An evaluation of nivolumab for the treatment of metastatic renal cell carcinoma

Introduction: The treatment paradigm for metastatic renal cell carcinoma (mRCC) has undergone a revolution with the rapid market approval of multiple agents over a three-year period. The immunogenicity of renal cell carcinoma (RCC) provided the biological rationale to assess the clinical efficacy of nivolumab, an immune checkpoint inhibitor. Nivolumab is approved for second-line treatment after failure of angiogenesis-targeted therapy and in combination therapy with ipilimumab for previously untreated intermediate- or poor-risk advanced RCC.

Areas covered: The authors review the preclinical and clinical data supporting nivolumab employment in mRCC. Discussion of the underlying mechanisms of immunotherapy, data on objective responses, safety and tolerability, regulatory affairs, and future directions of nivolumab therapy are highlighted.

Expert opinion: Nivolumab serves as a proof-of-principle of the efficacy of immunotherapy with checkpoint inhibition in mRCC. Nivolumab may be considered the leading monotherapy in the second-line setting for patients with low tumor volume considering its risks and benefits. Nivolumab was recently approved in the first-line setting as part of combination therapy with another immune modulator. Moreover, nivolumab use may offer clinicians the option for treatment beyond progression as emerging data has indicated possible overall survival benefits in this setting. Ongoing clinical studies may result in nivolumab use in the first-line setting, as monotherapy or in combination therapy with antiangiogenesis agents.     

PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer?

Introduction: Signaling through T-cell surface, an immune checkpoint protein such as PD-1 or CTLA-4 helps dampen or terminate unwanted immune responses. Blocking a single immune checkpoint or multiple checkpoints simultaneously can generate anti-tumor activity against a variety of cancers including lung cancer.

Area covered: This review highlights the results of recent clinical studies of single or combination checkpoint inhibitor immunotherapy in non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). The authors discuss pembrolizumab and pembrolizumab plus ipilimumab, durvalumab and durvalumab plus tremelimumab, nivolumab and nivolumab plus ipilimumab for NSCLC as well as nivolumab and nivolumab plus ipilimumab for SCLC.

Expert opinion: Available data suggest that, in both metastatic NSCLC and SCLC, combined PD-1 and CTLA-4 blockade may produce a higher tumor response rate than PD-1 blockade alone. Nevertheless, combination therapy is associated with an increased toxicity. Several larger-scale studies are currently ongoing. For checkpoint inhibitor immunotherapy in SCLC and NSCLC, combination therapy is associated with a higher incidence of toxicities than single therapy; however, it appears to help increase tumor response rate. The increased response rate, if confirmed in larger scale studies, will likely make combination therapy another useful therapeutic approach for lung cancer.     

Pembrolizumab use for the treatment of advanced melanoma

Introduction: Until recently, overall long term survival in patients with stage IV melanoma was lower than 10%. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab.

Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma.

Expert opinion: Phase II and III trials demonstrated that pembrolizumab is superior to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. Unfortunately, prospectively validated predictive markers are lacking. Immune-related adverse events are particularly interesting and should be managed per the published guidelines. There are still many issues that remain unresolved including: when to stop treatment, biomarkers for choosing a single agent or combination therapy, the optimal schedule of ipilimumab in combination with anti-PD1 monoclonal antibodies, optimal management of adverse events, the role of immunotherapy in specific populations, the optimal sequence of immunotherapy and the BRAF/MEK inhibitor combination in patients.     

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

Objective: The individual response to targeted tyrosine kinase inhibitors (TKIs) in the treatment of metastatic renal cell cancer (mRCC) is highly variable. Outlined in this article are findings on potential biomarkers for TKI treatment outcome in mRCC and an evaluation of the status of clinical implementation.

Methods: Articles were selected by two independent reviewers using a systematic search in five medical databases on renal cell carcinoma, TKIs, and pharmacogenetics.

Results: Many researchers have focused on predictive biomarkers for treatment outcome of targeted therapies in mRCC patients. Attempts to explain differences in efficacy and toxicity of TKIs by use of genetic variants in genes related to the pharmacokinetics and pharmacodynamics of the drug have been successful.

Conclusion: Most findings on potential biomarkers have not been validated and therefore biomarker testing to guide choice of therapy and dose in mRCC is not yet feasible.     

Single vs. combination immunotherapeutic strategies for glioma

Introduction: Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific features may substantially improve upon existing treatments.

Areas covered: Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review, the authors discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models.

