Cryptocurrency, nonfungible tokens, and marijuana stocks: Should I add alternative investments to my portfolio?

Investors often look for unique investments to boost their portfolio’s performance. As the world’s markets evolve and new technologies become essential parts of life, new investment opportunities tempt investors with the allure of getting in on “the next big thing” and earning quick and substantial returns. However, capitalizing on these types of investments requires an in-depth understanding of the product, the companies involved, and the market in which these companies operate. Substantial research is often needed to increase the probability of investment success, and even then, newly developing markets can come with substantial volatility and risk. Failure to understand the fundamentals driving these markets and the risk involved can lead to substantial losses.

Because of the risk involved with newly developing alternative investments, investors must ask themselves how much exposure they are willing to add to their portfolios. Should you put most of your retirement savings into an investment that is just as likely to drop significantly as it is to rise? Probably not. Are you just trying to have a little fun with a relatively small percentage of your investable assets? That is much easier to stomach. Overall, the decision should come down to your risk appetite and overall investment objectives.

The following alternative investments have been getting a lot of attention. (This is not an endorsement to buy or sell these investments.)

 Since 2012, when Colorado and Washington legalized marijuana, 13 other states have passed similar legislation. This has led to a wave of companies in the medical and recreational marijuana space going public, with some trading on major stock exchanges. These businesses range widely, including seed-to-sale producers, equipment distributors, and packaging and marketing companies. The success of legal marijuana on the state level has resulted in significant discussions of decriminalizing it at the federal level. Investors are attracted to the possibility of rapid expansion of an industry very much in its infancy.

 A more recent phenomena, an NFT is a digital asset that exists on a blockchain, which allows anyone to verify the asset’s authenticity and ownership. Each NFT has a unique digital signature and acts as a virtual deed, conveying ownership of a digital asset. Digital assets vary widely, but commonly purchased NFTs include images, video clips, gifs, and memes. As with cryptocurrencies, the free market determines the NTFs’ value, so investors can look to purchase an NFT with a value they perceive to be low and aim to sell it in the future for a higher amount. The concept is like buying and selling art, but instead of purchasing a physical piece, an investor buys a unique digital token that conveys ownership of the digital asset.

 There are thousands of cryptocurrencies, and the value of each is derived by the free market. This creates an investment opportunity to purchase a currency at a low perceived value and sell if the value has increased.

 Although the previous 3 alternative investments have been garnering a lot of attention, investors can explore other options such as private equity or venture capital, hedge funds, managed futures, art and antiques, commodities, and derivatives contracts.

Alternative investments are not for the faint of heart. They often come with significant risk as investors try to determine their value on a local and global level. Investors need to carefully evaluate these opportunities before putting their money into them. Considerable research must be done to ensure a thorough understanding of the product, companies, and industry. Even more consideration must be given to the percentage of their portfolio an investor is willing to devote to these options. Although all investing carries risk of loss, a rule of thumb regarding alternative investments is to not put in more money than you are willing to lose.

The information in this column is designed to be authoritative. The publisher is not engaged in rendering legal, investment, or tax advice. If you would like assistance with your individual investment strategy, please email witz@mediqus.com.

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Cryptocurrency, nonfungible tokens, and marijuana stocks: Should you add alternative investments to your portfolio?

Urology Times Money Matters: Alternative Investments

 explains what is required for an expert witness to be successful in a medical malpractice case. Steele is an attorney in the Columbus, Ohio office of Reminger Co., LPA and specializes in malpractice defense and insurance litigation.

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“The side that can take…complex issues and make them simple…is likely going to be the side that wins in a case,” says Kenton H. Steele, Esq.

Urology Malpractice: What qualities make an expert witness successful?

The FDA recently approved a second drug for prostate-specific membrane antigen (PSMA)-targeted positive emission tomography (PET) imaging of PSMA-positive lesions in men with prostate cancer. With the FDA approval of piflufolastat F 18 (Pylarify), men with prostate cancer suspected of harboring metastases who are potentially curable with local therapy will be indicated to undergo PSMA-targeted PET imaging that will aid in decision-making.

This is also indicated for patients with suspected recurrence of prostate cancer based on PSA levels after primary treatment.

Piflufolastat F 18 is expected to be distributed from multiple sites in the United States. The first FDA PSMA-targeted PET imaging drug, Ga 68 PSMA-11, was approved on December 1, 2020, for the same indications.

 Ga 68 PSMA-11, based on available information, is only available locally at 2 sites in California. These tools will inevitably reveal (or exclude) early metastasis, and that is good news.

