On April 10, 2021 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that a Phase 1b trial of GMI-1359, being conducted at Duke University Cancer Center, showed evidence of on-target effects, immune-activation and cell mobilization in the initial two patients treated with the Company’s dual antagonist of E-selectin and CXCR4 (Press release, GlycoMimetics, APR 10, 2021, View Source [SID1234577818]). Dorothy Sipkins, MD, PhD, Associate Research Professor in Pharmacology and Cancer Biology at Duke University School of Medicine, will present results from the proof-of-concept clinical study as well as a separate preclinical study supporting the positive biologic findings of the Phase 1b study. The presentation will be made at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting, which is being held virtually on April 10-15 and May 17-21. GMI-1359 is GlycoMimetics’ novel small molecule drug candidate, a dual antagonist of E-selectin and CXCR4, designed to target tumor-microenvironment resistance to chemotherapy in cancers with bone metastases.

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The initial data from the study confirmed the dual CXCR4 and E-selectin antagonist’s on-target effects. In the two patients who completed treatment, evaluations of peripheral blood showed a consistent mobilization of CD34+ hematopoietic stem and progenitor cells at doses beginning at 5 mg/kg and a reduction of plasma levels of soluble E-selectin. Furthermore, in one individual, following the administration of 7.0 mg/kg of GMI-1359, an immunophenotyping assessment of peripheral blood showed a redistribution of myeloid derived suppressor cells (MDSCs) as evidenced by increased percentages of both the monocytic and granulocytic MDSCs. In this same individual following administration of 7.0 mg/kg GMI-1359, the incidence of M1 proinflammatory macrophages increased while the M2 anti-inflammatory macrophages, often associated with tumor progression, decreased. The clinical poster concludes that GMI-1359 demonstrated an acceptable safety and tolerability profile in the patients treated to date. No dose limiting toxicities were observed following multiple dose administration up to 7 mg/kg.

Dr. Sipkins noted, "Despite the fact that our patient numbers are very small due to COVID’s impact on recruitment, we are seeing the on-target effects of antagonizing both CXCR4 and E-selectin with use of GMI-1359, and that the drug is well-tolerated at all dose levels. Our pilot immune profile analysis also suggests that the drug could have favorable effects on the tumor immune microenvironment, echoing results seen in our preclinical work."

Dr. Sipkins will disclose preclinical evidence that it may be possible for GMI-1359 to augment immune recognition of the tumor. The data in the poster from a mouse metastatic breast carcinoma model demonstrated a reduction in the immune suppressive monocytic MDSCs at the primary tumor site and a significant increase in the CD8/Treg ratio in both the primary tumor and at the bone metastatic sites. These findings on immune cell redistributions strongly suggest the induction of a more favorable anti-tumor environment following GMI-1359 administration.

According to Dr. Eric J. Feldman, GlycoMimetics Senior Vice President and Chief Medical Officer, "The information shared in this AACR (Free AACR Whitepaper) poster provides us with important understandings upon which we expect to identify a potential indication for advancing GMI-1359 in the clinic. It suggests that this small molecule drug candidate could improve responses to therapies and potentially reduce the burden of metastatic breast cancer disease."

In prior preclinical research supported by GlycoMimetics, Dr. Sipkins’ laboratory demonstrated that E-selectin and CXCR4/SDF-1 interactions were critical for breast carcinoma cells (BCCs) invasion and retention, respectively, into bone. Moreover, they found that dormant and proliferating BCCs occupy distinct regions of the bone microenvironment, with dormant BCCs predominantly found in SDF-1 and E-selectin rich regions. These dormant BCCs are expected to be highly susceptible to GMI-1359 mobilization, suggesting a new intervention to break the foothold of dormant BC micrometastases in bone.