Expert opinion: Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While a limited number of combination immunotherapies are described which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration.     

Nivolumab for the treatment of bladder cancer

Introduction: The checkpoint inhibitor nivolumab has recently demonstrated effectiveness against metatstatic urothelial carcinoma. Nivolumab is a fully human monoclonal antibody blocking PD-1 and thereby enhancing antitumour immune mechanisms.

Areas covered: In this review, the authors describe the treatment of metastatic bladder cancer with nivolumab against the background of the standard treatment with cisplatin-based chemotherapy which can prolong overall survival from 3–6 months in untreated cases to over one year. Different combinations of cisplatin-based chemotherapy can further prolong survival by only a few months. The authors highlight that cancer immunotherapy by checkpoint inhibition offers potential to further prolong patient survival with limited and well manageable toxicity although serious immune-related adverse events may occur.

Expert opinion: The response rate to nivolumab and other checkpoint inhibitors after first line chemotherapy remains under 30%. Patients unfit for cisplatin may benefit from first-line cancer immunotherapy. It is unclear which patients will respond and PD-1/PD-L1 expression alone is not a sufficiently reliable response marker. Treatment costs are extreme and further trials will have to clarify which subset of patients in which context of management will have a substantial benefit.     

The emerging role of non-coding circulating RNA as a biomarker in renal cell carcinoma

Introduction: Bodily fluids like serum and plasma contain significant amounts of tumor-derived circulating cell-free RNA, which holds the potential to serve as diagnostic biomarker. Consequently, liquid biopsies comprising circulating cell-free RNA might help to facilitate personalized treatment strategies for patients with renal cell carcinoma (RCC).

Areas covered: The present review provides a summary of the literature obtained by a PubMed search and covers the current knowledge on circulating non-coding cell-free RNA in patients with RCC.

Expert commentary: Altered circulating microRNA and long non-coding RNAs signatures allow for the discrimination of patients with RCC and healthy individuals. On the other hand, little is known about non-coding RNA expression in benign tumors. Cell-free microRNA expression levels may help to identify patients at risk for disease recurrence. However, accurate determination of cell-free RNAs is methodologically challenging and currently no biomarker candidate has reached a sufficient level of clinical validation. Thus, short-term implementation of cell-free circulating microRNA into clinical routine seems unlikely.     

Immuno-oncology for renal cell carcinoma treatment: future perspectives for combinations and sequences with molecularly targeted agents

Introduction: From a theoretical viewpoint, combining molecularly targeted agents endowed with antiangiogenic properties with immunotherapy makes sense in treatment of metastatic renal cell carcinoma (RCC); this neoplasm is highly angiogenesis-dependent, as well as potentially immunogenic.

Areas covered: The authors performed a literature search looking for clinical trials aimed at evaluating efficacy and tolerability of combinations (or sequences) of molecularly targeted agents and different immunotherapeutic approaches in metastatic RCC.

Expert opinion: Combinations of molecularly targeted agents with old immunotherapeutics (i.e., cytokines) seem to add little to the presently available treatment standards (mainly monotherapy with targeted agents). Newer combinations with immune checkpoint inhibitors are promising but cumulative toxicity is an important issue, although highly dependent on the different companion drugs. Combinations with vaccines are ongoing, but first available data are not encouraging. A more thorough comprehension of the complex effects of these combinations on the immune system is mandatory to develop less empiric treatments.     

MEDI 4736 (durvalumab) in non-small cell lung cancer

Introduction: Immune checkpoint inhibitors (ICI) are now a therapeutic option for advanced non-small cell lung cancer (NSCLC) patients. ICI, such as the PD-1 inhibitors nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab, have already been marketed for the treatment of pretreated patients with advanced NSCLC. Other notable PD-L1 inhibitors under development include avelumab and durvalumab.

Areas covered: This article reviews literature on durvalumab development, from the preclinical data to the results of phase III clinical trials, whether published or presented at international scientific conferences. Ongoing clinical trials were also reviewed.

Expert opinion: Early phase trials of durvalumab monotherapy (and in combination) have demonstrated activity in advanced NSCLC patients and it has demonstrated a good safety profile. The authors believe that durvalumab will likely play an important role in future treatment strategies for NSCLC. The PACIFIC trial assessing durvalumab after standard chemoradiotherapy for locally advanced NSCLC has already met its primary endpoint and the potential of durvalumab will be reinforced if phase III randomized studies of first-line (MYSTIC trial) and second or subsequent (ARCTIC trial) lines of therapy demonstrate superiority over the current standard of care.     

