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Leiomyoma

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Neoplastic Syndromes, Hereditary

Renal Cell Carcinoma

Hereditary Leiomyomatosis and Renal Cell Cancer

Joshua Mann, MPH

MyVHL is a multi-patient database which helps researchers identify patterns across VHL patients. MyVHL provides you -and researchers -with more complete information about VHL, like how your lifestyle, medications, and other factors impact the disease and quality of life. These insights help you better understand the condition and help researchers know where to focus their efforts.

Due to its rarity, there is less understanding of VHL and the factors that may have an impact. The data individuals provide in MyVHL helps researchers identify and uncover factors that may increase risk, inhibit or slow tumor growth, or lead to an effective cure.

MyVHL: Patient Natural History Study

When participant information is stored, the investigators are careful to protect any patient identifying information from discovery by others. Strict security safeguards are in place to reduce the chance of misuse or unplanned release of information.

Researchers will only use participant information in a de-identified manner. De-identified means that the researchers will use participant information without knowing their identity. In some cases, they may use some identifying information about the participant for research purposes, subject to an approval process through the VHL Alliance MyVHL Research Committee. At times, the researchers will use participant information with a code, instead of their name; the code would allow results of the research to be linked back to the participant.

Data regarding changes in number of CNS, kidney, adrenal, retinal, ear, and pancreatic tumors, along with cystadenomas and lesions in the lungs, liver and skin, over a lifetime.

Data regarding changes in size of CNS, kidney, adrenal, retinal, ear, and pancreatic tumors, along with cystadenomas and lesions in the lungs, liver and skin, over a lifetime.

National Organization for Rare Disorders

Director of Health

Pain

Neoplasms, Connective Tissue

Connective Tissue Diseases

All Drugs and Chemicals

Vasodilator Agents

Botulinum Toxins

Botulinum Toxins, Type A

abobotulinumtoxinA

Acetylcholine

Cholinergic Agents

Neurotransmitter Agents

Botulinum toxin type A

Placebo

Edward W Cowen, M.D.

Cutaneous leiomyomas are benign tumors of smooth muscle origin. They can be very painful, and current treatments for the tumors and for the associated pain do not produce satisfactory results. One potential treatment for localized severe muscle pain involves injections with botulinum toxin A. This study will investigate the effectiveness, side effects, and dosage of botulinum toxin A (BOTOX) as a treatment for patients with pain associated with cutaneous leiomyomas.

This study will include 18 subjects, all of whom will be 18 years of age and older, who have pain associated with cutaneous leiomyomas.

For the 24-week study, patients will be randomly assigned to one of two treatment groups. Neither the study team nor the patient will know to which group patients have been assigned. Before the study begins, all participants must provide a full medical history for research and evaluation purposes, fill out pain and quality-of-life questionnaires, and undergo an ice test in which researchers will apply ice to the site of the cutaneous leiomyomas and ask participants to evaluate the level of pain before and after ice application. Both groups will be required to keep a pain diary throughout the study to record their level of pain on a daily basis, and will be asked to avoid or restrict the use of specific medications or other remedies to treat the pain.

At the first visit (Week 0), one group will receive a prescribed dose of botulinum toxin A, which will be administered as an injection into the leiomyoma, and the other (control) group will receive a placebo injection of a saline solution. Patients will return 4 weeks later, at which time they will undergo a medical examination, and the ice test, and complete questionnaires to assess responses and level of pain. Patients will return in Week 12, at which time the group assignment will be revealed (un-blinded) to investigators and patients. Patients who received placebo injections will be offered the opportunity to receive injection of botulinum toxin A into their leiomyomas. All patients will undergo a medical examination, the ice test, complete questionnaires, and continue completing their daily pain diaries at home. The final visit, in Week 24, will follow the same procedure as the Week 4 visit.

At the end of the study, patients may be eligible to have one or more of the painful cutaneous leiomyomas surgically removed if the researchers believe that the skin lesions can be removed with a reasonable cosmetic result.

