Successful treatment with pazopanib plus PD-1 inhibitor and RAK cells for advanced primary hepatic angiosarcoma: a case report

Yu Qiao
Jihong Yang
Lili Liu
Yixin Zeng
Jie Ma
Jing Jia
Li Zhang
Xiaoguang Li
Peihong Wu
Wenchao Wang
Dongge Liu
Huan Chen
Yunbo Zhao
Huan Xi
Yao Wang
Successful treatment with pazopanib plus PD-1 inhibitor and RAK cells for advanced primary hepatic angiosarcoma: a case report
10.1186/s12885-018-3996-3C A S E R E P O R T Open Access
Background: Primary hepatic angiosarcoma (PHA) is a rare and aggressive solid tumor, with high rates of local recurrence and distant metastasis, and poor prognosis. There are no established treatment guidelines for PHA. Case presentation: A 78-year-old asymptomatic man with PHA that was successfully treated with pazopanib plus PD-1 inhibitor and RetroNectin-activated killer cells (RAK cells). After one month of treatment, there was a clear reduction in the size and number of the liver metastases; and after nearly 15 months, most of the lesions were stable, no new lesions had developed, and the side effect of treatment was minor. Conclusion: Pazopanib, PD-1 inhibitor and RAK cells could serve as a potential option for the treatment of advanced PHA.

Background

Primary hepatic angiosarcoma (PHA) is a rare and aggressive solid tumor, with high rates of local recurrence and distant metastasis, and poor prognosis. Histopathology shows a variety of patterns of vascular channels, dilated sinusoidal or cavernous spaces, CD34, CD31 and factor VIII-related antigen can be positive [1]. Most effective treatment modality is liver resection, however, there are no established chemotherapy regimens and moreover, chemotherapy is only palliative [2].

Case presentation

A 78-year-old asymptomatic man, who was found to have multiple liver masses by magnetic resonance imaging (MRI) (Fig. 1a) done as part of his routine medical examination on Apr 22,2016. These masses increased in size over six weeks (Fig. 1b), with no symptoms or abnormal findings on his physical examination. There is no treatment during this time. He was admitted in our hospital on June 13,2016. Liver function tests, hematology parameters as well as tumor markers such as α-fetoprotein (AFP), carbohydrate antigen 199 (CA199), Carcinoembryonic antigen (CEA), and chromogranin A (CgA) were all normal. Percutaneous liver biopsy was performed in two days later, pathology revealed hepatic endothelial cells predominately proliferating in the dilated sinusoid, atypical endothelial cells with marked nuclear pleomorphism. The immunochemistry showed CD34(+++), CD31(+++),  Fig. 2a-i). Final pathologic diagnosis was primary hepatic angiosarcoma. Endoscopy was normal. Positron emission tomography/computed tomography (PET/CT) showed no metastatic lesions. Next generation sequencing (NGS) using the TruSeq Amplicon-Cancer 295 gene panel (Guangzhou Burning Rock Biotechnology Inc. China) for liver biopsy tissue and peripheral blood were done, including EGFR, HER-2, KRAS, ALK, ROS1, MET, RAT, BRAF, KIT, PDGFRA and so on. Unfortunately, the result revealed no known mutations. The patient has a history of hypertension, type 2 diabetes, multiple arteriosclerosis, the right renal artery stenosis and left subclavian artery stenosis treated with stent implantation one year ago, hyperlipidemia, chronic kidney disease 3a stage and acute cerebrovascular infarction two years ago. On June 24, four major lesions were treated with radiofrequency ablation (RFA), and this treatment was repeated on July 11. The patient had mild adverse effects including fatigue, transient elevated hepatic transaminase (ALT peaked at 280 U/ L and AST at 200 U/L) and hypoalbuminemia after RFA. Unfortunately, he developed new lesions seen by enhanced MRI on July 22 (Fig. 1c). Due to rapid progression of his angiosarcoma, the treatment team decided to initiate a combination of targeted therapy and immunotherapy. From July 22, the patient received pazopanib 200 mg daily for 2 days, 400 mg daily for 5 days, then 600 mg daily up to now. He experienced no adverse effects. Due to concern  regarding the aggressive behavior of the cancer, on August 1st, pembrolizumab at 100 mg every three weeks was started. Patient experienced no significant adverse effects from this combination. On August 9 the patient received 3 cycles of allogeneic RAK cells therapy. Dose was 3 billion cells daily in 3 consecutive days, given every 4 weeks. The combination of these three therapeutic agents was able to decrease the size and number of the liver masses as showed by MRI on Aug18 (Fig. 1d). Subsequent abdominal enhanced MRI demonstrated stable disease till last image on Oct 26,2017 ( Fig. 1e-j). Treatment course timeline is included as Fig. 3. Currently the patient is in stable clinical condition, without any complaints. His Karnofsky performance status (KPS) is 90. Routine laboratory examinations including blood routine, urine routine, blood coagulation, liver and renal function, thyroid gland function, ECG, etc. were all within normal parameters. The patient tolerated pazopanib and pembrolizumab very well. Just after He experienced mild infusion reactions with RAK cell treatment, including transient fever, mild hypertension.