Recent developments with immunotherapy for hepatocellular carcinoma

Introduction: Immunotherapy is on the way to become the new standard of care for advanced hepatocellular carcinoma (HCC) worldwide. With higher rates of objective responses, and overall less side effects compared to tyrosine-kinase inhibitors (TKIs) immunotherapeutics will probably replace sorafenib from standard first-line treatment.

Areas covered: This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC focusing on immunotherapy.

Expert opinion: In unselected patients with advanced HCC immunotherapeutics, namely the programmed cell death-1 (PD-1) antibodies, nivolumab and pembrolizumab have shown promising efficacy in therapy-naïve, as well as pre-treated patients with advanced HCC. However, only 10–20 percent of treated patients show an objective and durable response to the indicated therapeutics. Therefore, combination therapies including different immunotherapeutics, e.g. PD-1/programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, or combinations of immunotherapeutics and small molecules, or bifunctional antibodies will be needed to improve response rates.

Abbreviations: HCC: hepatocellular carcinoma; TKI: tyrosine-kinase inhibitors; PD-1: programmed death receptor-1; PD-L1: programmed cell death 1 ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated Protein 4; CAR-T: chimeric T cell receptors; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; SBRT: stereotactic body radiation therapy; VEGF: vascular endothelial growth factor; MEK: mitogen-activated protein kinase kinase; NK cell: natural killer cell; TGFβ: transforming growth factor-β; OV: Oncolytic viruses; PFU: plaque-forming unit     

Promising immunotherapies for esophageal cancer

Introduction: Esophageal cancer (EC) is the eighth most common cancer in the world, and the prognosis of EC is still poor. Although immunotherapy has been developed in melanoma and lung cancer, it is also expected to show efficacy in EC. Currently, several clinical trials are ongoing to evaluate the safety and efficacy of immunotherapies, immune checkpoint inhibitors, adoptive T cell transfer, and therapeutic cancer vaccines in EC.

Areas covered: This review provides an overview and the status of immunotherapy in EC. Clinical significance of molecules related immune checkpoints, especially PD-1 and PD-L1 is presented and the designs, results and future directions of clinical trials using immunotherapy in EC are provided.

Expert opinion: To bring immunotherapy to the forefront of treatment for EC, it is necessary to select patients who can obtain a high efficacy of immunotherapy and to also elucidate the correct timing for administration. Moreover, combination therapies of immunotherapy with existing chemotherapy or radiation or other immunotherapy with different mechanisms of action must be evaluated to achieve excellent outcomes in patients with EC.     

A double-blind placebo-controlled clinical investigation into pain reduction effect of placing the pain spot outside the intersection area of the two currents of interferential therapy compared to traditional method

Background: Interferential therapy (IFT) is applied to intersect in the painful area but no confirmed effect with this method. Experimentally, the highest voltage of IFT is induced outside the intersection of the two currents. Placing the painful area outside the intersection point (external application) would reveal a better effect.

Objectives: To examine the effect of external application in pain compared to traditional method.

Design: A double-blind placebo-controlled clinical investigation.

Setting: A public hospital.

Participants: 168 LBP subjects.

Interventions: Assignment: (1) external IFT, (2) placebo external IFT, (3) traditional IFT and (4) placebo traditional IFT. Groups 1 and 3 received 20 min of IFT at 100 Hz and groups 2 and 4 received sham IFT.

Main outcome measures: Before and after IFT session, pain severity (VAS), pressure threshold (PPT), pain distribution and ROM were assessed.

Results: IFT changed all outcomes similarly. VAS and ROM improved statistically, P < 0.03. A trend of better VAS reduced with active IFTs.

Conclusions: No therapeutic difference between the two methods.     

Immunotherapy for head and neck cancer: the future of treatment?

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with >500,000 cases diagnosed each year. HNSCC patients often present to the clinic with advanced disease and are managed with a multi-disciplinary approach consisting of surgery, chemotherapy, and/or radiation. Morbidity and quality of life issues are major challenges in this patient population due to the debilitating effects of standard of care treatment paradigms. There is a critical need for new therapeutic approaches to manage HNSCC with better anti-tumor activities and toxicity profiles. Immunotherapy has gained traction as a precision medicine initiative to manage solid malignancies.

Areas covered: The authors review current knowledge of immune escape mechanisms and discuss key immunotherapies in HNSCC with an emphasis on clinical trials data.

