Monitoring ctDNA RAS Mutational Status in Metastatic Colorectal Cancer: A Trial Protocol of RAS-trace and RAS-trace-2 Studies.

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy. Methods/Design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years. Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC.

Safety of immune checkpoint inhibitors in patients aged over 80 years: a retrospective cohort study.

BACKGROUND: Immuno-oncology (IO) drugs are essential for treating various cancer types; however, safety concerns persist in older patients. Although the incidence of immune-related adverse events (irAEs) is similar among age groups, higher rates of hospitalization or discontinuation of IO therapy have been reported in older patients. Limited research exists on IO drug safety and risk factors in older adults. Our investigation aimed to assess the incidence of irAEs and identify the potential risk factors associated with their development. METHODS: This retrospective analysis reviewed the clinical data extracted from the medical records of patients aged > 80 years who underwent IO treatment at our institution. Univariate and multivariate analyses were performed to assess the incidence of irAEs. RESULTS: Our study included 181 patients (median age: 82 years, range: 80-94), mostly men (73%), with a performance status of 0-1 in 87% of the cases; 64% received IO monotherapy. irAEs occurred in 35% of patients, contributing to IO therapy discontinuation in 19%. Our analysis highlighted increased body mass index, eosinophil counts, and albumin levels in patients with irAEs. Eosinophil count emerged as a significant risk factor for any grade irAEs, particularly Grade 3 or higher, with a cutoff of 118 (/µL). The group with eosinophil counts > 118 had a higher frequency of irAEs, and Grade 3 or higher events than the group with counts ≤ 118. CONCLUSION: IO therapy is a safe treatment option for patients > 80 years old. Furthermore, patients with elevated eosinophil counts at treatment initiation should be cautiously managed.

Comparison of patients with benzodiazepine receptor agonist-related psychiatric disorders and over-the-counter drug-related psychiatric disorders before and after the COVID-19 pandemic: Changes in psychosocial characteristics and types of abused drugs.

AIM: To investigate changes in the clinical characteristics of patients who abused benzodiazepine receptor agonists (BZRA) or over-the-counter (OTC) drugs before and after COVID-19 based on the 2018 and 2022 data of the "Nationwide Psychiatric Hospital (NPH) Survey on Drug-related Psychiatric Disorders." METHOD: A total of 446 and 155 cases, and 435 and 273 cases, who mainly abused BZRAs or OTC drugs, respectively, were extracted from the database of the two NPH Surveys. Demographic variables, education, employment, criminal record, drug use during the previous year, psychiatric diagnosis, and types of abused drugs were compared between 2018 and 2022. RESULT: A comparison of BZRA abusers revealed a decreased number of users during the previous year and an increase in the comorbidity rate of other disorders (F3 and F4 in ICD-10) in 2022. Etizolam, flunitrazepam, triazolam, and zolpidem were used most in both years, with an increase in zolpidem and a decrease in triazolam in 2022. A comparison of OTC drug abusers revealed a higher proportion of women and young patients in 2022. An increase in the comorbidity rate of F3 and F9 and a significant increase in the use of dextromethorphan products were observed in 2022, although codeine products were in the majority in both years. CONCLUSION: By comparing NPH Surveys before and after the COVID-19 pandemic, both BZRA abusers and OTC drug abusers present complex pathologies, requiring tailor-made treatment. The younger OTC drug abusers were particularly evident among women, and the abuse of dextromethorphan-containing OTC drugs has increased alarmingly.

Switching from FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab based on early tumor shrinkage in RAS wild-type metastatic colorectal cancer: A phase II trial (HYBRID).

BACKGROUND: Long-term anti-EGFR antibody treatment increases the risk of severe dermatologic toxicities. This single-arm, phase II trial aimed to investigate the strategy of switching from cetuximab to bevacizumab in combination with FOLFIRI based on early tumor shrinkage (ETS) in patients with RAS wild-type metastatic colorectal cancer (mCRC). METHODS: Radiologic assessment was performed to evaluate ETS, defined as ≥20% reduction in the sum of the largest diameters of target lesions 8 weeks after the introduction of FOLFIRI plus cetuximab. ETS-negative patients switched to FOLFIRI plus bevacizumab, whereas ETS-positive patients continued FOLFIRI plus cetuximab for eight more weeks, with a switch to FOLFIRI plus bevacizumab thereafter. The primary endpoint was progression-free survival. RESULTS: This trial was prematurely terminated due to poor accrual after a total enrollment of 30 patients. In 29 eligible patients, 7 were ETS-negative and 22 were ETS-positive. Two ETS-negative patients and 17 ETS-positive patients switched to FOLFIRI plus bevacizumab 8 weeks and 16 weeks after initial FOLFIRI plus cetuximab, respectively. Median progression-free and overall survival durations were 13.4 and 34.7 months, respectively. Six (20%) patients experienced grade ≥3 paronychia, which improved to grade ≤2 by 18 weeks. Grade ≥3 acneiform rash, dry skin, and pruritus were not observed in any patients. CONCLUSIONS: Our novel treatment strategy delivered acceptable survival outcomes and reduced severe dermatologic toxicities.

