A pilot study of virtual reality for inpatients with opioid use disorder.

BACKGROUND AND OBJECTIVES: While inpatient withdrawal management/acute stabilization can improve outcomes for individuals with opioid use disorder (OUD), patients often leave treatment early due to mood, tension, and cravings associated with opioid withdrawal. The aim of this study was to evaluate the feasibility and preliminary effectiveness of a novel virtual reality (VR) based intervention; 3D Therapy Thrive (3DTT). METHODS: Subjects with OUD (N = 32) were recruited from a community acute stabilization program and received up to two sessions of 3DTT. They completed questionnaires related to their overall satisfaction with the experience and side effects; as well as those related to mood, tension, and cravings. RESULTS: There were no reported side effects and the majority of subjects (94%) reported high satisfaction with the experience. Out of 62 patients approached, 33 patients agreed to participate (53%) 33 patients completed one, and 17 of these patients (52%) completed both sessions of 3DTT, with 19 participants (58%) completing their treatment protocols. Compared to baseline, 3DTT participants reported significant reductions in depression, tension, and cravings (p's < 0.001). DISCUSSION AND CONCLUSIONS: This pilot study supports the feasibility and preliminary effectiveness of 3DTT for improving outcomes for inpatients with OUD. Future randomized controlled trials are necessary to evaluate the efficacy of 3DTT for improving retention, reducing cravings, and improving mood and tension. SCIENTIFIC SIGNIFICANCE: This is the first study to evaluate the feasibility of a psychologically informed VR intervention in inpatients with OUD.

Early Real-World First-Line Treatment With Venetoclax Plus HMAs Versus HMA Monotherapy Among Patients With AML in a Predominately US Community Setting.

BACKGROUND: Venetoclax in combination with hypomethylating agents (HMAs) is standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are ≥ 75 years old or unfit for intensive chemotherapy. We examined early real-world treatment experience among patients with AML receiving venetoclax+HMAs or HMA monotherapy. PATIENTS AND METHODS: This retrospective cohort study used an electronic health record-derived, deidentified, United States nationwide database comprised of patient-level structured and unstructured data, curated via technology-enabled abstraction. Patients with an AML diagnosis on or after January 1, 2014, who had ≥ 2 clinic visits, and initiated treatment with venetoclax+HMAs from June 1, 2018 to March 31, 2021, or HMA monotherapy from January 1, 2016 to May 31, 2018, were included. Kaplan-Meier analysis was used to estimate time to last administration (TTLA) and overall survival (OS). RESULTS: Overall, 619 patients treated with venetoclax+HMAs and 480 treated with HMA monotherapy were selected from the database. Median age at diagnosis was 76 and 78 years, respectively, most patients were treated in community practice (83.4% and 89.4%, respectively), and almost half had secondary AML (47.2% and 47.3%, respectively). Adjusted analyses showed both significantly longer TTLA (3.6 months vs. 2.3 months; hazard ratio [HR] = 0.69 [95% confidence interval (CI), 0.60-0.80], P< .0001) and OS (9.3 months vs. 5.9 months; HR = 0.71 [95% CI, 0.61-0.82], P < .0001) in patients treated with venetoclax+HMAs versus HMA monotherapy, respectively. CONCLUSION: This study shows benefit in real-world outcomes of venetoclax+HMAs relative to HMA monotherapy in patients with newly diagnosed AML, using a predominantly community-based database.

Phase Ib study of avadomide (CC-122) in combination with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma.

The multicenter, phase Ib CC-122-DLBCL-001 dose-expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [n = 27], FL [n = 41; 31 lenalidomide-naïve, 10 lenalidomide-treated]). Median age was 62 years (range, 33-84 years), and patients had received a median of 3 (range, 1-8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab-refractory at study entry and 10.0% were lenalidomide-refractory. The most common any-grade avadomide-related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide-related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide-naïve and -treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL.

Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study.

BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.

Ublituximab (TG-1101), a novel glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukaemia: results of a phase 2 trial.