Discussion and conclusions

PHA is a rare and aggressive solid tumor. It originates from liver vascular endothelial cells and lymphatic vessels cells. An estimated 200 cases are diagnosed annually in the world [3], with a male-to-female ratio of 3:1. This disease has a predisposition to affect those between 60 and 80 years of age [4]. No specific etiologic agent is identified in majority of patients with PHA. Some important risk factors for this disease include the exposure to vinyl chloride, radiocontrast material, the use of androgenic steroid and arsenic, and other chemicals [5].

The symptoms of PHA are nonspecific. Many tumors are found incidentally by diagnostic imaging, others are found as patients present with abdominal pain, anorexia, fatigue, weight loss, fever, and low back pain. Other reported symptoms/findings include jaundice, hemoperitoneum and acute hepatic failure. Primary hepatic angiosarcoma can metastasize to the lungs and hilar lymph nodes [6]. Tumor markers such as AFP, CEA, CA19-9, and CA125 are usually not elevated. This makes PHA difficult to diagnose in its early stage.

Morphologically, PHA appear sole or multiple nodules or a dominant mass, or a mixed pattern. Pathologic diagnosis is golden standard for PHA. The optimal way to obtain tumor tissue is surgery. Percutaneous liver biopsy is considered to be dangerous and unreliable because of the necrosis and hemorrhage inside the tumor. Thus samples taken from these areas may produce false-negative results. Histopathology shows a variety of patterns of vascular channels, dilated sinusoidal or cavernous spaces. CD34, CD31 and factor VIII-related antigen can be positive. Other markers such ERG, Ki-67 and vimentin can be positive [7]. In our case, we did percutaneous core needle liver biopsy two times, first by ultrasound guidance and then by computed tomography (CT).

PHA has high rates of local recurrence and distant metastasis after surgical resection. Prognosis is poor. The median overall survival is 5 months. The causes of death of PHA patients include hepatic failure, disseminated intravascular coagulation, tumor rupture hemorrhagic shock and metastasis. Due to its low incidence, no standard treatment guideline exists for PHA. Some authors reported success with complete resection which can prolong the median survival to 17 months [8]. However, surgical treatment is difficult to carry out in most patients, due to presence of multiple liver metastases or extrahepatic metastasis at the time of diagnosis. Liver transplant is unproved and is not considered to be a viable option due to high recurrence rate. One study reported that the overall median survival of 22 patients who underwent liver transplant was 6 months [9]. Based on our patient's multiple liver metastases at the time of diagnosis, he was not a good candidate for surgical treatment or liver transplantation. Therefore, he was treated with palliative intent to prolong his survival.

RFA of liver tumors has proven to be an effective way to control local lesions. E. Berber reported that RFA for 18 patients with single liver metastases of sarcoma, local tumor recurrence is about 17% after 24 months of follow  [10]. Therefore, RFA offers an alternative to surgery for inoperable patients. RFA was performed twice in our patient in order to achieve local tumor control. However, the emergence of new lesions rapidly after RFA treatment indicates the aggressive behavior of the cancer, thus making it urgent to start appropriate systemic treatment.

Chemotherapy has been reported to show clinical efficacy in unresectable PHA [8]. Conventional chemotherapeutic agents for treatment of sarcoma include albumin paclitaxel, 5-fluorouracil, carboplatin, doxorubicin, ifosfamide, gemcitabine, dacarbazine, and newer agent trabectedin is approved for soft sarcoma in 2015 [11]. In recent years targeted therapies such as antiangiogenic drugs bevacizumab, sorafenib, and pazopanib showed shown efficacy in treatment of advanced soft tissue sarcoma. The small molecule vascular endothelial growth factor inhibitor pazopanib is a multiple target tyrosine kinase inhibitor, with activity against vascular endothelial growth factors 1, 2, and 3, and platelet derived growth factors. Pazopanib has received approval for the treatment of certain soft tissue sarcomas. In the phase III trial for metastatic soft tissue sarcoma, 372 patients with advanced soft tissue sarcoma whose tumors had progressed despite at least one line of chemotherapy, were randomly assigned either pazopanib or placebo. The difference in progression free survival in the pazopanib arm was statistically significant with a median of 4.6 months for pazopanib compared with 1.6 months for placebo [12]. Given our patient's more advanced age, we decided chemotherapy would have been too toxic. We instead selected pazopanib as our initial treatment.