Background:

* Cutaneous leiomyomas are smooth muscle tumors that may arise sporadically or in association with an inherited cancer-related genodermatosis.
* Leiomyomas may be severely painful, and current management is generally unsatisfactory.
* Studies demonstrate increased nerve density within and around leiomyomas as well as increased acetylcholinesterase staining of associated nerves.
* Botulinum toxin-A has been used in the treatment of pain syndromes.
* Based on the known mechanisms of action of botulinum toxin-A, treatment with botulinum toxin-A (BOTOX; Allergan, Inc.), may ameliorate the severe paroxysmal pain of symptomatic cutaneous leiomyomas.

Objectives:

* Primary: To assess change in worst lesional pain in the past week based on Brief Pain Inventory (BPI) from Week 0 to Week 4 in treated patients versus controls.
* Primary: To assess improvement in pain based on Visual Analog Scale (VAS) after application of ice at Week 4 compared to baseline in treated patients versus controls.
* Secondary: To assess change in magnitude and in frequency of painful episodes based on a weekly patient diary in treated patients versus controls.
* Secondary: To assess persistence of pain control at Weeks 12 based on the BPI and VAS.
* Secondary: To assess the frequency of rescue pain medication use in treated patients versus controls during the 24 week study period.
* Secondary: To determine the impact of leiomyoma treatment on quality of life.
* Secondary: To assess change in patient s condition based on the Patient Global Impression of Change.
* Secondary: To evaluate the immunohistochemical staining of nerve fibers and muscle in cutaneous leiomyomas in control and treated lesions following the conclusion of the study.

Eligibility:

* Subjects greater than or equal to18 years with at least 1 symptomatic cutaneous leiomyoma.
* Pain symptoms must occur at least once a week and be characterized as greater than or equal to 5 out of 10.

Design:

* A 12-week double-blind placebo controlled pilot study of 18 subjects with symptomatic leiomyomas will include initial assessment with BPI, photography, and skin biopsies, followed by treatment of subjects who initially received placebo.
* Cutaneous leiomyomas will undergo intralesional injection with botulinum toxin-A.
* Subjects will return at Weeks 4 and 12 for repeat assessment using pain and quality of life questionnaires and photography. Skin biopsies will be performed at week 12.

Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin

Change in worst lesional pain in the past week based on Brief Pain Inventory (BPI) from Week 0 to Week 4 in treated patients versus controls. The BPI uses an arbitrary units on a 0-10 scale. For the purposes of the statistical calculation, a difference of 1 standard deviation between groups at baseline vs. week 4 was considered significant. Any BPI value above zero (no pain) is abnormal. The mean change indicates mean change in pain score.

Change in average pain was assessed by the Brief Pain Inventory (BPI). The BPI is a validated pain assessment tool that assesses severity of pain, location of pain, impact of pain on daily functions, pain medications, and amount of pain relief in the past 24 hours or past week (e.g. scale of 0-10 (worst pain)).

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

The VAS is a commonly used validated tool for assessment of pain. For this measure, a 10-cm VAS was used to assess current patient pain/discomfort before application of ice to study lesions at week 0 and week 4. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Range is 0-10; 0 is no pain and 10 is worst possible pain.

The DLQI is a 10-question quality of life survey which has been extensively validated and frequently used in dermatologic disorders such as atopic dermatitis, acne, and psoriasis. Score is 0-30 based on 10 questions. The higher the score, the more quality of life is impaired.

The DLQI is a 10-question quality of life survey which has been extensively validated and frequently used in dermatologic disorders such as atopic dermatitis, acne, and psoriasis. Participants response to the question "Over the last week, how itchy, sore, painful or stinging has your skin been?" was assessed by the Dermatology Life Quality Index. This outcome refers to a single specific question on the DLQI, so the range for this outcome is 0-3. Lower values in the DLQI indicate less impairment (or greater improvement) in life quality from the skin disease.

The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale is 0-10. 10 denotes worse pain than 0.

AchE staining was scored as 0 (none), 1 (rare), 2 (scattered), or 3 (focal or greater).

c-fos, a marker of neuronal activation after pain stimulation, was scored as 0 (none), 1 (scattered), 2 (\<66% of tumor cells), or 3 (≥66% of tumor cells).

Average pain was determined from a 0-10 scale question on the Brief Pain Inventory (BPI). 10 denotes worse pain.

The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale of 0-10. 10 = worse pain.