Ibrutinib is effective in patients with chronic lymphocytic leukaemia (CLL); however, treatment resistance remains a problem. Ublituximab is a novel, glycoengineered anti-CD20 monoclonal antibody with single-agent activity in relapsed CLL. We report the results of a phase 2 study evaluating combination therapy with ibrutinib and ublituximab in patients with relapsed or refractory CLL. Patients received ibrutinib 420 mg once daily. Ublituximab was administered on days 1, 8 and 15 of cycle 1 followed by day 1 of cycles 2-6. Response assessments were completed at cycles 3 and 6; patients then continued on ibrutinib monotherapy per standard of care. Forty-one of 45 enrolled patients were evaluable for efficacy. Safety was consistent with prior experience for each drug, with infusion reactions the most prevalent adverse event. Combination therapy resulted in an overall response rate (ORR) of 88% at 6 months. In the 20 patients with high-risk features (17p or 11q deletions or TP53 mutation) and evaluable for efficacy, the ORR was 95%, with three patients (15%) achieving negative minimal residual disease. Median time to response was 8 weeks. Ublituximab in combination with ibrutinib resulted in rapid and high response rates. The long-term clinical benefit of ublituximab will be defined by an ongoing phase 3 trial (NCT 02301156).

Genetically Engineered In Vitro Erythropoiesis.

BACKGROUND: Engineered blood has the greatest potential to combat a predicted future shortfall in the US blood supply for transfusion treatments. Engineered blood produced from hematopoietic stem cell (HSC) derived red blood cells in a laboratory is possible, but critical barriers exist to the production of clinically relevant quantities of red blood cells required to create a unit of blood. Erythroblasts have a finite expansion capacity and there are many negative regulatory mechanisms that inhibit in vitro erythropoiesis. In order to overcome these barriers and enable mass production, the expansion capacity of erythroblasts in culture will need to be exponentially improved over the current state of art. This work focused on the hypothesis that genetic engineering of HSC derived erythroblasts can overcome these obstacles. OBJECTIVES: The objective of this research effort was to improve in vitro erythropoiesis efficiency from human adult stem cell derived erythroblasts utilizing genetic engineering. The ultimate goal is to enable the mass production of engineered blood. METHODS: HSCs were isolated from blood samples and cultured in a liquid media containing growth factors. Cells were transfected using a Piggybac plasmid transposon. RESULTS: Cells transfected with SPI-1 continued to proliferate in a liquid culture media. Fluorescence-activated cell sorting (FACS) analysis on culture day 45 revealed a single population of CD71⁺CD117⁺ proerythroblast cells. The results of this study suggest that genetically modified erythroblasts could be immortalized in vitro by way of a system modeling murine erythroleukemia. CONCLUSION: Genetic modification can increase erythroblast expansion capacity and potentially enable mass production of red blood cells.

Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.

Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.

Exogenous c-Myc Blocks Differentiation and Improves Expansion of Human Erythroblasts In vitro.

BACKGROUND: Engineered blood has the greatest potential to combat a predicted future shortfall in the blood supply for transfusion treatment. The production of red blood cells from hematopoietic stem cells in the laboratory is possible but the mass production of red blood cells to the level present in a blood transfusion unit is currently not possible. The proliferation capacity of the immature red blood cell will need to be increased to enable mass production. This work focused on the hypothesis that exogenous c-Myc can delay the differentiation process of highly proliferative immature erythroblasts, and increase the proliferation capacity of erythroblast cell cultures. OBJECTIVES: The objective of this research effort was to improve in vitro erythropoiesis from stem cells without gene transfection with the eventual goal of producing blood for transfusion treatment in a manner that could be easily translated into clinical medicine. METHODS: The hematopoietic stem cell containing mononuclear cell fraction of venous blood samples was cultured in a liquid media containing erythroblasts growth factors with and without exogenous c-Myc combined with a cell -penetrating peptide. The cells were maintained in the liquid culture media for 23 days. Viable cells were counted and analyzed with flow cytometry. RESULTS: Our results show a 4 fold increase in expansion of the erythroblasts grown in the c-Myc containing growth media compared to the control. Eighty percent of these cells retained the CD117 surface receptor, indicating immature cells. CONCLUSION: Exogenous c-Myc blocks the differentiation and improves in vitro expansion of human erythroblasts.

Synchronous Gastric Metastasis of Renal Cell Carcinoma With Absence of Gastrointestinal Symptoms.

Renal cell carcinoma (RCC) is a rare adult malignancy, and one-third of cases present with distant metastases at the time of diagnosis. Early gastric metastasis is exceedingly rare. We describe an adult male with synchronous gastric metastasis of RCC at the time of diagnosis in the absence of gastrointestinal symptoms. We report the fifth case of RCC with synchronous gastric metastasis and the only case with early presentation in the absence of gastrointestinal symptoms.

A phase II study of sorafenib (BAY 43-9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404).

Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43-9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1-12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 - 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 - 5 months). Median overall survival (OS) was 9 months (90% CI, 5 - 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL.