In recent years, tumor immunotherapy has become an important therapeutic option for treatment of advanced cancer. Immune checkpoint inhibitors such as anti-PD-1 monoclonal antibodies have shown considerable efficacy in advanced tumors, especially for melanoma, renal cancer, and lung cancer. A retrospective analysis has shown a cohort of patients with relapsed metastatic sarcomas treated with nivolumab, the clinical benefit was observed in 50% of the evaluable patients [13]. Currently, a clinical trial of PD-1 inhibitor nivolumab for sarcoma being conducted in the NCI (NCT02500797). Previous study suggested that targeting the VEGF axis may attenuate tumor-induced immunosuppression, allowing the tumor to become more responsive to immunotherapy when used in combination [14]. It is in this context that Amin et al. designed a phase I clinical trial of nivolumab in combination with sunitinib or pazopanib in metastatic renal clear cell carcinoma (mRCC) NCI(NCT01472081). nivolumab combined with TKI showed encouraging antitumor activity in this study with 53 patients. Objective response rate was higher with combination therapy up to about 50% than seen previously with nivolumab or TKI monotherapy in RCC, with a manageable toxicity profile, although renal and hepatic adverse effects were higher compared to monotherapy. The encouraging results of that study inspired us to consider treating our patient with combination of pazopanib and PD-1 inhibitor. Additionally, if the tumor progressed rapidly, we were afraid the patient's physical condition may get worse, making him lose the opportunity to treat with pembrolizumab. Therefore, based on pazopanib, we decided to use pembrolizumab as soon as possible. However, considering there is a high incidence of adverse effects with pazopanib, and this case is an elderly man, we worried about his tolerance to combination treatments initially. So, after we determined the patient can tolerable the adverse effects of pazopanib, we started a combination treatment with pembrolizumab.

Moreover, we were concerned that the combination of pazopanib and anti-PD1 monoclonal antibody was insufficient to inhibit the rapid progression of the patient's primary hepatic angiosarcoma. RAK cells have been reported to be effective in liver, colorectal, lung, pancreatic and other advanced cancers [15,16]. We hypothesis pazopanib plus PD-1 inhibitor and RAK cells together could bring more benefit in the treatment of our patient. RAK cells is a new kind of cytokine induced killer cells which use the proliferation technique of RetroNectin [17,18]. One study found that RAK cells are heterogeneous cells in CD3 + CD8 + CD56 + T cells. These cells appear to secrete more IL-2 and less IL-4 and IL-5, indicating that Retro-Nectin can potentially enhance the activity of Th1 cells, while suppressing the activity of Th2 cells. This may be a clinically significant advantage for RAK cells, since cancer immunotherapy needs the help of Th1 cells, while the Th2 cells always inhibit antitumor activity of immune system [19]. RAK cells have been shown to grow faster, with a lower ratio of spontaneous apoptosis [17]. Therefore, compared with the traditional technique for cultivating CIK cells, the biggest advantage of RAK cell is the ability to obtain more lymphocytes for the final infusion. In addition, RAK could continue to grow for more days in the patient body, so the therapeutic number of RAK cells needed for cancer patients may be less than that of traditional CIK cells, meanwhile, appearing longer survival time in vitro, possibly leading to a more lasting therapeutic effect after transfusion in vivo [17]. RetroNectin induced autologous and allogeneic cells have some key differences. Even though allogeneic RAK cells have potential for allergic reaction or infections such as viral hepatitis or HIV, it may have potential advantages. In our case, the source of allogeneic RAK cells were from the patient's children, the donor of allogeneic RAK cells are young and with normal immune ability; besides the anti-tumor effect, allogeneic RAK cells can also stimulate immune responses and repair the low immune surveillance in this patient.

