitaxel chemotherapy. Tumor tissue is analyzed by IHC and RT-PCR for COX-2 and VEGF-A and -C expression levels, as well as T-cell and DC infiltration of the tumor. T-cell and DC infiltration is evaluated for correlation with clinical outcomes at diagnosis, at the midpoint biopsy following paclitaxel chemotherapy, and at definitive surgery.
After completion of study therapy, patients are followed periodically for up to 2 years.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Vaccine | Experimental | Patients with HER-2/neu negative tumors will receive IT DCs one week after the first three of four cycles of dose dense T therapy and then four cycles of dose dense AC therapy will be given (i.e. T-AC). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| therapeutic autologous dendritic cells | Biological | injected into the primary breast mass or palpable axillary node, one week after the first, second and third T treatments. If, after a cycle(s) of chemotherapy, no tumor can be localized by ultrasound, the DCs will be injected where the tumor bed was localized by the clip or marker. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Patients With Pathological Complete Response | Assessed by the institutional pathologist.
| At definitive surgery. |
| Measure | Description | Time Frame |
|---|---|---|
| Inflammatory Cell Infiltration | T cell response to tumor-specific Ag, will be measured by ELISPOT assay with a biologic response defined as double the average ELISPOT reactivity in post-vaccination peripheral blood (PB) compared to pre-vaccination PB. | Post-vaccination peripheral blood (PB) after the last chemotherapy. |
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Inclusion Criteria:
Histologically confirmed invasive breast cancer meeting the following criteria:
HER2/neu-negative tumor by IHC
o If 2+ or in the indeterminate range, further testing of HER2/neu overexpression by fluorescent in situ hybridization (FISH) is required
Hormone receptor status known
Female
Pre-, peri-, or postmenopausal
ECOG performance status 0-1
Fertile patients must use effective contraception during and for up to 6 months following completion of study therapy
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN)
Total bilirubin ≤ 1.5 times ULN
AST and ALT ≤ 1.5 times ULN
Creatinine < 1.5 times ULN
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Elizabeth C Reed, MD | University of Nebraska | Principal Investigator |
| Kenneth H Cowan, MD, PhD | University of Nebraska | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| H. Lee Moffitt Cancer Center and Research Institute, University of South Florida | Tampa | Florida | 33612-9497 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 35135810 | Derived | Hong WX, Sagiv-Barfi I, Czerwinski DK, Sallets A, Levy R. Neoadjuvant Intratumoral Immunotherapy with TLR9 Activation and Anti-OX40 Antibody Eradicates Metastatic Cancer. Cancer Res. 2022 Apr 1;82(7):1396-1408. doi: 10.1158/0008-5472.CAN-21-1382. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Vaccine | Patients with HER-2/neu negative tumors received therapeutic autologous dendritic cells: injected into the primary breast mass or palpable axillary node, one week after the first, second and third T treatments. Adjuvant hormone therapy for patients having tumors with estrogen and/or progesterone receptors. Premenopausal patients will be treated with tamoxifen. Post or perimenopausal women may receive tamoxifen or an aromatase inhibitor. Patients received 4 cycles of paclitaxel: 175 mg/m2 (IV), followed by 4 cycles of cyclophosphamide: 600 mg/m2 IV and doxorubicin hydrochloride: 60 mg/m2 IV in a bi-weekly dose dense fashion All patients had pre-treatment biopsy and second tumor biopsy after 4 cycles of paclitaxel to evaluate responses to the dendritic cell injections. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| aromatase inhibition therapy | Drug | Adjuvant hormone therapy for patients having tumors with estrogen and/or progesterone receptors. Premenopausal patients will be treated with tamoxifen. Post or perimenopausal women may receive tamoxifen or an aromatase inhibitor (AI) or those drugs in sequence as determined by the treating oncologist. Hormone therapy will be given for at least 5 years. |
|
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| cyclophosphamide | Drug | 600 mg/m2 IV day 1 every 2 weeks for 4 cycles |
|
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| doxorubicin hydrochloride | Drug | 60 mg/m2 IV day 1 every 2 weeks for 4 cycles |
|
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| paclitaxel | Drug | 175 mg/m2 intravenously (IV) over at least 3 hours day 1 every 2 weeks for 4 cycles. |
|
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| tamoxifen citrate | Drug | Adjuvant hormone therapy for patients having tumors with estrogen and/or progesterone receptors. Premenopausal patients will be treated with tamoxifen. Post or perimenopausal women may receive tamoxifen or an aromatase inhibitor (AI) or those drugs in sequence as determined by the treating oncologist. Hormone therapy will be given for at least 5 years. |