Details on the GMI-1359 e-presentation at the AACR (Free AACR Whitepaper) Meeting are as follows:

Title: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer
Presenter: Dorothy Sipkins, MD, PhD, Associate Research Professor in Pharmacology and Cancer Biology at Duke University School of Medicine
Session: e-Presentation
Date and Time: Saturday, April 10, 2021 (available online through Monday, June 21)

About GMI-1359

GMI-1359 is designed to simultaneously inhibit both E-selectin and CXCR4, which are adhesion molecules involved in tumor trafficking and metastatic spread. Preclinical studies indicate that targeting both E-selectin and CXCR4 with a single compound could improve efficacy in the treatment of cancers that involve the bone marrow, such as AML and multiple myeloma, or in solid tumors that metastasize to the bone, such as prostate cancer and breast cancer, as well as in osteosarcoma, a rare pediatric tumor affecting about 900 adolescents a year in the United States. GMI-1359 completed a Phase 1 clinical trial in healthy volunteers, and a Phase 1b clinical study is underway in breast cancer patients and is designed to enable investigators to identify study dose ranging and to generate initial biomarker data around the drug’s activity. In the first two patients evaluated, the study showed evidence of on-target effects, immune-activation and cell mobilization. GMI-1359 has received Orphan Drug designation and Rare Pediatric Disease designation from the FDA for the treatment of osteosarcoma.

On April 10, 2021 GlycoMimetics, Inc. (Nasdaq: GLYC) reported that an abstract presenting the results of a recent preclinical study on the therapeutic effects of GMI-1757, a new glycomimetic with dual antagonism to E-selectin and galectin-3, has been accepted for a poster presentation at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting, to be held virtually on April 10-15 and May 17-21 (Press release, GlycoMimetics, APR 10, 2021, View Source [SID1234577817]).

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The study demonstrates that GMI-1757 significantly improved anti-PD-L1 therapeutic activity in a pancreatic adenocarcinoma model. Results showed 50% partial regressions and an approximate 99% reduction of median tumor volume. Microscopic evaluations also showed that in groups treated with GMI-1757 both the incidence and area of intratumoral fibrosis were markedly reduced. Additionally, GMI-1757 strongly increased the incidence of mononuclear cell tumor infiltration. These results suggest that the decreased intratumoral fibrotic development and increased mononuclear cell infiltration obtained with GMI-1757 created a favorable immune environment so that when combined with anti-PD-L1 it produced a more robust anti-tumor effect compared to anti-PD-L1 treatment alone. Investigations will continue on GMI-1757’s impact when combined with immune modulators where fibrosis and restricted host cell infiltration negatively impact tumor response.

GlycoMimetics Senior Vice President, Research and Chief Scientific Officer John Magnani commented, "We look forward to presenting the latest research on our novel glycomimetic compound at AACR (Free AACR Whitepaper)’s annual meeting. Our hope is that as this research progresses, we will move ever closer to achieving promising therapies for individuals living with forms of cancer where medical needs remain unmet."

Details on GlycoMimetics e-presentation at the AACR (Free AACR Whitepaper) Meeting are as follows:

Title: A novel glycomimetic compound (GMI-1757) with dual functional antagonism to E-selectin and galectin-3 attenuates fibrosis, facilitates mononuclear cell infiltration and optimizes anti-PD-L1 therapeutic activity in a pancreatic adenocarcinoma model
Presenter: William E. Fogler, Ph.D., GlycoMimetics
Session: e-Presentation
Date and Time: Saturday, April 10, 2021 (available online through Monday, June 21)

About GMI-1757

An innovative dual antagonist of E-selectin and galectin-3, GMI-1757 has shown anti-thrombotic and anti-fibrotic activity in preclinical models presented at major scientific meetings. Data suggest the compound may be able to play a role in the treatment of a variety of cancers and fibrotic conditions.

On April 10, 2021 Zentalis Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company focused on discovering and developing small molecule therapeutics targeting fundamental biological pathways of cancers, reported initial efficacy and safety data from the Phase 1 dose-escalation portion of its ongoing Phase 1/2 clinical trial of ZN-c3 in patients with advanced solid tumors who are refractory to or ineligible for standard therapy or for whom no standard therapy is available (Press release, Zentalis Pharmaceuticals, APR 10, 2021, View Source [SID1234577815]). Initial results showed that monotherapy ZN-c3 use resulted in Exceptional Responses in heavily pre-treated patients in a range of solid tumors, including Partial Responses (PRs) in ovarian cancer, colorectal cancer, non-small cell lung carcinoma and uterine serous carcinoma. Data were reviewed as a late-breaking abstract during the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held virtually April 10-15, 2021 and May 17-21, 2021.

