Nano-revolution in hepatocellular carcinoma: A multidisciplinary odyssey - Are we there yet?

In this editorial we comment on the review by Zhou et al reviewing the landscape of nanomedicine in the treatment of hepatocellular carcinoma (HCC). We focus on the immense potential of nanotechnology, particularly ligand-receptor mediated nanotherapy, in revolutionizing the treatment landscape of HCC. Despite advancements in multidisciplinary treatment, HCC remains a significant global health challenge. Ligand-mediated nanotherapy offers the opportunity for precise drug delivery to tumor sites, targeting specific receptors overexpressed in HCC cells, thereby enhancing efficacy and minimizing side effects. Overcoming drug resistance and aggressive tumor biology is facilitated by nanomedicine, bypassing traditional hurdles encountered in chemotherapy. Examples include targeting glypican-3, asialoglycoprotein, transferrin receptor or folic acid receptors, capitalizing on their over-expression in tumor cells. The ability for multi-receptor targeting through dual-ligand nanoparticle modification holds the prospect of further enhancement in specificity and efficacy of directed therapy. However, challenges including immune responses, reproducibility in nanoparticle synthesis, and production scalability remain. Future directions involve refining targeting strategies, improving drug release mechanisms, and streamlining production processes to enable personalized and multifunctional nanotherapies. Overall, the integration of nanotherapy in HCC treatment holds immense promise, but continued partnership and effort are needed in offering hope for more effective, precise, and accessible clinical care in the management of HCC.

A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real-World Data: A Retrospective Observational Study.

Background: Rapid reduction of leukemic cells in the bone marrow during remission induction chemotherapy (RIC) can lead to significant complications such as tumor lysis syndrome (TLS). We investigated whether prephase steroid treatment before RIC could decrease TLS incidence and improve overall survival in pediatric patients with acute lymphoblastic leukemia (ALL). Methods: Data were extracted from the Common Data Model databases in two tertiary-care hospitals in Seoul, South Korea. Patients were classified into the treated or untreated group if they had received RIC with prephase steroid treatment ≥7 days before RIC in 2012-2021 or not, respectively. Stabilized Inverse Probability of Treatment Weighting (sIPTW) was applied to ensure compatibility between the treated and untreated groups. The incidence of TLS within 14 days of starting RIC, overall survival (OS), and the incidence of adverse events of special interest were the primary endpoints. Multiple sensitivity analyses were performed. Results: Baseline characteristics were effectively balanced between the treated (n=308.4) and untreated (n=246.6) groups after sIPTW. Prephase steroid treatment was associated with a significant 88% reduction in the risk of TLS (OR 0.12, 95% CI: 0.03-0.41). OS was numerically greater in the treated group than in the untreated group although the difference was not statistically significant (HR 0.64, 95% CI 0.25-1.64). The treated group experienced significantly elevated risks for hyperbilirubinemia and hyperglycemia. The reduction in TLS risk by prephase steroid treatment was maintained in all of the sensitivity analyses. Conclusion: Prephase steroid treatment for ≥7 days before RIC in pediatric patients with ALL reduces the risk of TLS, while careful monitoring for toxicities is necessary. If adequately analyzed, real-world data can provide crucial effectiveness and safety information for proper management of pediatric patients with ALL, for whom prospective randomized studies may be difficult to perform for ethical and practical reasons.

A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer.

PURPOSE: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). MATERIALS AND METHODS: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. RESULTS: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). CONCLUSION: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Trends in medical care utilization in patients with cancer: An analysis of real-world data in a tertiary hospital in Korea, 2014-2019.

BACKGROUND: Rising costs of cancer treatments challenge even areas with universal health coverage. There's a need to assess current medical care utilization trends among patients with cancer to guide public health policy, resource allocation, and set informed healthcare goals. METHODS: We analyzed the latest trends in medical care utilization by cancer patients in four areas-drugs, radiation therapy (RT), surgery, and diagnostic procedures-using clinical databases extracted from electronic medical records of a tertiary hospital in Korea between 2014 and 2019. Compound adjusted growth rates (CAGR) were computed to capture the annual growth over the study period. RESULTS: A total of 74,285 cancer patients were identified, with 40.3% (29,962), 14.2% (10,577), 31.1% (23,066), and 92.6% (68,849) of patients having received at least one anticancer agent, RT, surgery, and diagnostic procedure, respectively, over the period. We observed a 1.7-fold increase in the use of targeted · immune-oncology agents (from 6.8% to 11.6%) and a 21-fold increase (from 3.0% in 2014 to 65.7%) in intensity-modulated RT (IMRT) use over the period. In contrast, we observed a continuous decrease in the proportion of patients who underwent surgical treatment from 12.2% in 2014 to 10.9% in 2019. This decrease was particularly noticeable in patients with colon cancer (from 28.5% to 24.2%) and liver cancer (from 4.1% to 2.9%). CONCLUSION: From 2014 to 2019, there was a significant rise in the use of targeted · immune-oncology agents and IMRT, alongside a decline in surgeries. While targeted · immune-oncology agents and IMRT may offer promising outcomes, their financial impact and potential for overuse necessitate careful oversight and long-term cost-effectiveness studies.