|
|
| gene expression analysis | Genetic | IHC for CEA and Survivin with appropriate controls will be done on the tumor biopsy material (preferably from the initial diagnostic biopsy). |
|
| protein expression analysis | Genetic | Tumor biopsymaterial (preferably from the initial diagnostic biopsy) will be stained by IHC with appropriate controls for COX-2, VEGF A, T cell and Dendritic Cell infiltration. |
|
| reverse transcriptase-polymerase chain reaction | Genetic | delta Ct (quantitative real time- reverse transcription-polymerase chain reaction (qRT-PCR)) of COX-2 and VEGF will be divided into the upper or lower median and Fisher Exact test used to assess the difference in response. |
|
| immunoenzyme technique | Other | Estrogen and progesterone receptor, Her2/neu testing: Tumor biopsy material (preferably the initial diagnostic biopsy if tissue is available) will be examined by Immunohistochemistry (IHC) with appropriate controls for estrogen, progesterone receptors and Her2/neu. If the IHC is 2+ or in the indeterminate range, further testing of over-expression of Her2/neu by fluorescent in situ hybridization (FISH) will be done . If this has already been done and reported by the referring hospital, it will not be repeated. These tests are standard of care. CEA and Survivin testing: IHC for CEA and Survivin with appropriate controls will be done on the tumor biopsy material (preferably from the initial diagnostic biopsy). COX-2 and VEGF A , T cell and Dendritic Cells: Tumor biopsymaterial (preferably from the initial diagnostic biopsy) will be stained by IHC with appropriate controls for COX-2, VEGF A, T cell and Dendritic Cell infiltration. |
|
| immunohistochemistry staining method | Other | Estrogen and progesterone receptor, Her2/neu testing: Tumor biopsy material (preferably the initial diagnostic biopsy if tissue is available) will be examined by Immunohistochemistry (IHC) with appropriate controls for estrogen, progesterone receptors and Her2/neu. If the IHC is 2+ or in the indeterminate range, further testing of over-expression of Her2/neu by fluorescent in situ hybridization (FISH) will be done . If this has already been done and reported by the referring hospital, it will not be repeated. These tests are standard of care. CEA and Survivin testing: IHC for CEA and Survivin with appropriate controls will be done on the tumor biopsy material (preferably from the initial diagnostic biopsy). COX-2 and VEGF A , T cell and Dendritic Cells: Tumor biopsymaterial (preferably from the initial diagnostic biopsy) will be stained by IHC with appropriate controls for COX-2, VEGF A, T cell and Dendritic Cell infiltration. |
|
| laboratory biomarker analysis | Other | Estrogen and progesterone receptor, Her2/neu testing: Tumor biopsy material (preferably the initial diagnostic biopsy if tissue is available) will be examined by Immunohistochemistry (IHC) with appropriate controls for estrogen, progesterone receptors and Her2/neu. If the IHC is 2+ or in the indeterminate range, further testing of over-expression of Her2/neu by fluorescent in situ hybridization (FISH) will be done . If this has already been done and reported by the referring hospital, it will not be repeated. These tests are standard of care. CEA and Survivin testing: IHC for CEA and Survivin with appropriate controls will be done on the tumor biopsy material (preferably from the initial diagnostic biopsy). COX-2 and VEGF A , T cell and Dendritic Cells: Tumor biopsymaterial (preferably from the initial diagnostic biopsy) will be stained by IHC with appropriate controls for COX-2, VEGF A, T cell and Dendritic Cell infiltration. |
|
| adjuvant therapy | Procedure | Hormone manipulation Adjuvant hormone therapy for patients having tumors with estrogen and/or progesterone receptors. Premenopausal patients will be treated with tamoxifen. Post or perimenopausal women may receive tamoxifen or an aromatase inhibitor (AI) or those drugs in sequence as determined by the treating oncologist. Hormone therapy will be given for at least 5 years. |
|
| biopsy | Procedure | Two tumor biopsies will be performed. The first tumor biopsy will be performed before apheresis for diagnostic purposes, and again after completion of the first four chemotherapy treatments. Patients will undergo local anesthesia with lidocaine and 1% epinephrine followed by 1-2 core biopsies of the breast primary and/or palpable axillary node with a 14 gauge, 16 cm. Bard needle or other similar needle. The procedure may be done under ultrasound guidance. If a metal clip or marker has not been previously placed in the tumor, it will be placed before treatment. |
|
| conventional surgery | Procedure | Definitive breast surgery Surgery will occur two to four weeks after the last course of chemotherapy. Modified radical mastectomy or lumpectomy and standard axillary dissection could be performed and the specific procedure will be decided by the patient and physician team. If a sentinel node dissection was done prior to chemotherapy and was negative, no further node dissection is necessary. A standard node dissection will be necessary if no node assessment was done prior to chemotherapy or if the pre- chemotherapy sentinel node was positive. |