The clinical impact of preoperative percutaneous drainage of abdominopelvic abscesses in patients with Crohn's disease.

PURPOSE: Although image-guided percutaneous drainage is increasingly being used to treat Crohn's disease-related abdominopelvic abscesses, surgery is seldom avoided. The aim of this study was to compare outcomes following the treatment of intra-abdominal Crohn's abscesses with percutaneous drainage followed by surgery to those after surgery alone. METHODS: We retrospectively reviewed the charts of patients treated for Crohn's-related abdominopelvic abscesses at Mount Sinai Medical Center between April 2001 and June 2010. Patients who underwent drainage followed by surgery were compared to those who underwent surgery alone. Differences in operative and postoperative outcomes were compared. RESULTS: Seventy patients with Crohn's disease-related abdominopelvic abscesses were identified, 38 (54%) of whom underwent drainage before surgery. Percutaneous drainage was technically successful in 92% of patients and clinically successful in 74% of patients. No differences in rate of septic complications (p = 0.14) or need for stoma creation (p = 0.78) were found. Patients who underwent percutaneous drainage had greater overall hospital lengths of stay (mean 15.8 versus 12.2 days, p = 0.007); 8.6% of patients had long-term postponement of surgery after percutaneous drainage. CONCLUSIONS: In our series, the treatment of Crohn's abscesses with percutaneous drainage prior to surgery did not decrease the rate of postoperative septic complications.

Modified Rives-Stoppa technique for repair of complex incisional hernias in 59 patients.

Incisional hernias develop in 2% to 11% of patients who undergo laparotomy. Prosthetic mesh repair provides more strength, tension-free closure, and decreased recurrence rates as compared to primary tissue repairs. Complications-fistula formation, adhesions, skin erosion, and seroma/abscess formation-however, include increased rates of infection, sometimes requiring complete mesh removal. The Rives-Stoppa repair for complex incisional hernias confers the benefits of prosthetic repair and lower recurrence rates, but decreases certain complications by preventing direct mesh contact with the bowel. A total of 89 consecutive patients (mean age, 58.1) underwent a modified Rives-Stoppa repair for purposes of this review, all the patients who lost to follow-up before 6 months postoperatively were excluded from the study. Of the remaining 59 patients, 32.2% (n = 19) had expanded polytetrafluoroethylene mesh, and 67.8% (n = 40) had polypropylene mesh. Average range of follow-up was 40.0 months. Hernia recurred in 1 patient (1.7%). Infection requiring explantation of the prosthesis occurred in 3 patients (5.1%). The Rives-Stoppa repair is reportedly the best open technique for complex incisional hernias with comparatively lower recurrence rates. Additionally, patients with inflammatory bowel disease (64.4% of our series), who often require later reoperation for their primary disease, may benefit from this technique of herniorrhaphy where no interface exists between intrabdominal contents and the prosthesis. This lack of interface decreases intrabdominal adhesions and facilitates re-entry if future surgery is needed for inflammatory bowel disease.

Synthesis and evaluation of inhibitors of bacterial drug efflux pumps of the major facilitator superfamily.

Inhibitors of drug efflux pumps have great potential as pharmacological agents that restore the drug susceptibility of multidrug resistant bacterial pathogens. Most attention has been focused on the discovery of small molecules that inhibit the resistance nodulation division (RND) family drug efflux pumps in Gram-negative bacteria. The prototypical inhibitor of RND-family efflux pumps in Gram-negative bacteria is MC-207,110 (Phe-Arg-ß-naphthylamide), a C-capped dipeptide. Here, we report that C-capped dipeptides inhibit two chloramphenicol-specific efflux pumps in Streptomyces coelicolor, a Gram-positive bacterium that is a relative of the human pathogen Mycobacterium tuberculosis. Diversity-oriented synthesis of a library of structurally related C-capped dipeptides via an Ugi four component reaction and screening of the resulting compounds resulted in the discovery of a compound that is threefold more potent as a suppressor of chloramphenicol resistance in S. coelicolor than MC-207,110. Since chloramphenicol resistance in S. coelicolor is mediated by major facilitator superfamily drug efflux pumps, our findings provide the first evidence that C-capped dipeptides can inhibit drug efflux pumps outside of the RND superfamily.

Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs.