Multifocal Pyloric Gland Adenoma of the Esophagus Treated by Circumferential Endoscopic Submucosal Dissection.

Pyloric gland adenoma is a rare neoplasm of the gastrointestinal tract typically observed in the stomach with a substantial malignant potential warranting its resection. While isolated esophageal pyloric gland adenoma has been reported, there is no literature on the encounter of diffuse, multifocal esophageal pyloric gland adenoma or its management. We present a unique case of multifocal pyloric gland adenoma of the esophagus treated by circumferential endoscopic submucosal dissection. We demonstrate endoscopic submucosal dissection to be a feasible management option.

Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer.

PURPOSE: Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures. METHODS: In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis. RESULTS: In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04). CONCLUSION: Combining a computer prognosis model with care coaches increased ACP documentation.

A Randomized, Double-Blind, Placebo- and Active-Controlled, Escalating Single-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Subcutaneous Eflapegrastim in Healthy Japanese and Caucasian Subjects.

BACKGROUND: Eflapegrastim (Rolontis®) is a novel long-acting pegylated recombinant human granulocyte colony-stimulating factor (G-CSF). Eflapegrastim has been developed to reduce the duration and incidence of chemotherapy-induced neutropenia in cancer patients using patient-friendly, less-frequent administration. OBJECTIVE: This phase I study aimed to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of eflapegrastim following a single subcutaneous administration to healthy Japanese and Caucasian subjects. METHODS: A randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted in healthy Japanese and Caucasian subjects. Eligible subjects randomly received a single subcutaneous administration of eflapegrastim (1.1, 3.3, 10, 45, 135, and 270 µg/kg), pegfilgrastim 6 mg, or placebo in a ratio of 6:2:2 (Cohorts 1-2, Caucasian subjects only) or 12:2:2 (Cohorts 3-6, Japanese and Caucasian subjects). Safety and tolerability were assessed throughout the study. Serial blood samples were collected predose and up to day 22 postdose for PK and PD analyses. PK assessments were performed in the 45, 135, and 270 µg/kg dose groups. Antidrug antibodies to eflapegrastim were determined at baseline up to day 42 after the first dose for immunogenicity. RESULTS: A total of 84 subjects (42 males and 42 females) were enrolled, and 78 (31 Japanese and 47 Caucasian subjects) completed the study as planned. Japanese and Caucasian subjects showed similar PK and PD profiles. In the 45, 135, and 270 µg/kg dose groups, the maximum serum concentration (Cmax) of eflapegrastim exhibited a dose-proportional increase, whereas its exposure increased greater than dose proportional in both ethnic groups. The mean area under the effect-time curve (AUEClast) and maximum serum concentration of both absolute neutrophil count (ANCmax) and CD34+ cell count (CD34+max) increased in a dose-dependent manner. There were no significant adverse events attributable to eflapegrastim or pegfilgrastim in both Japanese and Caucasian subjects. No neutralizing antibodies against G-CSF were detected. CONCLUSIONS: Eflapegrastim was safe and well tolerated at doses up to 270 µg/kg in healthy Japanese and Caucasian subjects. In both ethnic groups, eflapegrastim showed dose-dependent PK and the exposure to eflapegrastim was positively correlated with ANC and CD34+ cell count. The comparable PK and PD profiles of eflapegrastim in Japanese and Caucasian subjects may indicate the same dosage regimen is acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01037543 (23 December 2009).

Communicating the Information Needed for Treatment Decision Making Among Patients With Pancreatic Cancer Receiving Preoperative Therapy.