Expert opinion: The excitement over the potential of immunotherapy to manage solid malignancies, including HNSCC is high and warranted based on the impressive clinical data accrued to date. Research in immunity and immune modulation in cancer has been invigorated and offers the potential to reveal novel vulnerabilities that may be exploitable pharmacologically. The evolution of immunotherapy will continue and move toward rational combinations with other immunotherapies or molecularly-targeted agents in the first-line, adjuvant, and recurrent/metastatic settings in HNSCC.     

Repetition of intentional drug overdose: a population-based study

Context: Intentional overdose is a leading method of self-harm and suicide, and repeat attempts strongly predict eventual death by suicide.

Objectives: To determine the risk of recurrence after a first intentional overdose. Secondary objectives included characterization of the temporal course and potential predictors of repeat overdose, a strong risk factor for death from suicide.

Methods: Design: Population-based cohort study.

Setting: Ontario, Canada, from 1 April 2002 to 31 March 2013.

Participants: All Ontario residents presenting to an emergency department after a first intentional overdose.

Main outcome measures: The incidence and timing of recurrent overdose.

Results: We followed 81,675 patients discharged from hospital after a first intentional overdose. Overall, 13,903 (17.0%) returned with a repeat overdose after a median interval of 288 (inter-quartile range: 62 to 834) days. Of these, 4493 (5.5%) had multiple repeat episodes. Factors associated with repeat self-poisoning included psychiatric care in the preceding year (adjusted hazard ratio [aHR] 1.55; 95% confidence interval [CI] 1.50 to 1.61), alcohol dependence (aHR 1.41; 95% CI 1.35 to 1.46) and documented depression (aHR 1.39; 95% CI 1.34 to 1.44). Female sex, rural residence, lower socioeconomic status, ingestion of psychoactive drugs and younger age were also weakly associated with repeat overdose.

Discussion: Hospital presentation for repetition of intentional overdose is common, with recurrent episodes often far removed from the first. While several factors predict overdose repetition, none is particularly strong.

Conclusion: Secondary prevention initiatives should be implemented for all individuals who present to the emergency department and survive intentional overdose.     

Effect of changing from first- to second-line antiretroviral therapy on renal function: a retrospective study based on data from a single health facility in Namibia

Background: Tenofovir disoproxil fumarate (TDF) and lopinavir/ritonavir (LPV/r) can cause renal impairment with this combination co-administered during second-line combination antiretroviral therapy (cART) potentially associated with greater risk of nephrotoxicity. As a result, the aim of this study is to assess effects of second-line cART on renal function.

Methods: Retrospective longitudinal study in patients receiving cART.

Results: 71 patients received TDF, zidovudine or stavudine, each combined with 3TC/NVP or 3TC/EFV. Before second-line cART, 46.5% had abnormal kidney function. First-line cART had no relationship with calculated creatinine clearance (CrCl). During second-line cART, more males than females had abnormal renal function and more females experienced increases in CrCl. Calculated CrCl during second-line cART related strongly with CrCl during first-line cART. Time spent on cART weak had a week relationship with CrCl.

Conclusion: Patients on first-line cART for several years without renal impairment may experience new onset impairment during second line cART. Patients with pre-existing renal impairment just before switching to second-line cART may experience a further decline.     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

Pain pattern classification and directional preference for patients with neck pain

Objectives:

Pain Pattern Classification (PPC) and Directional Preference (DP) have been shown to be predictive of health care outcomes and serve to guide orthopedic clinical decision making. We conducted a prospective, observational cohort study to verify the association between PPC, DP, and clinical outcomes.

Methods:

Clinical outcome measures including pain intensity and disability were completed at first examination and follow-up by 335 patients. A Pearson’s chi-squared test was used to determine differences in prevalence rates for the categorical variables, and two-sample t-tests were used to determine differences in rates for the continuous variables. A Tukey’s range test was used to determine differences in follow-up pain intensity and disability for neck pain dual-classification schemes.

Results:

The prevalence of DP was 82.4%. The prevalence of CEN, Non-CEN, and Non-Classifiable (NC) was 15.2%, 42.1%, and 25.1%, respectively. The prevalence of DP was lowest for patients with sub-acute symptoms and who were <45 years old. Patients classified as DP CEN had, on average 2.62 NDI units less than patients classified as Non-DP. Patients classified as DP CEN had, on average, 0.90 pain intensity units less than patients classified as Non-DP at follow-up. Patients who demonstrated DP CEN did not have clinically significant lower pain intensity or disability at follow-up than patients who demonstrated Non-DP.