A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G.

BACKGROUND: Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients. OBJECTIVE: We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses. METHODS: This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit. RESULTS: Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1). CONCLUSIONS: This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment. CLINICAL TRIAL REGISTRATION: jRCTs041190100.

Risk and protective factors for early dropout from telephone monitoring for individuals with drug convictions in community mental health centers in Japan.

INTRODUCTION: Individuals involved with the criminal justice system face challenges in receiving and maintaining substance use disorder (SUD) treatment and support. Although telephone monitoring (TM) could reduce these barriers, data on TM for community-dwelling individuals involved with the criminal justice system and research on individuals who drop out of TM are scarce. We examined the factors associated with dropping out early from the Voice Bridges Project, which provides TM for individuals on probation for drug-related convictions through community mental health centers in Japan. METHODS: Participants (n = 546) were individuals aged ≥20 years with methamphetamine-related convictions who were on probation. Univariate analyses examine the associations between one-year follow-up status and baseline variables, and multivariate Cox proportional hazards regression analyses identify the risk and protective factors associated with dropping out. Stratified analyses report results based on sex and halfway-house residency. RESULTS: The one-year dropout rate was 43.6 % (n = 238). Multivariate analysis identified two risk factors for dropping out-halfway-house residency and suicide attempts in the past year, and two protective factors-higher education and the current use of SUD services. Sex-stratified analyses showed that halfway-house residency was a risk factor for both men and women. Attempted suicide was a risk factor for women. Conversely, higher education and current use of SUD services were protective factors for men. CONCLUSIONS: Our results identify unique risk factors for women, such as a recent history of suicide attempts, and distinctive protective factors for men, including higher education and current use of SUD services, emphasizing the importance of sex-specific approaches. Furthermore, the study reveals that irrespective of sex, vulnerable individuals, such as halfway-house residents, are at a higher risk of dropping out from TM.

Clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan: Comparison of single and multiple OTC product abusers.

OBJECTIVE: To examine the clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan. METHOD: We examined the attributes, ICD-10 subcategory, and comorbid mental disorders of patients who mainly abuse OTC products and compared the clinical characteristics of single product and multiple products abusers, using the database of the "2022 Nationwide Mental Hospital Survey of Drug-related Disorders." RESULTS: Among the 2468 subjects included in this survey, 273 (11.1%) used OTC products as main drugs. Of these, 209 (78.3%) and 58 (21.7%) were classified into the single product group and the multiple products group, respectively. Six were excluded for unknown ingredients. By comparing these groups, we found that many of the multiple products group consisted of young women who were recently treated for drug problems. Many subjects in the group also had a short treatment period. No differences were observed between the groups regarding the ICD-10 F1 subcategory, but many subjects in the multiple products group fulfilled the criteria of F6 "disorders of adult personality and behavior." CONCLUSION: OTC products are easily accessible drugs of abuse for young women in Japan. The results of this study indicate the necessity to reconsider the educational approach for preventing drug abuse, which has focused on illicit drugs. The study also indicates that some OTC products, which contain ingredients banned overseas due to their harmful effects, are still sold in Japan and that abusers for those products exist. Measures by the government are considered urgently needed.

[The Science of Drug Addiction].

Several causes of drug addiction in people remain unknown. It is known that only a small percentage of those who use potent dependent drugs, such as methamphetamine and heroin, develop addiction. In addition, some studies suggest that the choice of preferred drugs among drug addicts is made proactively according to criteria other than the strength of pharmacological dependence. Therefore, this paper discusses the pathogenesis of drug dependence, focusing on the "self-medication hypothesis" of Khantzian et al.

Varying impact of lenvatinib or sorafenib therapy on skeletal muscle loss in patients with hepatocellular carcinoma.