PURPOSE: Preoperative therapy for pancreatic cancer represents a new treatment option with the potential to improve outcomes for patients, yet with complex risks. By not discussing the potential risks and benefits of new treatment options, clinicians may hinder patients from making informed decisions. METHODS: From 2017 to 2019, we conducted a mixed-methods study. First, we elicited clinicians' (n = 13 medical, radiation, and surgery clinicians), patients' (n = 18), and caregivers' (n = 14) perceptions of information needed for decision making regarding preoperative therapy and generated a list of key elements. Next, we audio-recorded patients' (n = 20) initial multidisciplinary oncology visits and used qualitative content analyses to describe how clinicians discussed this information and surveyed patients to ask if they heard each key element. RESULTS: We identified 13 key elements of information patients need when making decisions regarding preoperative therapy, including treatment complications, alternatives, logistics, and potential outcomes. Patients reported hearing infrequently about complications (eg, hospitalizations [n = 3 of 20]) and alternatives (n = 8 of 20) but frequently recalled logistics and potential outcomes (eg, likelihood of surgery [n = 19 of 20]). Clinicians infrequently discussed complications (eg, hospitalizations [n = 7 of 20]), but frequently discussed alternatives, logistics, and potential outcomes (eg, likelihood of surgery [n = 20 of 20]). No overarching differences in clinician discussion content emerged to explain why patients did or did not hear about each key element. CONCLUSION: We identified key elements of information patients with pancreatic cancer need when considering preoperative therapy. Patients infrequently heard about treatment complications and alternatives, while frequently hearing about logistics and potential outcomes, underscoring areas for improvement in educating patients about new treatment options in oncology.

Anesthetic management of a parturient with Marfan syndrome scheduled for cesarean section: case report and review of literature / Manejo anestésico de una parturienta con síndrome de Marfan programada para cesárea: informe de un caso y revisión de la literatura

Abstract: Introduction: Marfan syndrome is an inherited disorder that affects connective tissue. Case: We report the anesthetic management of a parturient with Marfan syndrome scheduled for an elective C-section. Successful use of a combined spinal-epidural technique was used to provide neuraxial anesthesia; however, she presented an unfavorable evolution due to maternal sepsis. Likewise, a literature review of combined spinal-epidural anesthesia for C-sections in Marfan syndrome pregnant women was performed. Conclusion: Anesthetic management of parturients affected by Marfan syndrome during the cesarean section can be challenging. Strict blood pressure control during the intraoperative period has cornerstone importance. Likewise, neuraxial techniques have a significant percentage of failure in these patients.

Resumen: Introducción: El síndrome de Marfan es un desorden hereditario que afecta el tejido conectivo. Caso: Reportamos el manejo anestésico de una parturienta con síndrome de Marfan programada para una cesárea electiva. Para administrar anestesia neuroaxial se utilizó un bloqueo combinado espinal-epidural; sin embargo, la paciente presentó una evolución desfavorable debido a sepsis materna. Asimismo, se realizó una revisión de la literatura del uso de esta técnica anestésica para cesárea en gestantes con síndrome de Marfan. Conclusión: El manejo anestésico de parturientas afectadas por este síndrome puede ser complicado. El control estricto de la presión arterial durante el intraoperatorio tiene importancia fundamental. Además, las técnicas neuroaxiales tienen un porcentaje significativo de fallo en estas pacientes.

Mechanisms Driving Immune-Related Adverse Events in Cancer Patients Treated with Immune Checkpoint Inhibitors.

PURPOSE OF REVIEW: In the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer treatment. With the continuing rise in the number of cancer patients eligible for ICIs, a corresponding rise in immune-related adverse events (irAEs) is occurring. IrAEs are inflammatory reactions against normal, healthy tissue that occur due to ICI-induced activation of the immune system. Although the exact immune pathogenesis driving irAE development remains unknown, we review the main proposed mechanisms, highlighting how they may inform irAE prediction and treatment. RECENT FINDINGS: IrAEs are common and diverse, varying in incidence, timing, and severity. The possible mechanisms driving irAEs include (1) activation of cytotoxic T cells; (2) activation of B cells and increased autoantibody production; (3) direct molecular mimicry and off-target toxicity; (4) activation of intracellular signaling and pro-inflammatory cytokine production; and (5) environmental modifiers of immune system activation, including composition of the host gut microbiome. These mechanisms may help identify predictive biomarkers and targeted treatment strategies. IrAEs are driven by multiple components of the immune system. More research is needed to understand their immunopathogenesis so that clinicians across all specialties may more effectively monitor and manage these increasingly common conditions.