I could not help but take this opportunity to reflect on the historical nature of this. Interestingly, there is a tie to an Oklahoman. The “Will Rogers phenomenon” is a term used to describe an “epidemiological paradox” named after a comment the humorist made about migration during the Great Depression. Rogers is credited with stating, “When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”

So what does this have to do with PET imaging? In 1985, Dr Alvan Feinstein proposed the term “Will Rogers phenomenon” to describe the “stage migration” he observed in patients with lung cancer undergoing a new imaging test, the CT scan.

Suddenly, small-volume metastases could be seen (or excluded). In addition, by detecting metastases that had been silent and unidentified, this “new technological data” resulted in a stage migration. Many patients who previously would have been classified in a “good” stage were assigned to a “bad” stage. Because the prognosis of those who migrated, although worse than that of other members of the good-stage group, was better than that of other members of the bad-stage group, survival rates rose in each group without any change in individual outcomes.

These new imaging tools, like the PSMA PET scans, allow for detection of cancer metastases before they became evident clinically. So now the clinical application will begin. However, the therapeutic interventions that have been approved for metastatic and castration-resistant prostate cancer were based on conventional imaging. Now, for the first time in urologic cancer care, we are presented with a novel tumor-directed therapy based on enhanced imaging.

The VISION trial (NCT03511664) compared standard of care to standard of care plus lutetium-177–PSMA-617 (Lu-PSMA) in men with CRPC who had received at least 1 next-generation androgen receptor signaling inhibitor and up to 2 chemotherapy regimens.

 This trial demonstrated improvement in its 2 primary end points, overall survival and radiographic progression-free survival, with the addition of Lu-PSMA. Therefore, the combination of enhanced detection of early metastasis coupled with tumor-directed therapy linked to that imaging should improve the outcome of patients with this advanced disease. The Will Rogers phenomenon continues to be impactful, and when combined with a precision treatment, the outcomes of this disease state will be “doubly improved” for generations to come.

 professor and chair of urology at the University of Oklahoma College of Medicine, Oklahoma City, is coeditor in chief for 

1. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. FDA. May 27, 2021. Accessed June 28, 2021. https://bit.ly/3A8UEZq

2. Drug trials snapshot: Ga 68 PSMA-11. FDA. December 9, 2020. Accessed June 28, 2021. https://bit.ly/2Te2O2b

3. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. 

1985;312(25):1604-1608. doi:10.1056/NEJM198506203122504

4. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. 

Published online June 23, 2021. doi:10.1056/NEJMoa2107322

"The Will Rogers phenomenon continues to be impactful, and when combined with a precision treatment, the outcomes of this disease state will be “doubly improved” for generations to come," writes Michael S. Cookson, MD, MMHC.

PSMA, VISION, and the Will Rogers phenomenon

The 2021 ASCO Annual meeting has come and gone, with its annual release of thousands of abstracts across every tumor type. Here are the key genitourinary cancer highlights for the practicing urologist.

The major buzz in prostate cancer at ASCO was the reporting of the phase 3 VISION trial results of the targeted radioligand therapy 177Lu-PSMA-617 (LuPSMA) in patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

 The results of the trial showed that adding LuPSMA to standard of care (SOC) led to a nearly 40% reduction in the risk of death versus SOC alone.

The open-label phase 3 VISION trial (NCT03511664) included 831 patients with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens. Patients were randomized in a 2:1 ratio to LuPSMA (n = 551) plus SOC or SOC alone (n = 280).

The median overall survival (OS) was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 

 <.001). The median radiographic progression-free survival was 8.7 versus 3.4 months, respectively (HR, 0.40; P <.001). The objective response rates and disease control rates were 29.8% versus 1.7% and 89.0% versus 66.7%, respectively.

Based on the VISION data, the FDA recently granted LuPSMA a Breakthrough Therapy Designation in this setting. The designation will expedite the development and regulatory review of LuPSMA. The FDA has already approved 2 PSMA PET imaging agents for prostate cancer: piflufolastat F 18 (Pylarify) and Ga 68 PSMA-11. LuPSMA is now on track to likely become the first PSMA-targeted agent approved in the space.

Research presented at ASCO also showed how other novel PSMA-targeted agents are rapidly emerging on the heels of LuPSMA. One such study highlighted how the investigational PSMA-targeted compound 225Ac-J591 demonstrated promising clinical activity with a tolerable safety profile in patients with progressive mCRPC who had previously received 1 or more androgen receptor–pathway inhibitors (eg, abiraterone, enzalutamide).