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"The initial clinical data on our WEE1 inhibitor are extremely promising and showcase ZN-c3’s strong potential to improve outcomes in patients with advanced solid tumors who have exhausted available treatment options," commented Dr. Anthony Sun, Chairman and Chief Executive Officer of Zentalis. "Our WEE1 candidate, which we believe is potentially a best-in-class small molecule, demonstrated favorable safety results with a wide therapeutic window, and resulted in Partial Responses in five patients with a range of cancers. Having identified a recommended dose for future studies, we look forward to advancing clinical trials in a larger number of patients, as well as novel biomarkers that may help select patients who are likely to respond to treatment with ZN-c3. We are looking to make Exceptional Responses commonplace."

Initial Efficacy and Safety Data

In the Phase 1 dose-escalation trial, ZN-c3 was dosed starting at 25 mg and going as high as 450 mg QD in patients with advanced or metastatic solid tumors. At the time of the data cutoff on February 12, 2021, 55 patients were evaluated for safety, the primary endpoint. The study remains ongoing and based on the data presented at AACR (Free AACR Whitepaper), ZN-c3 generated 5 Partial Responses.

Best Overall Responses:

Two confirmed PRs in ovarian cancer and colorectal cancer (CRC) patients

After receiving 18 prior lines of therapy, 11 prior lines in the advanced metastatic setting, a patient with Stage IV ovarian cancer had a RECIST-confirmed PR with a 56% reduction in overall target lesions. The patient also experienced a large rapid drop in CA-125 from 610 kU/L at baseline to 125 kU/L within 4 weeks on treatment, with her CA-125 level normalizing 3 weeks later. The patient was on study for 186 days and remains on study drug.

After receiving 5 prior lines of therapy in the advanced metastatic setting, a patient with Stage IV CRC had a RECIST-confirmed PR with a 42% reduction in overall target lesions, as well as a rapid decrease in CEA tumor marker from 327 ng/mL at baseline to <50 ng/mL after 3 weeks on treatment. The patient remained on study for 169 days until clinical disease progression.

In addition, three unconfirmed PRs—one in non-small cell lung carcinoma (NSCLC) and two in uterine serous carcinoma (USC) patients

After receiving 3 prior lines of therapy in the advanced metastatic setting, a patient with Stage IV NSCLC had an unconfirmed (per RECIST) PR with a 50% reduction in overall target lesions. The patient was on study for 145 days and remains on study drug.

ZN-c3 was generally well-tolerated as a single agent. As of the cutoff date, the most common treatment-related adverse events were mainly Grade 1/2, including nausea (49.0% of patients), diarrhea (32.7% of patients), fatigue (29.0% of patients) and vomiting (29.0% of patients) across all doses. Significant hematological adverse events were limited; treatment-related white blood cell count decrease / neutropenia (7.2% all Grades, 3.6% Grade ≥3), anemia (7.2% all Grades, 5.4% Grade ≥3) and thrombocytopenia (7.2% all Grades, 3.6% Grade ≥3).

Results from this study indicate that an oral dose of 300 mg QD with continuous dosing is the recommended Phase 2 dose of ZN-c3 when used as a monotherapy. The 300 mg QD dose demonstrated high plasma exposure levels, while minimizing adverse events. In addition, the pharmacodynamic marker of pCDK1 levels in skin punch biopsies showed active target engagement at relevant pharmacological doses. The Company initiated the Phase 1 expansion portion of the trial with the 300 mg QD dose earlier in 2021 and is exploring this candidate’s potential in combination trials including in ovarian cancer and osteosarcoma. Using this recommended dose, Zentalis will also coordinate with Zentera Therapeutics, Zentalis’ majority-owned joint venture, to initiate a Phase 1b trial investigating ZN-c3 as a single agent in China.