Tissue pharmacokinetics of DHP107, a novel lipid-based oral formulation of paclitaxel, in mice and patients by positron emission tomography.

DHP107 is a newly developed lipid-based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope-labeled [3 H]DHP107 and [18 F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107. In vivo tissue PK were assessed in healthy ICR mice and breast cancer xenografted SCID mice. Two patients with metastatic breast cancer were clinically evaluated for absorption at the target lesion after internal absorbed dose estimation. Whole-body PET/computed tomography data were acquired in healthy and xenografted mice and in patients up to 10-24 h after administration. Tissue [18 F]DHP107 signals were plotted against time and PK parameters were determined. The amounts of radioactivity in various organs and excreta were determined using a beta-counter and are expressed as the percentage of injected dose (ID). Oral [18 F]DHP107 was well-absorbed and reached the target lesion in mice and patients with breast cancer. Significant amounts of radioactivity were found in the stomach, intestine, and liver after oral administration of [3 H]- and [18 F]DHP107 in healthy mice. The [18 F]DHP107 reached a peak distribution of 0.7-0.8%ID in the tumor at 5.6-7.3 h in the xenograft model. The [18 F]DHP107 distribution in patients with metastatic breast cancer was the highest at 3-4 h postadministration. Systemic exposures after administration of a DHP107 therapeutic dose were comparable with those in previous studies. PET using radioisotope-labeled drug candidates is useful for drug development and can provide valuable information that can complement plasma PK data, particularly in early phase clinical trials.

A target-mediated drug disposition population pharmacokinetic model of GC1118, a novel anti-EGFR antibody, in patients with solid tumors.

GC1118 is a monoclonal antibody for epidermal growth factor receptor (EGFR) that is currently under clinical development to treat patients with solid tumors. In this study, the pharmacokinetics (PKs) of GC1118 were modeled in solid tumor patients who received a 2-h intravenous infusion of GC1118 at 0.3, 1, 3, 5, or 4 mg/kg once-weekly (Q1W) on days 1, 8, 15, and 22 or 8 mg/kg every other week on days 1 and 15. A target-mediated drug disposition population PK model adequately described the concentration-time profiles of GC1118. Monte-Carlo simulation experiments of the PK profiles and EGFR occupancies (ROs) by GC1118 based on the final model showed that Q1W at 4 or 5 mg/kg will produce a better antitumor effect than Q2W at 8 mg/kg. Because GC1118 was safer at 4 mg/kg than 5 mg/kg in the phase I study, we suggest to test the 4 mg/kg Q1W regimen in further clinical trials with GC1118. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GC1118, a fully human IgG1 monoclonal antibody (mAb) for epidermal growth factor receptor (EGFR), showed a nonlinear pharmacokinetic (PK) profile in monkeys and humans. The total clearance of GC1118 decreased as the dose was increased up to 3-4 mg/kg in humans, beyond which it remained stable. The recommended phase II dose for GC1118 was 4 mg/kg intravenously infused over 2 h once weekly. WHAT QUESTION DID THIS STUDY ADDRESS? We developed a target-mediated drug disposition (TMDD) population PK model that described the nonlinear PK profile of GC1118 in patients with solid tumors. We also simulated the PK profiles and receptor occupancies for different dosage regimens. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The TMDD population PK model adequately described the nonlinear and multiphasic PK profiles of GC1118 in humans. The simulation experiment showed that once-weekly GC1118 at 4-5 mg/kg could be more efficacious than the biweekly regimen at 8 mg/kg. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The pharmacometrics analysis could support better informed drug development decisions for GC1118, particularly for determining an optimal dosage regimen.

Simulation-Based Course Improves Resident Comfort, Knowledge, and Ability to Manage Surgical Intensive Care Unit Patients.