Poor penetration of anticancer drugs into tumors can be an important factor limiting their efficacy. We studied mouse tumor models to show that a previously characterized tumor-penetrating peptide, iRGD, increased vascular and tissue permeability in a tumor-specific and neuropilin-1-dependent manner, allowing coadministered drugs to penetrate into extravascular tumor tissue. Importantly, this effect did not require the drugs to be chemically conjugated to the peptide. Systemic injection with iRGD improved the therapeutic index of drugs of various compositions, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab). Thus, coadministration of iRGD may be a valuable way to enhance the efficacy of anticancer drugs while reducing their side effects, a primary goal of cancer therapy research.

Effective surgical treatment of cubital tunnel syndrome based on provocative clinical testing without electrodiagnostics.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe a method of clinical evaluation for accurate diagnosis of ulnar compression syndrome at the elbow. 2. Evaluate the accuracy and efficacy of the described method in diagnosing surgically correctable nerve entrapment. 3. Present a protocol for conservative management followed by surgical correction. 4. Discuss the results of the method and protocol in two series of patients treated by a single surgeon. BACKGROUND: This study of two patient populations addresses the effectiveness of identifying surgically correctable ulnar nerve compression at the elbow based on provocative clinical testing alone in patients with cubital tunnel syndrome after failure of conservative treatment. METHODS: Twenty-four patients were included in the preliminary study (mean age, 60 years). Three of these patients underwent bilateral procedures. Patients complaining of symptoms in the distribution of the ulnar nerve were tested by elicitation of Tinel's sign and combined flexion and pressure testing at the elbow and wrist. Two-point discrimination was determined. After a failed 6-week trial of conservative therapy, patients underwent anterior submuscular transposition of the ulnar nerve with carpal tunnel release. RESULTS: Postoperatively, the change in two-point discrimination as measured at 6 months was significantly improved, with a mean improvement per digital nerve of 2.52 mm (p < 0.001). Mean time to relief was 7.2 weeks. Complications included one hematoma and one seroma. A total of 26 of the 27 limbs chosen for surgical treatment by provocative clinical testing alone experienced relief of symptoms with anterior submuscular transposition of the ulnar nerve and carpal tunnel release. CONCLUSIONS: This study demonstrates the effectiveness of surgical therapy in patients with lesions identified by clinical examination without electrodiagnostic testing. After the completion of this study, an additional 87 patients were treated (18 bilateral) with cubital tunnel release. The data from these patients confirm the effectiveness of surgical treatment of ulnar entrapment neuropathy based on provocative clinical testing.

Mechanical and sensory testing of overfilled breast implants.

BACKGROUND: To obtain an ideal outcome in breast augmentation procedures, breast implants may be overfilled to reduce wrinkles and improve longevity. Determination of the optimal volume for saline-filled breast implants remains problematic for plastic surgeons. OBJECTIVE: We sought to evaluate the effect of overfilling or underfilling implants on sensory response and on implant shell mechanical properties. METHODS: Fifty-three Mentor Style 1600 smooth saline-filled mammary implants (275-cc base volume) were examined. Saline fill volumes ranged from 230 cc to 1650 cc. Implants were incubated at 37 degrees C and 100% humidity for 6 weeks. Before destructive testing to determine strength, elasticity, and toughness, 22 women ranging in age from 18 to 55 years graded the implants for firmness to palpation. Objective indices of firmness were measured by durometer. RESULTS: Implants filled 50% above manufacturer's recommended volume were considered firm, whereas implants 50% below manufacturer's recommended volume were considered natural or soft. A linear relationship was observed between sensory response and durometer hardness data. Fill volume did not affect shell mechanical properties: shell strength, toughness, and elasticity remained unchanged (P > .05). CONCLUSIONS: Saline-filled breast implants can be safely filled far beyond manufacturer's recommendations with regard to the mechanical properties of the Silastic polymer implant shell. Clinical judgment is required to avoid hardness due to overfill. Repeating this study using an in vivo incubation method is required to determine how overfill will affect implant shells over time in the harsh milieu of a biologic environment.

Rectus femoris myocutaneous flap for vulvoperineal reconstruction.

BACKGROUND: Many reconstructive procedures for large vulvoperineal defects have been described. The present report describes the use of the rectus femoris myocutaneous flap, which has not previously been described for this purpose. CASE: A 52-year-old woman suffered a local recurrence of a Bartholin's gland carcinoma after anterior exenteration and pubectomy. A palliative resection was performed which resulted in a large vulvoperineal defect with transpelvic herniation of the peritoneal contents. This was immediately reconstructed with a rectus femoris myocutaneous flap. Her postoperative course and healing were uneventful. CONCLUSION: This technique is an alternative method for vulvar reconstruction. It is especially useful for large defects when a gracilis or rectus abdominis flap is not available.