"WEE1 is a promising target for cancer therapy, and this dataset provides further validation on the importance of candidates like ZN-c3 that are designed to inhibit the DNA damage checkpoint, resulting in tumor cell death," said Dr. Anthony Tolcher, CEO, Founder and Director of Clinical Research at NEXT Oncology. "ZN-c3 was shown to be tolerable in this heavily pretreated patient population. Furthermore, this candidate’s early signals of anti-tumor activity are very exciting, and I am even more optimistic that WEE1 inhibition may become an important treatment approach for a wide range of cancers."

KOL Webcast Event:

Zentalis will host a webcast event with key opinion leaders Monday, April 12, 2021 at 4:00 p.m. EDT. To register and access the event, the webcast link is available on the Investors & Media section of the Zentalis website at www.zentalis.com.

About ZN-c3

ZN-c3 is an oral inhibitor of WEE1 in development for the treatment of advanced solid tumors. The inhibition of WEE1, a DNA damage response protein, aims to generate sufficient DNA damage in cancer cells, causing cell death, thereby preventing tumor growth and potentially causing tumor regression. Zentalis is currently conducting a Phase 1/2 clinical trial in patients with advanced solid tumors and reported initial data from the Phase 1 portion at the AACR (Free AACR Whitepaper) Annual Meeting 2021. In addition, the Company is also conducting a Phase 1b trial evaluating ZN-c3 in combination with chemotherapy in patients with advanced ovarian cancer, with plans to initiate a Phase 1/2 in combination with chemotherapy in osteosarcoma and a Phase 2 trial investigating ZN-c3 as a monotherapy in patients with uterine serous carcinoma in 2021.

On April 10, 2021 Gilead Sciences reported that The PI3K inhibitors were once viewed as a blockbuster opportunity in blood cancer (Press release, Gilead Sciences, APR 10, 2021, View Source [SID1234577814]). But patient deaths in clinical trials for earlier-line use of Gilead Sciences’ first-to-market Zydelig dashed that hope. Now, in what could be viewed as a redemption of the drug class, Bayer’s Aliqopa has come up with a success safely.

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Adding Aliqopa to Roche’s Rituxan cut the risk of disease progression or death by 48% in patients with indolent non-Hodgkin’s lymphoma (iNHL) who relapsed after at least one prior therapy, according to data presented at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting.

This showing makes Aliqopa the first PI3K inhibitor to demonstrate superior efficacy in combination with Rituxan with a manageable safety profile in patients with relapsed iNHL, Scott Fields, Bayer’s head of oncology development, said in a statement.

Bayer now plans to file the data to FDA and other drug regulators to potentially get Aliqopa into earlier, second-line iNHL, Barry Childs, Bayer’s global development lead for Aliqopa, said in an interview. The drug currently bears an accelerated approval in third-line follicular lymphoma (FL) based on tumor response data.

It also hopes the data, from the phase 3 Chronos-3 trial, could turn that conditional nod into a full one. The confirmatory trial Bayer has previously agreed with the FDA is actually the Chronos-4 study, which is testing Aliqopa in tandem with Rituxan and chemotherapy in relapsed iNHL. But Childs said the company will ask the FDA to consider using the current study instead, given that it’s also a randomized trial.

RELATED: Bayer gears up to take on Gilead in lymphoma with Aliqopa green light

For a second-line filing, Bayer intends to aim for a broader label for the whole iNHL population, though the FDA might pick apart each subset of disease, Childs and Fields cautioned during the interview.

Aliqopa’s benefits were shared across all prespecified iNHL subtypes in Chronos-3. For FL, the risk reduction amounted to 42%. The number was 52.5% for marginal zone lymphoma (MZL), 75.7% for small lymphocytic lymphoma (SLL) and 55.7% for Waldenstrom macroglobulinemia.

For the larger FL and MZL diseases, the subgroup analyses are powered to stand on their own, while the two smaller diseases aren’t statistically powered, according to Childs. That said, "there is consistent treatment effect," he added. "What we’re requesting of the FDA is that they will consider the treatment effect consistency to be part of their approval decision for the smaller subsets."

As for the perhaps more important data on Aliqopa’s ability to extend patient’s lives, Childs said the overall survival data were still immature after a median follow-up of 30 months as neither treatment arms has reached a median survival mark.