In summary, PHA is a rare disease, our case is characterized by older age, complicated basic disease, rapidly tumor progression, high degree of malignancy. Pazopanib plus PD-1 inhibitor and RAK cells therapy together have worked and control the tumor in a stable situation, side effects are tolerable. From making a definite diagnosis to now, 15 months have passed, the patient feels good, KPS score is 90, followup is necessary. The combination of pazopanib, PD-1 inhibitor and RAK cells warrants further exploration as a potential treatment of high advanced PHA.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions YQ and JY drafted the initial manuscript, reviewed and revised the manuscript. LL was the primary physician during the patient's inpatient stay. WW and DL conceived the report and provided the images. PW and XL were involved in the surgical management of the patient. YZ, JM, JJ, LZ, HC, YZ, HX and YW were involved in the patient's medicine care as well as the editing and overseeing of the text. All authors have read and approved the final manuscript.

Ethics approval and consent to participate Informed Consent as documented by signature is obtained from this patient.

Consent for publication

Written informed consent was obtained from the patient for publication of the Case Report and any accompanying images.

FVIII(+), Ki-67(50%+), CD3(−), CD20(−), CD68(−), CD163(−), GPC3(−), HCC(−), CD5(−), CK19(−), PD-1(−), PD-L1(−), C-MET(−), ROS-1(−), VEGF(+), EGFR(−), HER2(−), ALK D5F3(−), VEGFR2(60%+), VEGFR3(−). (

Fig. 1
1Abdomen MRI T2WI changes in liver lesions. a Apr-22-2016 MRI showing multiple hepatic lesions found. b Jun-08-2016 MRI showing hepatic lesions increase in number and size. c Jul-22-2016 MRI showing new lesions emerge after RFA. d Aug-18-2016 MRI showing tumor up to PR after first cycle of pazopanib plus PD-1 inhibitor and RAK cell. e-j From Oct-08-2016 to Oct-26-2017 MRI showing tumor stable disease. Arrows indicate the lesion. MRI, magnetic resonance imaging; PR, partial response; RAK cell. RetroNectin-activated killer cells

Fig. 2
2Histopathology staining of the core needle liver biopsy specimen. a H&E low-magnification view (× 40) and high-magnification view (× 400) in black frame showing sinusoids lined by atypical endothelial cells with marked nuclear pleomorphism, and vascular channels. b-f Immunohistochemistry low-magnification view (× 40-100) and high-magnification view (× 200-400) in black frame showing the cells were positive for Ki-67, CD31, CD34, FVIII and VEGF respectively. g-i Immunohistochemistry magnification view (× 100-200) showing the cells were negative for VEGFR3, PD-1 and PD-L1 respectively. H&E, hematoxylin and eosin

Fig. 3
3Timeline of patient's clinical course up

Abbreviations KPS: Karnofsky performance status; NGS: Next generation sequencing; PET/ CT: Positron emission tomography/computed tomography; PHA: Primary hepatic angiosarcoma; RAK: Cells RetroNectin-activated killer cells; RFA: Radiofrequency ablation Funding This study was supported by National Nature Science Foundation of China (Grant No. 81373803) to Dr. Jihong Yang. The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing of this manuscript.
AcknowledgementsThe authors thank Dr. Michael Lee (Department of Oncology, Kaiser Permanente Medical Center San Francisco, USA) for English writing assistance. I am very grateful to all physicians, nursing staff, and other caregivers of the geriatric division at the Beijing Hospital.Competing interestsThe authors declare that they have no competing interests.Publisher's Note
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GPs' and child and adolescent psychiatry specialists' experiences of joint consultations in the GP's office: a qualitative study
2017

Tori Guldahl Seierstad
Mette Brekke
Ingun Toftemo
Ole Rikard Haavet
GPs' and child and adolescent psychiatry specialists' experiences of joint consultations in the GP's office: a qualitative study

BMC Res Notes
10458201710.1186/s13104-017-2766-7RESEARCH ARTICLEChildrenAdolescentsMental healthGeneral practiceCollaborationJoint consultation
Background:The study is an exploration of a joint consultation model, a collaboration between general practitioners (GPs) and specialists from child and adolescent mental health services (CAMHS) in Lillehammer, Norway.Methods:A qualitative study based on two focus group interviews, one with participating GPs and one with participating specialists from the local CAMHS. Participants were five GPs, with work experience varying from 6 months to 20 years (four of them specialists in general medicine) and two CAMHS specialists-a psychiatrist and a psychologist-both with more than 20 years of experience.Results:The focus group discussions revealed that both GPs and CAMHS specialists saw the joint consultations as a good teaching method for improving GPs' skills in child and adolescent psychiatry. Both groups believed that this low-threshold service benefits the patients and that the joint consultation is especially suited to sort problems and determine the level of help required.Conclusions:The GPs and CAMHS specialists shared the impression that the collaboration model is beneficial for both patients and health care providers. Close collaboration with primary health care is recommended in the guidelines for child and adolescent psychiatry outpatient clinics. We suggest that the joint consultation model could be a good way for GPs and CAMHS specialists to collaborate.