 In a cohort of 32 men, 68.8% of patients had at least some level of PSA decline and 43.8% had a PSA decline of over 50%.

Other abstracts hinted at some of the broader impact the PSMA revolution might have in prostate cancer. Findings from a phase 1b study showed that a single dose of LuPSMA primed prostate tumors to respond to the immune checkpoint inhibitor pembrolizumab (Keytruda).

 Among 18 patients with mCRPC who received the single LuPSMA dose and an extensive regimen of pembrolizumab, 44% (n = 8) achieved a response. Five of these patients—all of whom were microsatellite stable, homologous recombination deficiency wild-type—reached a response greater than 8 months.

Several abstracts presented at ASCO highlighted how integrating immune checkpoint inhibitors into bladder-sparing approaches may enhance the efficacy of these strategies in patients with bladder cancer.

“The biggest impact from studies at ASCO this year in the bladder cancer field had to do with bladder-sparing approaches, and the studies really mark a ‘new dawn’ in bladder-sparing approaches in bladder cancer in terms of integrating immune checkpoint blockade with radiation or even without radiation to achieve bladder sparing,” Matthew Galsky, MD, said in an interview with 

2 ASCO abstracts in particular demonstrated the emergence of immune checkpoint inhibitors as a major component of the bladder-sparing treatment paradigm.

Findings from the phase 2 HCRN GU16-257 trial showed that combining transurethral resection of the bladder tumor (TURBT) with nivolumab (Opdivo) and chemotherapy is a promising bladder-sparing approach in patients with muscle-invasive bladder cancer (MIBC).

The study enrolled 76 patients with cisplatin-eligible cT2 to T4aN0M0 clinically localized urothelial bladder cancer. At the time of the data cutoff, 64 patients had completed clinical restaging. Of these patients, 31 (48%) achieved a clinical CR. Thirty of these patients chose not to undergo cystectomy and instead receive an additional 4 months of nivolumab monotherapy. Only 1 patient opted for immediate cystectomy. On surgical pathology, that patient had a low-grade papillary tumor. The remaining 33 patients did not reach a clinical CR and cystectomy was recommended.

The other key abstract was an early analysis from a phase 2 study showing positive efficacy and safety signals with pembrolizumab in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) in patients with MIBC.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m2 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

A total of 42 patients (85%) completed all protocol therapy in the study. Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort. The investigators reported a 1-year bladder-intact disease-free survival rate in the efficacy cohort of 88%. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

The main news from ASCO in the kidney cancer arena was the report of the results from the phase 3 KEYNOTE-564 trial showing that adjuvant pembrolizumab led to a significant reduction in the risk of disease recurrence or death versus placebo in patients with clear cell renal cell carcinoma (RCC).

 The results showed that adjuvant pembrolizumab induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; 

The standard-of-care treatment for patients with locoregional RCC is surgery; however, nearly half of patients eventually experience disease recurrence. Currently, there is no standard adjuvant systemic therapy that is supported by high levels of evidence worldwide.

“KEYNOTE-564 is the first positive phase 3 study of an adjuvant immunotherapy for patients with RCC. Pembrolizumab is a potential new standard of care for patients with RCC in the adjuvant setting,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, said when reporting the results.

1. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). 

 39, 2021 (suppl 15; abstr LBA4). 10.1200/JCO.2021.39.15_suppl.LBA4

2. Tagawa ST, Sun M, Sartor AO, et al. Phase I study of 225Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC). 

 39, 2021 (suppl 15; abstr 5015). doi: 10.1200/JCO.2021.39.15_suppl.5015.

3. Aggarwal RR, Sam SL, Koshkin VS, et al. Immunogenic priming with 177Lu-PSMA-617 plus pembrolizumab in metastatic castration resistant prostate cancer (mCRPC): A phase 1b study. ­­ 

 39, 2021 (suppl 15; abstr 5053). doi: 10.1200/JCO.2021.39.15_suppl.5053

4. Galsky MD, Daneshmand S, Chan KG et al. Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257. 

 39, 2021 (suppl 15; abstr 4503). doi: 10.1200/JCO.2021.39.15_suppl.4503

5. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. 

39, 2021 (suppl 15; abstr 4504). doi: 10.1200/JCO.2021.39.15_suppl.4504

6. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study

 39, 2021 (suppl 15; abstr LBA5). doi: 10.1200/JCO.2021.39.15_suppl.LBA5

The 2021 ASCO Annual meeting has come and gone, with its annual release of thousands of abstracts across every tumor type. Here are the key genitourinary cancer highlights for the practicing urologist. 