Discussion:

The results of this investigation need to be interpreted with caution with respect to the study design and it’s subsequent strengths and limitations.

Level of Evidence:

1b.     

Quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections in general practice: a RAND Appropriateness Method

Objective: To develop quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections, tailored to the Danish general practice setting.

Design: A RAND/UCLA Appropriateness Method was used.

Setting: General practice.

Subjects: A panel of nine experts, mainly general practitioners, was asked to rate the relevance of 64 quality indicators for the diagnosis and antibiotic treatment of acute respiratory tract infections based on guidelines. Subsequently, a face-to-face meeting was held to resolve misinterpretations and to achieve consensus.

Main outcome measures: The experts were asked to rate the indicators on a nine-point Likert scale. Consensus of appropriateness for a quality indicator was reached if the overall panel median rating was 7–9 with agreement.

Results: A total of 50 of the 64 proposed quality indicators attained consensus. Consensus was achieved for 12 indicators focusing on the diagnostic process and 19 indicators focusing on the decision about antibiotic treatment and choice of antibiotics, respectively.

Conclusion: These newly developed quality indicators may be used to strengthen Danish general practitioners’ focus on their management of patients with acute respiratory tract infections and to identify where there is a need for future quality improvements.     

Drug-related problems and changes in drug utilization after medication reviews in nursing homes in Oslo,Norway

Objective: We describe the drug-related problems (DRPs) identified during medication reviews (MRs) and the changes in drug utilization after MRs at nursing homes in Oslo, Norway. We explored predictors for the observed changes.

Design: Observational before-after study.

Setting: Forty-one nursing homes.

Intervention: MRs performed by multidisciplinary teams during November 2011 to February 2014.

Subjects: In all, 2465 long-term care patients.

Main outcome measures: DRPs identified by explicit criteria (STOPP/START and NORGEP) and drug–drug interaction database; interventions to resolve DRPs; drug use changes after MR.

Results: A total of 6158 DRPs were identified, an average of 2.6 DRPs/patient, 2.0 for regular and 0.6 for pro re nata (prn) drugs. Of these patients, 17.3% had no DRPs. The remaining 82.7% of the patients had on average 3.0 DRPs/patient. Use of unnecessary drugs (43.5%), excess dosing (12.5%) and lack of monitoring of the drug use (11%) were the most frequent DRPs. Opioids and psychotropic drugs were involved in 34.4% of all DRPs. The mean number of drugs decreased after the MR from 6.8 to 6.3 for regular drugs and from 3.0 to 2.6 for prn drugs. Patients with DRPs experienced a decrease of 1.1 drugs after MR (0.5 for regular and 0.6 for prn drugs). The reduction was most pronounced for the regular use of antipsychotics, antidepressants, hypnotics/sedatives, diuretics, antithrombotic agents, antacid drugs; and for prn use of anxiolytics, opioids, hypnotics/sedatives, metoclopramide and NSAIDs.

Conclusion: The medication review resulted in less drug use, especially opioids and psychotropic drugs.     

Patient trajectories in a Norwegian unit of municipal emergency beds

Objective: The Coordination reform was implemented in Norway from 2012, aiming at seamless patient trajectories. All municipalities are required to establish emergency care beds (MEBs) to avoid unnecessary hospital admissions. We aimed to examine occupancy rate, patient characteristics, diagnoses and discharge level of municipal care in a small MEB unit.

Design: Cross-sectional, observational study.

Setting: A two-bed emergency care unit.

Subjects: All patients admitted to the unit during one year.

Main outcome measures: Patients’ age and gender, comorbidity, main diagnoses and municipal care level on admission and discharge, diagnostic and therapeutic initiatives, occupancy rate.

Results: Sixty admissions were registered, with total bed occupancy 194 days, and an occupancy rate of 0.27. The patients (median age 83 years, 57% women) had mostly infections, musculoskeletal symptoms or undefined conditions. Some 48% of the stays exceeded three days and 43% of the patients were subsequently transferred to nursing homes or hospitals.

Conclusion: Occupancy rate was low. Patient selection was not according to national standards, and stays were longer. Many patients were transferred to nursing homes, indicating that the unit was an intermediate pathway or a short cut to institutional care. It is unclear whether the unit avoided hospital admissions.