Background

GPs do have a role in child and adolescent mental health care [1][2][3][4]. It is, however, shown that GPs' skills in child and adolescent psychiatry could be improved [1,3,[5][6][7][8][9][10][11]. Hafting has shown that an interested GP is in a good position to provide services to children and adolescents with mental health problems, but that many GPs believe that they lack specific knowledge in child and adolescent psychiatry [1]. Zwaanswijk found that approximately 80% of children and adolescents with psychological problems had seen their GP within the preceding year, but GPs' identification of psychological problems was limited [6]. These findings are consistent with other studies [5,12].

Alexander and Heikkinen have both displayed that GPs perceive their skills in child psychiatry as somewhat inadequate [7,8]. The need for increased knowledge and skills among the GPs in this field is addressed several in other papers [3,9,11,13]. It is therefore important to gain more knowledge as to how GPs' competence and skills can be further developed. Generally, collaborative programmes seem to be more effective than more theoretical educational programmes [14][15][16][17][18][19][20], in line with theories of experiential learning [21]. A Cochrane review examining interventions to change outpatient referral rates or improve outpatient referral appropriateness found that active local educational interventions involving secondary care specialists and structured referral sheets are the only interventions that lower referral rates, based on current evidence [22].

There are various types of on-site mental health interventions, and in the literature, it is not always clear exactly what is included [23]. Different types of collaboration have been described, ranging from a consultative role only for a psychiatrist, [24,25] to consultation-liaison psychiatry [26][27][28][29], specialist clinics in a primary care setting [30], telepsychiatry [29,31] or collaborative care with various mental health care providers [20,32,33]. We have found joint consultations with GPs described in adult psychiatry [34][35][36] and in paediatrics [16,17], but we have found no studies that specifically describe joint consultation in a general practice with child and adolescent psychiatry specialists. In an adult psychiatry setting, Saillant describes collaboration between primary care physicians in training and a psychiatrist, and suggests that joint consultation is an efficient way to transfer skills and build confidence among primary care physicians in their care of patients with mental health problems [34]. Mouland describes a model in which adult patients often obtained sufficient help from one joint consultation with the GP and the psychiatrist [35]. Macaulay shows that joint clinics with GPs and pediatric specialists can improve clinical knowledge and skills for both [16]. Similar results are described in an evaluation of a model where hospital paediatricians and GPs participate in joint clinics and multidisciplinary team meetings in GP practices [17]. In a pilot study from 1997, a primary mental health care worker provided expert support and advice and specialist consultations to GPs in Portsmouth [26]. This programme resulted in fewer referrals to child and adolescent mental health services in the intervention group, and the referrals that did occur were more likely to be assessed as appropriate.

Norwegian guidelines for mental health services for children and adolescents state that outpatient clinics should collaborate closely with primary health care givers, including GPs [37]. A qualitative study from 2011 that examines the collaboration between GPs and mental health care professionals in Norway suggests that face-toface contact between GPs and mental health professionals seems to be superior to written or telephonic contact in easing collaboration [38].

Since joint consultations with GPs have been suggested to be useful in both adult psychiatry [34,35] and paediatrics [16,17], it is interesting to see how a similar approach will work in child and adolescent psychiatry. This paper describes such a model: During the period 2008-2014, the GPs in one group practice in Lillehammer, Norway practiced joint consultations with professionals from the local child and adolescent psychiatry clinic. Our study is an exploration of the experiences of this collaboration among participating GPs and specialists from the local CAMHS Outpatient Clinic. Our aim has been to evaluate possible benefits and downsides of the collaboration, which could be useful to other GPs and CAMHSs who consider implementing something similar.