BACKGROUND: Simulation-based education can augment residents' skills and knowledge. We assessed the effectiveness of a simulation-based course for surgery interns designed to improve their comfort, knowledge, and ability to manage common surgical critical care (SCC) conditions. MATERIALS AND METHODS: For 2 y, all first year residents (n = 31) in general surgery, urology, interventional radiology, and the integrated plastics, vascular, and cardiothoracic surgery training programs at our institution participated in a simulation-based course emphasizing evidence-based management of SCC conditions. Precourse and postcourse surveys and multiple-choice tests, as well as summative simulation tests, assessed interns' comfort, knowledge, and ability to manage SCC conditions. Changes in these measures were assessed with Wilcoxon matched-pairs signed rank tests. Factors associated with summative performance were determined by linear regression. RESULTS: The course consisted of four simulation-based teaching sessions in year 1 and six in year 2. The course taught seven of the 18 core SCC conditions in the Surgical Council on Resident Education general surgery curriculum in year 1 and 10 in year 2. Interns' self-reported comfort, knowledge, and ability to manage each condition taught in the course increased (P < 0.02). Their knowledge of each condition, as assessed by written tests, also increased (P < 0.02). Their summative simulation test performance correlated with the number of course sessions attended (P < 0.03) and status as general surgery residents (P < 0.01). CONCLUSIONS: A simulation-based SCC training course for surgery interns that emphasizes evidence-based management of SCC conditions improves interns' comfort, knowledge, and ability to manage these conditions.

Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome.

CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of ß-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.

A Machine Learning-Based Identification of Genes Affecting the Pharmacokinetics of Tacrolimus Using the DMETTM Plus Platform.

Tacrolimus is an immunosuppressive drug with a narrow therapeutic index and larger interindividual variability. We identified genetic variants to predict tacrolimus exposure in healthy Korean males using machine learning algorithms such as decision tree, random forest, and least absolute shrinkage and selection operator (LASSO) regression. rs776746 (CYP3A5) and rs1137115 (CYP2A6) are single nucleotide polymorphisms (SNPs) that can affect exposure to tacrolimus. A decision tree, when coupled with random forest analysis, is an efficient tool for predicting the exposure to tacrolimus based on genotype. These tools are helpful to determine an individualized dose of tacrolimus.

Rectal Hydrogel Spacer Improves Late Gastrointestinal Toxicity Compared to Rectal Balloon Immobilization After Proton Beam Radiation Therapy for Localized Prostate Cancer: A Retrospective Observational Study.

PURPOSE: Our purpose was to compare dosimetric parameters and late gastrointestinal outcomes between patients treated with proton beam therapy (PBT) for localized prostate cancer with rectal balloon immobilization versus a hydrogel rectal spacer. METHODS AND MATERIALS: Patients with localized, clinical stage T1-4 prostate adenocarcinoma were treated at a single institution using conventionally fractionated, dose-escalated PBT from 2013 to 2018. Patient-reported gastrointestinal toxicity was prospectively collected, and the incidence of rectal bleeding was retrospectively reviewed from patient records. RESULTS: One hundred ninety-two patients were treated with rectal balloon immobilization, and 75 were treated with a rectal spacer. Rectal hydrogel spacer significantly improved rectal dosimetry while maintaining excellent target coverage. The 2-year actuarial rate of grade 2+ late rectal bleeding was 19% and 3% in the rectal balloon and hydrogel spacer groups, respectively (P = .003). In univariable analysis, the probability of grade 2+ rectal bleeding was significantly correlated with increasing rectal dose. In multivariable analysis, only receipt of spacer hydrogel (hazard ratio, 0.145; P = .010) and anticoagulation use (hazard ratio, 5.019; P < .001) were significantly associated with grade 2+ bleeding. At 2-year follow-up, patient-reported Expanded Prostate Cancer Index Composite bowel quality of life composite scores were less diminished in the hydrogel spacer group (absolute mean difference, 5.5; P = .030). CONCLUSIONS: Use of rectal hydrogel spacer for prostate PBT is associated with a significantly lower incidence of clinically relevant, late rectal bleeding and lower decrement in long-term, patient-reported bowel quality of life compared with rectal balloon immobilization. Our results suggest that hydrogel spacer may improve rectal sparing compared with rectal balloon immobilization during PBT for prostate cancer.

Weekly Dose-Dense Paclitaxel and Triweekly Low-Dose Cisplatin: A Well-Tolerated and Effective Chemotherapeutic Regimen for First-Line Treatment of Advanced Ovarian, Fallopian Tube, and Primary Peritoneal Cancer.