RELATED: Watch out, Gilead: TG Therapeutics wins FDA nod for potentially safer Zydelig rival

Gilead’s PI3K inhibitor Zydelig entered the U.S. market in 2014 for previously treated chronic lymphocytic leukemia, FL and SLL, bearing blockbuster hopes. However, the company was forced to cap several trials—including ones equivalent to Aliqopa’s Chronos-3 and Chronos-4—after reports of multiple deaths in its clinical programs in 2016. After that, the drug’s sales have never picked up, with just $72 million in 2020.

In Chronos-3, the Aliqopa regimen showed side effects that were generally consistent with the individual drugs, according to Bayer. Some of the frequent side effects such as hyperglycemia were transient and manageable, the company said.

There was however a relatively high discontinuation rate of 32% in the Aliqopa arm, versus 8% for solo Rituxan. The company is still exploring the exact reason, but Childs pointed to a higher rate of complete tumor clearance among Aliqopa patients, suggesting that some investigators may have chosen to discontinue patients especially during the pandemic because they were already in good remission. He also noted that the company took a very conservative protocol to discontinue patients who developed pneumonitis but only later realized that the side effect can be managed without taking patients off treatment.

RELATED: Bayer unveils first look at its post-Xarelto, post-Eylea life—and it’s better than expected

In terms of managing side effects, Childs pointed to Aliqopa’s intravenous administration—versus Zydelig and other PI3K inhibitors’ oral dosing—as an advantage as it can be given intermittently to allow normal tissues to recover between doses.

So far, Aliqopa still hasn’t earned a place in Bayer’s annual report, meaning that its 2020 sales were below the €262 million ($312 million) prostate cancer drug Xofigo raked in during the period. Verastem Oncology recently transferred its PI3K drug Copiktra to Secura Bio for $70 million upfront. That drug sold merely $9.3 million in the first half of 2020. TG Therapeutics just got a go-ahead for Ukoniq, and Incyte’s waiting in the wings with parsaclisib.

But as Bayer pharma chief Stefan Oelrich laid out at a recent investor event, the German company expects to see about €500 million in Aliqopa peak sales. With the Choronos-3 win, Bayer may now seek to move Aliqopa into earlier line of treatment and to markets beyond the U.S., Fields said.

On April 9, 2021 Transgene (Paris:TNG) (Euronext Paris: TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported initial promising results from a Phase I study combining intravenous (IV) oncolytic virus TG6002 and oral 5-FC in patients with advanced gastrointestinal carcinomas (Press release, Transgene, APR 9, 2021, View Source [SID1234621819]). These data provide a clinical proof of concept for Transgene’s double deleted VVcopTK-RR- patented virus backbone: after IV administration, TG6002 reached the tumor, multiplied within tumor cells, and induced the local expression of its payload (the FCU1 gene).

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These results will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual meeting taking place from April 10-15, 2021.

DATA CONFIRM THAT THE CHEMOTHERAPY AGENT 5-FU IS PRODUCED IN PATIENTS’ TUMORS AFTER INTRAVENOUS ADMINISTRATION

TG6002 is a novel oncolytic virus that has been engineered to combine multiple mechanisms of action. It has been designed to:

selectively replicate within cancer cells. This is due to the deletion of the viral genes encoding TK and RR, which reduces the virus’s ability to grow in normal cells. This selective viral replication leads to the breakdown of the infected tumor cells in a process called oncolysis,
prime an immune response against the primary tumor and metastases,
and to induce the local expression of a biologically active enzyme able to convert 5-FC into its active cytotoxic metabolite 5-FU, directly in the tumor.
The data demonstrate that high concentration and continuous production of 5-FU chemotherapy can be obtained within the tumors through the local conversion of the pro-drug 5-FC (administered orally). This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been integrated within the genome of TG6002.

In this study, extensive analyses are being performed including metastasis biopsy with synchronous blood sampling, assessment of virus presence, quantification of 5-FC and 5-FU and assessment of neutralizing antibody titers.

These analyses have allowed Transgene to document TG6002’s pharmacokinetics (PK) and biodistribution, and the functioning of the FCU1 gene when given by IV administration.