BACKGROUND: Lenvatinib and sorafenib are key therapeutic agents for hepatocellular carcinoma. However, there are no useful biomarkers for selecting molecular-targeted agents (MTAs). Skeletal muscle volume is associated with the clinical outcomes in these patients. We investigated the effects of lenvatinib and sorafenib on the skeletal muscles of patients with HCC. METHODS: We evaluated the impact of skeletal muscle changes over a 3-month period for each MTA (n = 117; lenvatinib/sorafenib, 45/72). The skeletal muscle mass index (SMI) was measured at the third lumbar vertebra. Furthermore, we evaluated the direct effect of each MTA on primary human skeletal muscle cells by estimating muscle protein synthesis using western blot analysis. RESULTS: The median change in SMI was -0.7% (p = 0.959) and -5.9% (p <0.001) for the lenvatinib and sorafenib groups, respectively. Sorafenib had a greater effect on skeletal muscle loss than lenvatinib (p < 0.001). Additionally, SMI significantly decreased in the sorafenib group regardless of initial skeletal muscle volume (p < 0.001), whereas no significant differences were observed in the lenvatinib group. Sorafenib therapy (odds ratio [OR], 2.98; p = 0.023) and non-muscle depletion (OR, 3.31; p = 0.009) were associated with a decreased SMI. In vitro analysis showed that sorafenib negatively affected muscle synthesis compared to lenvatinib. CONCLUSIONS: Sorafenib may have a more negative effect on skeletal muscle than lenvatinib.

Trifluridine/Tipiracil Plus Bevacizumab for Vulnerable Patients With Pretreated Metastatic Colorectal Cancer: A Retrospective Study (WJOG14520G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab has shown clinical benefit for metastatic colorectal cancer (mCRC) refractory to standard therapy. However, few data have been available for patients with pretreated mCRC who are intolerant of intensive therapy (vulnerable). METHODS: We performed a multicenter retrospective study (WJOG14520G; TWILIGHT) of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC. Eligibility criteria included previous chemotherapy (although patients treated with all key cytotoxic agents, a fluoropyrimidine, oxaliplatin, and irinotecan, were excluded) and intolerance of full-dose combination therapy with oxaliplatin or irinotecan at the start of FTD/TPI plus bevacizumab. RESULTS: The median age of 93 evaluable patients was 79 years (range, 21-90). Intolerance of intensive therapy was attributable to an older age in 60 (65%) patients, serious concomitant disease in 24 (26%) patients, and a poor performance status in 19 (20%) patients. FTD/TPI plus bevacizumab was administered as second-line treatment in 74 (80%) patients and as third- or fourth-line treatment in 19 (20%) patients. The objective response rate was 4.9% (95% confidence interval [CI], 1.4%-12.2%), and the disease control rate was 67.9% (95% CI, 56.6%-77.8%). With a median follow-up time of 21.6 months, median overall survival and progression-free survival were 18.6 months (95% CI, 12.1-23.2) and 6.3 months (95% CI, 5.0-8.3), respectively. Neutropenia of grade ≥3 developed in 50 (54%) patients, whereas 2 (2%) patients experienced febrile neutropenia, and no treatment-related death was observed. CONCLUSION: Our data show the potential efficacy and acceptable safety profile of FTD/TPI plus bevacizumab for vulnerable patients with pretreated mCRC.

Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy.

Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.

Stigmatized attitudes of medical staff toward people who use drugs and their determinants in Japanese medical facilities specialized in addiction treatment.

AIM: Stigma within healthcare settings significantly impact the lives of people who use drugs (PWUD). Given the lack of quantitative data on stigma toward PWUD in healthcare settings and the unknown factors that contribute to it in the Japanese context, this study aimed to investigate the current status of stigma toward PWUD and its determinants. METHODS: We conducted a survey in five specialized addiction medical facilities across three prefectures in Japan. The survey included questions related to stigmatizing attitudes toward PWUD, knowledge about illicit drug use, and personal and professional interactions with PWUD. RESULTS: A substantial portion of respondents rejected the notion that drug addiction can be overcome through sheer willpower or attributed it solely to moral failings. However, the majority still considered them untrustworthy and viewing drug use as unacceptable and incomprehensible. Many respondents perceived PWUD as dangerous, despite the limited occurrence of hostile behavior from PWUD in clinical practice. A considerable proportion of respondents did not seek support for their own or their relatives' drug-related issues, and less than half had collaborated with recovered PWUD, which serves as potential indicators of reduced stigma. While healthcare professionals recognized that involving law enforcement does not contribute to the recovery of PWUD, a considerable number still believed it was necessary to report them to the authorities. CONCLUSION: Healthcare professionals in specialized addiction medical facilities demonstrate strong stigmatizing attitudes toward PWUD. Comprehensive educational programs and large-scale awareness campaigns are necessary to address and mitigate stigma in this context.