A combination of cytoreductive surgery, either primary (PCS) or interval (ICS), and chemotherapy with a platinum-paclitaxel regimen is the well-accepted treatment for advanced-stage epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), and primary peritoneal serous carcinoma (PPSC), but it is still uncertain whether a combination of dose-dense weekly paclitaxel and low-dose triweekly cisplatin is useful in the management of these patients. Therefore, we retrospectively evaluated the outcomes of women with advanced-stage EOC, FTC, and PPSC treated with PCS and subsequent dose-dense weekly paclitaxel (80 mg/m2) and low-dose triweekly cisplatin (20 mg/m2). Between January 2011 and December 2017, 32 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV EOC, FTC, or PPSC were enrolled. Optimal PCS was achieved in 63.5% of patients. The mean and median progression-free survival was 36.5 and 27.0 months, respectively (95% confidence interval (CI): 26.8-46.2 and 11.3-42.7 months, respectively). The mean overall survival was 56.0 months (95% CI: 43.9-68.1 months), and the median overall survival could not be obtained. The most common all-grade adverse events (AEs) were anemia (96.9%), neutropenia (50%), peripheral neuropathy (28.1%), nausea and vomiting (34.4%), and thrombocytopenia (15.6%). These AEs were predominantly grade 1/2, and only a few patients were complicated by grade 3/4 neutropenia (21.9%) and anemia (6.3%). A multivariate analysis indicated that only suboptimal PCS was significantly correlated with a worse prognosis, resulting in an 11.6-fold increase in the odds of disease progression. In conclusion, our data suggest that dose-dense weekly paclitaxel (80 mg/m2) combined with low-dose triweekly cisplatin (20 mg/m2) is a potentially effective and highly tolerable front-line treatment in advanced EOC, FTC, and PPSC. Randomized trials comparing the outcome of this regimen to other standard therapies for FIGO stage IIIC-IV EOC, FTC, and PPSC are warranted.

Association of metabolic and genetic heterogeneity in head and neck squamous cell carcinoma with prognostic implications: integration of FDG PET and genomic analysis.

PURPOSE: The linkage between the genetic and phenotypic heterogeneity of the tumor has not been thoroughly evaluated. Herein, we investigated how the genetic and metabolic heterogeneity features of the tumor are associated with each other in head and neck squamous cell carcinoma (HNSC). We further assessed the prognostic significance of those features. METHODS: The mutant-allele tumor heterogeneity (MATH) score (n = 508), a genetic heterogeneity feature, and tumor glycolysis feature (GlycoS) (n = 503) were obtained from the HNSC dataset in the cancer genome atlas (TCGA). We identified matching patients (n = 33) who underwent 18F-fluorodeoxyglucose positron emission tomography (FDG PET) from the cancer imaging archive (TCIA) and obtained the following information from the primary tumor: metabolic, metabolic-volumetric, and metabolic heterogeneity features. The association between the genetic and metabolic features and their prognostic values were assessed. RESULTS: Tumor metabolic heterogeneity and metabolic-volumetric features showed a mild degree of association with MATH (n = 25, ρ = 0.4~0.5, P < 0.05 for all features). The patients with higher FDG PET features and MATH died sooner. Combination of MATH and tumor metabolic heterogeneity features showed a better stratification of prognosis than MATH. Also, higher MATH and GlycoS were associated with significantly worse overall survival (n = 499, P = 0.002 and 0.0001 for MATH and GlycoS, respectively). Furthermore, both MATH and GlycoS independently predicted overall survival after adjusting for clinicopathologic features and the other (P = 0.015 and 0.006, respectively). CONCLUSION: Both tumor metabolic heterogeneity and metabolic-volumetric features assessed by FDG PET showed a mild degree of association with genetic heterogeneity in HNSC. Both metabolic and genetic heterogeneity features were predictive of survival and there was an additive prognostic value when the metabolic and genetic heterogeneity features were combined. Also, MATH and GlycoS were independent prognostic factors in HNSC; they can be used for precise prognostication once validated.

Paclitaxel-related dermatological problems: Not only alopecia occurs.

OBJECTIVE: Dermatological problems after chemotherapy are often neglected with gynecological oncologists. Since paclitaxel is one of most popular agents for gynecology organ-related cancers, dermatologic change after paclitaxel treatment is seldom reported before. CASE REPORT: Two patients with gynecological organ malignancy who underwent the postoperative dose-dense weekly schedule of paclitaxel 80 mg/m2 plus carboplatin (area of curve 5) every three weeks had repeat dermatological problems (skull, facial and upper trunk areas) during the treatment. They included dermatitis, eczema, and folliculitis. Topical use of anti-fungal cream and oral anti-histamine agents stopped the disease progression and all had completed their chemotherapy without interruption. CONCLUSION: Clinicians should be aware of paclitaxel-induced skin toxicities, especially on the skull, face and upper trunk areas to minimize the occurrence of severe morbidity and to provide the better quality of life when cure is our primary priority in the management of gynecological organs-related malignancies.