ASCO 2021 Recap: What urologists need to know

Our physicians will review the results of a Sexual Health Inventory for Men (SHIM) score, an International Prostate Symptom Score (IPSS) questionnaire, and a Prostate Cancer Survivorship questionnaire. Can I count the review of these 3 tests to obtain a “moderate” level of data reviewed using the new 2021 evaluation and management (E/M) guidelines?

No. As many of you know, “moderate”-level data can be achieved by satisfying any 1 

of 3 categories within the Data section as defined in the 2021 E/M guidelines:

 Any combination of 3 from the following:

• Review of prior external note(s) from each unique source

• Review of the result(s) of each unique test

• Assessment requiring an independent historian(s)

 Independent interpretation of a test performed by another physician/other qualified health care professional (not separately reported).

 Discussion of management or test interpretation with external physician/other qualified health care professional/appropriate source (not separately reported).

As categories 2 and 3 are clearly not appropriate for classifying any of these questionnaires, we look to Category 1.

Under Category 1, patient questionnaires cannot be considered “review of prior external note(s) from each unique source.” The questionnaires meet neither the definition of external note nor of unique source as defined by Current Procedural Terminology (CPT) below:

“A unique source is defined as a physician or qualified heath care professional in a distinct group or different specialty or subspecialty, or a unique entity”; and

“External records, communications and/or test results are from an external physician, other qualified health care professional, facility, or health care organization.”

Questionnaires cannot be considered tests under these guidelines, as tests are defined by CPT as “imaging, laboratory, psychometric, or physiologic data,” and they are further defined within the guidelines as services designated by CPT codes, with the differentiation between a single or multiple unique tests being defined in accordance with the CPT code set.

Finally, these questionnaires are typically provided to and answered by the patient, and therefore they cannot not be considered an assessment by an independent historian.

Therefore, questionnaires, including the SHIM, IPSS, and Prostate Cancer Survivorship Questionnaire, no matter how useful, are not considered data points under the new guidelines. The only exceptions would be if the patient’s overall history was provided by an independent historian or if the information was gleaned from review of another physician’s record which, in either case, would result in only 1 data category.

Send coding and reimbursement questions to Rubenstein and Painter c/o

Questions of general interest will be chosen for publication. The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules.

SHIM and other questionnaires do not satisfy categories within Data section.

Questionnaires are not counted as tests under new E/M coding guidelines

Roughly 1 in 10 Americans will have a kidney stone during their lifetime, according to the Urology Care Foundation Kidney Stones Patient Guide. A contributing factor to kidney stones is hyperoxaluria, for which the treatment lumasiran (Oxlumo) was recently approved by FDA, and other treatments are in the pipeline. In an interview with 

, an assistant professor of urology at the University of Alabama, Birmingham, discussed the different types of hyperoxaluria, the urologist’s role in managing the condition, and the treatments for it.

What is hyperoxaluria, and are there different types?

To answer those questions, it's important to understand where oxalate is derived from. Oxalate has both a dietary and an endogenous source. Dietary oxalate comes mostly from food sources that grow in the ground. With endogenous oxalate, the body creates oxalate as an end metabolite and oxalate is then excreted in urine. The presumed major source of oxalate has always been the liver, but other organs may also play a role. There are different definitions of hyperoxaluria, but it is usually defined as greater than 40 or 45 mg per day of urinary oxalate excretion.

In its simplest form, [hyperoxaluria] is broken out into primary and secondary hyperoxaluria. Primary hyperoxaluria has known monogenetic conditions that cause the increased oxalate and is currently broken out into 3 known types—PH1, PH2, and PH3. Each corresponds to a specific gene, [and] each of the genes codes for a protein involved in the endogenous oxalate pathway. PH1 is the most common and severe form, representing close to 70% of the known cases of primary hyperoxaluria. Historically, many of these patients were treated with liver-kidney transplant. PH2 and PH3 are less common and less severe but still can result in recurrent kidney stones, nephrocalcinosis, and renal failure.

Secondary hyperoxalurias can be characterized as either dietary indiscretion or enteric. Dietary indiscretion-related hyperoxaluria occurs when patients consume too much oxalate and thus absorb and excrete too much oxalate. This subtype benefits from dietary restriction. Enteric hyperoxaluria results from increased uptake of oxalate from the gastrointestinal tract and usually results because of malabsorptive processes, such as bowel surgery.

Finally, there is idiopathic hyperoxaluria. This classification is reserved for those that have an unknown cause to explain the hyperoxaluria. Presumably, the heightened oxalate excretion is derived from the endogenous pathway, some altered handling of oxalate, dietary indiscretion, or some other unknown source.