Real-World Treatment Sequencing in Vulnerable Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Study.

BACKGROUND: Data regarding treatment sequence for vulnerable patients with metastatic colorectal cancer (mCRC) in a real-world setting are lacking. OBJECTIVE: We aimed to assess treatment outcomes in second-line or later chemotherapy for vulnerable patients with mCRC in a real-world setting. PATIENTS AND METHODS: Vulnerable patients with mCRC who received less intensive treatment ('vulnerable') regimens, i.e. fluoropyrimidines with or without biologics (FP), reduced-dose doublet regimens with or without biologics (Doublet), and anti-epidermal growth factor receptor monotherapy (Anti-EGFR), as first-line therapy between June 2015 and December 2018 were retrospectively reviewed. RESULTS: A total of 210 patients from 15 hospitals were analyzed. The median age was 78 years (range 28-90), and 44 patients (21%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 2. In the entire population, the median time to treatment failure (TTF) and overall survival (OS) were 7.6 and 21.4 months, respectively. Following the failure of first-line therapy in 195 patients, 74 (38%), 24 (12%), and 13 (7%) patients received vulnerable regimens, full-dose doublet regimens with or without biologics, and other regimens, respectively, whereas 84 (43%) received best supportive care (BSC). In patients receiving vulnerable regimens as second-line therapy, the median TTF and OS were 4.4 and 13.7 months, respectively, while response rate and disease control rate were 18% and 62%, respectively. In 84 patients who received BSC, the median OS was 3.5 months. CONCLUSIONS: Second-line chemotherapy for vulnerable patients with mCRC showed clinically meaningful outcomes; however, few patients received second-line therapy, and survival among patients who received BSC was dismal.

Highly Efficient One-Pot Synthesis of Hexakis(m-phenyleneimine) Macrocyle Cm6 and the Thermostimulated Self-Healing Property through Dynamic Covalent Chemistry.

Highly efficient one-pot synthesis of hexakis(m-phenyleneimine) macrocycle Cm6 from acetalprotected AB-type monomer, m-aminobenzaldehyde diethylacetal, was successfully achieved based on imine dynamic covalent chemistry and precipitation-driven cyclization. The structure of Cm6 in the solid state was determined using CP/MAS NMR, X-ray single crystallographic analysis, and WAXD. Macrocycle Cm6 is composed of six phenylene and imine bonds facing the same direction, with nitrogen atoms arranged on the outside of the ring, and has a chair conformation, as predicted from DFT calculation. The macrocycle forms π-stacked columnar aggregates and hexagonally closest-packed structure. The cyclization process was investigated using MALDI-TOF MS and NMR. A mechanism of precipitation-driven cyclization based on imine dynamic covalent chemistry and π-stacked columnar aggregation is proposed. Both the nature of imine linkage and the shape anisotropy of the macrocycle played an important role in the single one-pot synthesis. The water-mediated mutual conversion between macrocycle Cm6 and linear oligomers driven by thermal stimulation was analyzed using MALDI-TOF MS and GPC methods. Macrocycle Cm6 with a dynamic covalent imine bond exhibited self-healing properties when stimulated using heat.

Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. METHODS: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. DISCUSSION: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. TRIAL REGISTRATION: jRCTs041220120.

Sex differences in the characteristics of stimulant offenders with a history of substance use disorder treatment.

We analyzed the results of a nationwide questionnaire administered to 699 stimulant offenders and examined sex differences in the association between various psychosocial problems and treatment history for substance use disorder. Based on their attributes, we predominantly evaluated the treatment and support provided to women with substance use disorder. The rates of childhood (before the age of 18) traumatic experiences (physical, psychological, and sexual abuse and neglect) and lifetime intimate partner violence were significantly higher in women than in men. The history of treatment for substance use disorder was also significantly higher in women than in men, at 15.8% for men and 42.4% for women [χ2 (1) = 41.223, p < 0.001]. Logistic regression analysis was performed using the treatment history of substance use disorder as the dependent variable. The results showed that treatment history was significantly associated with the total drug abuse screening test-20 score and suicidal ideation in men and with survivors of child abuse and eating disorders in women. A comprehensive assessment is required for several issues, such as child abuse, domestic violence, trauma symptoms, eating disorders, and drug problems. Moreover, an integrated treatment for substance use disorder, trauma, and eating disorders is required for female stimulant offenders.