Detailed results:

✔ TG6002 infects tumors after intravenous administration, remains active and effectively express FCU1 gene selectively in tumor tissue;
✔ Absence of widespread virus distribution in the body and association of FCU1 activity with high virus concentration in tumor tissue suggest that the replication of TG6002 is concentrated in tumor cells;
✔ None of the patients presented clinical signs of extra-tumoral dissemination of the virus suggesting a high tumor specificity of the viral replication;
✔ The study is continuing with escalating dosing of TG6002.

CLINICAL PROOF OF CONCEPT OF THE FEASIBILITY OF THE IV ADMINISTRATION OF TRANSGENE’S PROPRIETARY ONCOLYTIC VIRUS

To-date, the only oncolytic virus that has received regulatory approval is only approved for intra-tumoral administration, restricting its use to superficial lesions.

Transgene aims to enlarge the number of solid tumors, such as gastro-intestinal tumors, that could be addressed by an oncolytic virus, by developing oncolytics that can be administered intravenously.

The findings that will be presented at AACR (Free AACR Whitepaper) demonstrate the relevance of intravenous administration of Transgene’s next generation oncolytic viruses including TG6002.

These data also suggest that candidates derived from Transgene’s unique Invir.IO platform could also be given intravenously, extending the use of these therapies to a broad range of solid tumors.

Title of the poster: "Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas"
Authors: Kaidre Bendjama, Philippe Cassier, Victor Moreno, Bernard Doger, Emiliano Calvo, Maria De Miguel, Christiane Jungels, Philippe Erbs, Damien Carpentier, Alain Sadoun.
Abstract/Poster Number: LB179
Session: PO.IM02.11 – Vaccines
The e-poster presentation will be available on the AACR (Free AACR Whitepaper) website beginning at 8:30 am US EDT on Saturday, April 10, until Monday, June 21. The text of this abstract will be posted at 12:01 am US EDT on Friday, April 9 on the AACR (Free AACR Whitepaper) website.

About the trial (NCT03724071)
This trial is a single-arm open-label Phase I/II trial evaluating the safety and tolerability of multiple ascending doses of TG6002 administered intravenously in combination with oral 5-FC, a non-cytotoxic pro-drug that can be converted in 5-FU, its active metabolite. Based on the safety profile of TG6002, several dose levels have been added to the initial Phase I clinical protocol. At the end of this Phase I part, Phase II patients will receive the recommended dose of TG6002. The trial has safety as primary endpoint for the Phase I part and efficacy for the Phase II part. The trial also evaluates pharmacokinetic properties and biodistribution of TG6002, along with immune modulation of the tumor micro-environment. This European study will enroll up to 40 patients suffering from advanced gastrointestinal carcinomas who have failed and/or are intolerant to standard therapeutic options in the Phase I part. Patients with colon cancer and liver metastases will be enrolled in the Phase II part.

Dr. Philippe Cassier, M.D., PhD, head of the early-phase trials unit at Centre Léon Bérard (Lyon, France) is the principal investigator of the trial.

About TG6002
TG6002 has been engineered to directly kill cancer cells (oncolysis), to enable the production of a chemotherapy agent (5-FU) within the tumor, and to elicit an immune response by the body against the tumor cells. In preclinical experiments, TG6002 has been shown to induce the shrinkage of the primary tumor as well as the regression of distant metastases (Foloppe, et al., Molecular Therapy Oncolytics, View Source).

The production of 5-FU directly in the tumor aims to achieve a better anti-tumoral effect with limited chemotherapy-induced side effects.

TG6002 induces the production of 5-FU in the cancer cells it has infected, by enabling the local conversion of the pro-drug 5-FC (administered orally) into 5-FU. 5-FU is a common chemotherapy agent for patients with gastro-intestinal cancers. This mechanism of action is based on the in-tumor expression of the proprietary FCU1 gene that has been encoded in the genome of TG6002, taking advantage of the virus selective replication in the tumor cells.

When administered systemically, 5-FU is associated with side effects that can lead to treatment discontinuation. With TG6002, 5-FU is produced within the tumor where it is expected to be present at a high concentration level in contrast to the very low levels anticipated in the rest of the patient’s body.