In November 2020, the FDA approved lumasiran for the treatment of PH1. How does this medication work?

Lumasiran addresses and is approved to treat PH1. It uses RNA interference technology, which binds to specific messenger RNA and prevents the protein/enzyme from being translated. GalNAc [N-Acetylgalactosamine]-siRNA [small interfering RNA] conjugates are liver specific and thus can target the endogenous oxalate pathway. Lumasiran targets glycolate oxidase, which is an enzyme involved in the conversion of glycolate to glyoxylate. Glyoxylate is the main precursor to oxalate and thus, by reducing the creation of glyoxylate, there is less oxalate production. It is delivered subcutaneously and has been approved for PH1 in children and adults.

Can you discuss the key findings from the pivotal phase 3 ILLUMINATE-A trial (NCT03681184) of lumasiran?

ILLUMINATE-A was a study of 39 adult and pediatric patients [6 years and older] who had a diagnosis of PH1. [These patients] did not have severe kidney damage and were not on dialysis. Twenty-six patients received lumasiran subcutaneously, and this was compared with 13 patients that received placebo. All patients were followed for 6 months with an extension arm. The primary end point was urinary oxalate excretion. Those patients who received lumasiran had a 53% reduction in urinary oxalate excretion compared with placebo (highly significant). Further, 84% of the patients receiving lumasiran had normalization or near normalization (defined as less than 1.5 times above the normal range).

What is the practicing urologist's role in the treatment of hyperoxaluria?

Hyperoxaluria can be one of the many contributing factors to stone disease. When we’re talking about primary hyperoxaluria, I think the role of the urologist is to help diagnose [the disease in] these individuals. Diagnosis and treatment of primary hyperoxaluria can be life-changing for the patient. In regard to secondary hyperoxaluria, it is important for the urologist to diagnose and treat as well, as this can reduce the stone risk and other sequelae of hyperoxaluria. As urologists, we need to determine the cause of the hyperoxaluria. For example, if it is dietary indiscretion, we need to give sound dietary advice. Determining the underlying cause of hyperoxaluria becomes important. For [instance], if a patient has enteric hyperoxaluria, the urologist, knowing the pathophysiology, may give specific dietary advice, begin medical management, and potentially involve other specialty services.

Three other treatments—nedosiran, reloxaliase, and Oxabact—are being investigated for hyperoxaluria. What is their status? If approved, how would they differ from lumasiran?

Lumasiran addresses the endogenous production of oxalate and is only used in PH1. Nedosiran, which is being developed by Dicerna and is in phase 3 [clinical] trials, uses GalNAc-siRNA technology similar to lumasiran but targets liver lactate dehydrogenase. Lactate dehydrogenase is the final enzyme and converts glyoxylate to oxalate. If approved, nedosiran could be used to treat PH1, PH2, and PH3.

Reloxaliase is an crystalline formulation of the enzyme, oxalate decarboxylase, which breaks down oxalate. It specifically breaks down oxalate in the gastrointestinal tract and is being studied in enteric hyperoxaluria. In the URIROX-1 phase 3 study, 115 patients with enteric hyperoxaluria were randomized to reloxaliase or placebo. Those receiving reloxaliase had a 22.6% reduction in urinary oxalate excretion compared with the 9.7% reduction in the placebo group. Reloxaliase is taken with meals and snacks and requires multiple doses per day. Further studies are being performed to determine if reloxaliase treatment translates into reduced clinical stone events.

, [which] is a bacteria that uses oxalate as its energy source. Oxabact degrades gastrointestinal oxalate and is being studied in primary hyperoxaluria.

Lumasiran will be used in the PH1 population, whereas nedosiran is being studied in all known types of primary hyperoxaluria. Reloxaliase is being studied in enteric hyperoxaluria, and Oxabact is being studied in the primary hyperoxaluria population. Whether these treatments will have a role in other types of hyperoxaluria is certainly of interest and will require future research studies.

Kyle Wood, MD, discusses the different types of hyperoxaluria, the urologist’s role in managing the condition, and the treatments for it.

Vol 49 No 07

Urology Times Money Matters: Alternative Investments

Urology Malpractice: What qualities make an expert witness successful?

PSMA, VISION, and the Will Rogers phenomenon

ASCO 2021 Recap: What urologists need to know

Questionnaires are not counted as tests under new E/M coding guidelines

Hyperoxaluria: What is the urologist’s role in diagnosis and treatment?