|
| neoadjuvant therapy | Procedure | Chemotherapy: Paclitaxel (T) 175 mg/m2 intravenously (IV) over at least 3 hours day 1. Repeat every 2 weeks for 4 cycles. IT DCs will be injected into the primary breast mass or palpable axillary node, one week after the first, second and third T treatments. |
|
| radiation therapy | Radiation | Radiation therapy Radiation is started two to four weeks after surgery for all patients receiving lumpectomy and those patients after mastectomy that the physician feels chest wall radiation is warranted (example: T3 or T4 breast lesion, four or more axillary nodes etc.). The exact doses and methods of administration will be determined by the treating radiation therapist, but should be standard breast radiotherapy and not partial breast or investigational methods. |
|
| Antibody-dependent Cell-mediated Cytotoxicity |
T cell response to tumor-specific Ag, will be measured by ELISPOT assay with a biologic response defined as double the average ELISPOT reactivity in post-vaccination peripheral blood (PB) compared to pre-vaccination PB. |
| Post-vaccination peripheral blood (PB) after the last chemotherapy. |
| Influence of Tumor COX-2 and VEGF Expression on Dendritic Cell-mediated Tumor-specific Immunity | T cell response to tumor-specific Ag, will be measured by ELISPOT assay with a biologic response defined as double the average ELISPOT reactivity in post-vaccination peripheral blood (PB) compared to pre-vaccination PB. | Post-vaccination peripheral blood (PB) after the last chemotherapy. |
| Eppley Cancer Center, University of Nebraska Medical Center |
| Omaha |
| Nebraska |
| 68198-6805 |
| United States |
| Participants at UNMC |
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| Participants at Moffitt Cancer Center |
|
| COMPLETED |
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| NOT COMPLETED |
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Numbers are based on number of evaluable participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Vaccine | Patients with HER-2/neu negative tumors received therapeutic autologous dendritic cells: injected into the primary breast mass or palpable axillary node, one week after the first, second and third T treatments. Adjuvant hormone therapy for patients having tumors with estrogen and/or progesterone receptors. Premenopausal patients will be treated with tamoxifen. Post or perimenopausal women may receive tamoxifen or an aromatase inhibitor. Patients received 4 cycles of paclitaxel: 175 mg/m2 (IV), followed by 4 cycles of cyclophosphamide: 600 mg/m2 IV and doxorubicin hydrochloride: 60 mg/m2 IV in a bi-weekly dose dense fashion All patients had pre-treatment biopsy and second tumor biopsy after 4 cycles of paclitaxel to evaluate responses to the dendritic cell injections. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median | Full Range | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Patients With Pathological Complete Response | Assessed by the institutional pathologist.
| Posted | Number | participants | At definitive surgery. |
|
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| |||||||||||||||||||||||||||
| Secondary | Inflammatory Cell Infiltration | T cell response to tumor-specific Ag, will be measured by ELISPOT assay with a biologic response defined as double the average ELISPOT reactivity in post-vaccination peripheral blood (PB) compared to pre-vaccination PB. | Evaluation of this data is unknown as was not provided by collaborating center performing the analysis. | Posted | Post-vaccination peripheral blood (PB) after the last chemotherapy. |
|
| |||||||||||||||||||||||||||||
| Secondary | Antibody-dependent Cell-mediated Cytotoxicity | T cell response to tumor-specific Ag, will be measured by ELISPOT assay with a biologic response defined as double the average ELISPOT reactivity in post-vaccination peripheral blood (PB) compared to pre-vaccination PB. | Evaluation of this data is unknown as was not provided by collaborating center performing the analysis. | Posted | Post-vaccination peripheral blood (PB) after the last chemotherapy. |
|
| |||||||||||||||||||||||||||||
| Secondary | Influence of Tumor COX-2 and VEGF Expression on Dendritic Cell-mediated Tumor-specific Immunity | T cell response to tumor-specific Ag, will be measured by ELISPOT assay with a biologic response defined as double the average ELISPOT reactivity in post-vaccination peripheral blood (PB) compared to pre-vaccination PB. | Evaluation of this data is unknown as was not provided by collaborating center performing the analysis. | Posted | Post-vaccination peripheral blood (PB) after the last chemotherapy. |
|
|
Adverse events were collected from the time of when patients consented to the study until 30 day after completion of the study treatment, up to 6 months.