The VAS is a commonly used validated tool for assessment of pain. The 10-cm VAS was used to assess current patient pain/discomfort before and after application of ice to study lesions. A clinically meaningful change in chronic pain intensity using the VAS has been determined as a reduction of 2 points or 30%. Scale is 0-10. 10 = worse pain.

Pain severity was assessed by the Brief Pain Inventory (BPI). The BPI is a validated pain assessment tool that assesses severity of pain, location of pain, impact of pain on daily functions, pain medications, and amount of pain relief in the past 24 hours or past week (e.g. scale of 0-10 (worst pain)). This outcome was based on a single 0-10 question on the BPI.

National Cancer Institute (NCI)

Principal Investigator

There are no unexpected adverse events at grade 2 or higher.

BTX-A

Placebo/Saline

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Single

Segmental

Disseminated

Leiomyoma Distribution

Neck

Torso

Extremity

Location of Lesions

Volume of Drug Administered

Dr. Edward Cowen

Change in Worst Lesional Pain in the Past Week Based on Brief Pain Inventory

Median Change in Average Pain Between Two Arms

Number of Participants With Adverse Events

Visual Analog Scale (VAS) of Patient Perceived Pain at Leiomyoma Site Prior to Ice Provocation at Week 0 vs. Week 4

Comparison of Change in Skin Related Quality of Life by Total Dermatology Life Quality Index (DLQI) at Week 0 vs. Week 4

Specific Skin Pain-Related Question on the Dermatology Life Quality Index

Change in Post-Ice Provocation Visual Analog Score (VAS) Between Week 12 and Week 24

Immunohistochemical Staining of Cutaneous Leiomyomas for Acetylcholinesterase (AchE) Before (i.e.,Week 0) and 12 Weeks After Botulinum Toxin Administration

Immunohistochemical Staining of Cutaneous Leiomyomas for C-fos Before (i.e., Week 0) and 12 Weeks After Botulinum Toxin Administration

>50% pain reduction

≤50% pain reduction

No change in pain

Increased pain

Missing

Percentage of Patients With a Change in Average Pain Score

Percentage of Patients With a Change in Pre-Ice Visual Analog Score (VAS) Between Week 0 and Week 4

Percentage of Patients With a Change in Post-Ice Visual Analog Score (VAS) Between Week 0 and Week 4

Worst Pain Severity

Overall Study

Carcinoma, Transitional Cell

Adenocarcinoma, Clear Cell

Adenomyoepithelioma

Clear Cell Renal Cell Carcinoma

Transitional Cell Carcinoma

Papillary Renal Cell Carcinoma

Chromophil Renal Cell Carcinoma

Chromophobe Renal Cell Carcinoma

Epithelial-myoepithelial Carcinoma

Fumarase Deficiency

Pharmaceutical Solutions

Amino Acids

Glutamine

Patients in the 13C-glucose arm will receive an infusion of a 13C-glucose solution. In most cases, the glucose infusion will be administered for 2-3 hours prior to resection of the mass. During the surgical procedure, 2-4mL of blood will be obtained approximately every 30 minutes to monitor blood glucose and/or blood pH. The infusion will be stopped after resection.

13C-Glucose

Patients in the 13C-acetate arm will receive an infusion of a 13C-acetate solution. In most cases, the acetate infusion will be administered for 2-3 hours prior to resection of the mass. During the surgical procedure, 2-4mL of blood will be obtained approximately every 30 minutes to monitor blood glucose and/or blood pH. The infusion will be stopped after resection.

13C-Acetate

Patients in the 13C-lactate arm will receive an infusion of a 13C-lactate solution. In most cases, the lactate infusion will be administered for 2-3 hours prior to resection of the mass. During the surgical procedure, 2-4mL of blood will be obtained approximately every 30 minutes to monitor blood glucose and/or blood pH. The infusion will be stopped after resection.

13C-Lactate

Patients in the 13C-glutamine arm will receive an infusion of a 13C-glutamine solution. In most cases, the glutamine infusion will be administered for 2-3 hours prior to resection of the mass. During the surgical procedure, 2-4mL of blood will be obtained approximately every 30 minutes to monitor blood glucose and/or blood pH. The infusion will be stopped after resection.