Grade 3/4 toxicities were collected for this study. Complete evaluation of this data is unknown. We only have adverse event data from UNMC.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Vaccine | Patients with HER-2/neu negative tumors received therapeutic autologous dendritic cells: injected into the primary breast mass or palpable axillary node, one week after the first, second and third T treatments. Adjuvant hormone therapy for patients having tumors with estrogen and/or progesterone receptors. Premenopausal patients will be treated with tamoxifen. Post or perimenopausal women may receive tamoxifen or an aromatase inhibitor. Patients received 4 cycles of paclitaxel: 175 mg/m2 (IV), followed by 4 cycles of cyclophosphamide: 600 mg/m2 IV and doxorubicin hydrochloride: 60 mg/m2 IV in a bi-weekly dose dense fashion All patients had pre-treatment biopsy and second tumor biopsy after 4 cycles of paclitaxel to evaluate responses to the dendritic cell injections. | 0 | 3 | 1 | 3 | 3 | 3 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thromboembolic event | Vascular disorders | CTCAE (3.0) | Systematic Assessment |
| |
| hypokalemia | Metabolism and nutrition disorders | CTCAE (3.0) | Systematic Assessment |
| |
| mucositis oral | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
| |
| palmar-plantar erythrodysesthesia | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Systematic Assessment |
| |
| bone pain | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | Systematic Assessment |
| |
| white blood cell decreased | Investigations | CTCAE (3.0) | Systematic Assessment |
| |
| neutrophil count decreased | Investigations | CTCAE (3.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Elizabeth Reed | University of Nebraska Medical Center | 402-559-5166 | ereed@unmc.edu |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
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| ID | Term |
|---|---|
| D047072 | Aromatase Inhibitors |
| D003520 | Cyclophosphamide |
| D004317 | Doxorubicin |
| C506643 | liposomal doxorubicin |
| D017239 | Paclitaxel |
| D000068196 | Albumin-Bound Paclitaxel |
| D013629 | Tamoxifen |
| D020869 | Gene Expression Profiling |
| D020133 | Reverse Transcriptase Polymerase Chain Reaction |
| D007124 | Immunoenzyme Techniques |
| D007150 | Immunohistochemistry |
| D017024 | Chemotherapy, Adjuvant |
| D001706 | Biopsy |
| D020360 | Neoadjuvant Therapy |
| D011878 | Radiotherapy |
| ID | Term |
|---|---|
| D065088 | Steroid Synthesis Inhibitors |
| D004791 | Enzyme Inhibitors |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D004965 | Estrogen Antagonists |
| D006727 | Hormone Antagonists |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045505 | Physiological Effects of Drugs |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D003630 | Daunorubicin |
| D018943 | Anthracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D011083 | Polycyclic Compounds |
| D000617 | Aminoglycosides |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D043823 | Taxoids |
| D043822 | Cyclodecanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D004224 | Diterpenes |
| D013729 | Terpenes |
| D000418 | Albumins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D013267 | Stilbenes |
| D001597 | Benzylidene Compounds |
| D001555 | Benzene Derivatives |
| D005821 | Genetic Techniques |
| D008919 | Investigative Techniques |
| D016133 | Polymerase Chain Reaction |
| D021141 | Nucleic Acid Amplification Techniques |
| D007118 | Immunoassay |
| D007158 | Immunologic Techniques |
| D015336 | Molecular Probe Techniques |
| D006651 | Histocytochemistry |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D006652 | Histological Techniques |
| D003131 | Combined Modality Therapy |
| D013812 | Therapeutics |
| D004358 | Drug Therapy |
| D003581 | Cytodiagnosis |
| D013048 | Specimen Handling |
| D003949 | Diagnostic Techniques, Surgical |
| D013514 | Surgical Procedures, Operative |
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|