13C-Glutamine

Patients in the 13C-fructose arm will receive an infusion of a 13C-fructose solution. In most cases, the fructose infusion will be administered for 2-3 hours prior to resection of the mass. During the surgical procedure, 2-4mL of blood will be obtained approximately every 30 minutes to monitor blood glucose and/or blood pH. The infusion will be stopped after resection.

13C-Fructose

Vitaly Margulis, MD

Ralph J DeBerardinis, MD, PhD

Vitaly Margulis

The purpose of this study is to understand the metabolism of cancers involving the kidney, including renal cell carcinomas and urothelial cell carcinomas, and how kidney cancers use different types of fuel to support tumor growth. This study uses specially labeled nutrient tracers of compounds normally found circulating in the blood. The nutrients (glucose, fructose, glutamine, acetate, and lactate) are also found in common foods. A nutrient tracer will be given to the participants through an intravenous (IV) catheter during surgery or biopsy, and blood will be collected every 30 minutes during the infusion to monitor safety parameters and the nutrient tracers. The investigators will collect a tissue sample after the completion of surgery. Participants not having an infusion will have their tissue collected after surgery or biopsy.

Participation in this study will not change patient care. All patients will receive standard of care treatment as determined by their doctors.

The purpose of this study is to understand the metabolism of kidney cancers (renal cell carcinomas and urothelial cell carcinomas involving the kidney) in patients. Metabolism is the term used to describe how cells take up different nutrients and convert them to energy and materials needed for cell growth. In cancer, metabolism is hijacked to support the needs of cancer cells. Cancer cells can use multiple nutrients in the blood to fuel their growth, but it is not known what materials cancer cells make with those nutrients in patients.

Many participants in this study will be infused with a 13C-labeled nutrient during their surgery or biopsy. 13C means that the carbon in the nutrient is heavier than 12C carbons that are the most abundant carbon atoms in nature. 13C carbons account for about 1% of natural carbon atoms are not radioactive or harmful in any way. Using the tissue collected during or after surgery and/or biopsy, the researchers can track how the heavier 13C carbons from the infused nutrient are being used to make different materials that cancer cells need to grow.

The researchers hope to understand how kidney cancers change their metabolism to adapt, grow, and survive in patients. The knowledge learned from this study will be used to support the development of therapies that target metabolic adaptations, and the development of new non-invasive imaging techniques that will improve the care and survival of future kidney cancer patients.

An Investigation of Kidney and Urothelial Tumor Metabolism in Patients Undergoing Surgical Resection and/or Biopsy

Tissue and blood samples will be analyzed for 13C isotopologue distributions (percent) in central carbon metabolites using mass spectrometry. This allows the Investigators to understand how different subtypes of kidney and urothelial cancers alter utilization of the 13C tracers.

Howard Hughes Medical Institute

University of Texas Southwestern Medical Center

Principal Investigator, Professor of Urology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
MyVHL: Patient Natural History Study	NCT03749980	Von Hippel-Lind... Hereditary Leio... Birt-Hogg-Dube ... SDHB Gene Mutat...		-	VHL Alliance
Randomized Pilot Study for the Treatment of Cutaneous Leiomyomas With Botulinum Toxin	NCT00971620	Cutaneous Leiom... Hereditary Leio...	Botulinum toxin... Placebo	18 Years -	National Institutes of Health Clinical Center (CC)
MyVHL: Patient Natural History Study	NCT03749980	Von Hippel-Lind... Hereditary Leio... Birt-Hogg-Dube ... SDHB Gene Mutat...		-	VHL Alliance
An Investigation of Kidney and Urothelial Tumor Metabolism in Patients Undergoing Surgical Resection and/or Biopsy	NCT04623502	Kidney Cancer Renal Cell Carc... Clear Cell Carc... Urothelial Carc... Metastatic Kidn... Metastatic Urot... Papillary Renal... Chromophobe Ren... Fumarate Hydrat... Succinate Dehyd... HLRCC Hereditary Leio...	13C-Glucose 13C-Acetate 13C-Lactate 13C-Glutamine 13C-Fructose	18 Years -	University of Texas Southwestern Medical Center

Spots Global Cancer Trial Database for hereditary leiomyomatosis and renal cell cancer