Methods

Settings

The collaboration incorporates joint consultations at the GP's office at Svingen Health Centre. When there is concern about the psychological health of a child or adolescent, the GP can make an appointment with one of the participating child psychiatry specialists. Every fortnight (except during school holidays) the GPs have two available 1-h appointments. If it is obvious that the child needs specialist psychiatric care, the GP can still refer directly to the specialist clinic. The collaboration began in August 2008 as an experiment. When the focus group discussions took place in October and November 2014, 100 joint consultations had been held, with 76 children and adolescents. We encourage both parents to come with the child. The GP and the child psychiatry specialist usually have a brief talk before the GP fetches the family from the waiting room. The GP starts by presenting the visiting specialist to the parents and child and informing them about the collaboration. The GP then briefly introduces the background for the consultation and invites the parents and the child if they have any questions or comments. The CAMHS specialist usually takes the lead in establishing contact with the child and the parents. From time to time, the GP makes a comment or is consulted by the CAMHS specialist, especially where somatic symptoms are involved. The primary function of the joint consultation is to decide whether the child requires a referral or if the problem can be handled in primary care-whether by the GP, the school psychology services, the family team at the child health centre, the child welfare services, or others.

During these consultations, the CAMHS specialist acts as a consultant. The documentation is the GP's responsibility; nothing is registered at the CAMHS clinic. If the patient is not referred, the GP is responsible for followup and referral to other services as needed. Sometimes a new joint consultation is established; sometimes the GP who had decided that a referral was unnecessary later decides to refer the child after all.

Design

Two focus group discussions based on semi-structured interviews, one with the participating GPs (October 2014) and one with the participating CAMHS specialists (November 2014).

Participants

Five GPs working in the same practice; their experience in general practice varied from 6 months to 20 years, with a median of 12 years. Two CAMHS specialists-one psychiatrist and one psychologist-both had more than 20 years of experience and worked together.

Data sampling

The participants gave their informed consent to take part in semi-structured interviews conducted by the third author, a GP from another health centre in town with experience from qualitative research. The first author was present, but did not participate in the discussions. An interview guide was used to generate discussion. Topics included a general impression of the collaboration, whether the participants had learned something from the collaboration, examples of successful and unsuccessful consultations, suitable and unsuitable issues for collaboration, and ways of making the collaboration work in practice. Our aim was to evaluate possible benefits and downsides of the collaboration. TS prepared a question guide to shed light on these questions. All authors commented on the guide and the question guide was finalized by TS and IT. The following questions were used as guidance for the semi-structured interviews (Table 1).

Analysis

Interviews were recorded digitally and transcribed verbatim. The transcripts were imported into the software package NVivo 10 [39]. All authors read through the interviews by themselves. Interviews were then analysed via systematic text condensation by the first author, as described by Malterud [40]. During the process of coding for units of meaning TS and IT discussed and agreed on the different codes. Analysis followed four steps: (i) listening to sound tracks and reading transcripts to obtain an overall impression; (ii) identifying and coding for units of meaning representing different aspects of the collaboration in question; (iii) condensing and summarizing contents of each coded group; and (iv) based on these groupings, describing the participants' experiences and opinions about the collaboration model via the thematic categorization as presented below.

Results

Between August 2008 and August 2014, a total of 76 patients were seen in 100 consultations. One or both parents attended most consultations, another carer attended four consultations, six adolescents came alone, and in eight consultations one or both parents came without their child. Table 2 shows the gender and age at first consultation and Table 3 shows the age distribution of all consultations.   The median time between presenting the problem to the GP and participating in the joint consultation was 20 days; 38% had their appointment within 2 weeks, 24% of patients had to wait more than 4 weeks (often during holiday times). Of the 76 children, 11 were referred to the CAMHS at the initial joint consultation, and 11 were referred later; thus 71% were not referred.

Behavioural problems and concerns about hyperkinetic disorder were the most common presenting problem, each present in 19% of the consultations. Other common issues were anxiety (15%); depression (12%); psychiatric or drug-related problems in the family (12%); reaction to stress (11%-often parents' divorce); non-attendance at school (10%); and psychosocial problems at school, including bullying (10%). Issues present in less than 10% of the consultations were, from most to least frequent, need for consultation about a known diagnosis, tics, psychosomatic symptoms (including enuresis and encopresis), learning difficulties, worries about autism spectrum disorder, sleeping problems, eating disorders, self-harming, and concerns about early mother-child interaction.

Analysis revealed the same main themes in both focus groups: The GPs and CAMHS specialists agreed that children and families receive help from the consultations and that there are learning effects for the GPs and benefits for the CAMHS. The value of the two groups of health care providers having the opportunity to meet and talk person-to-person was emphasized. Downsides of the collaboration were also reflected upon, along with practical issues like when to use the joint consultation and how to make it work. These themes are presented below.

Help for children and their families

In both focus groups, the collaboration was viewed as a low-threshold service, where help can be given close to the patient.

GP: It's like an ordinary consultation, right, just with a hired expert.

The interviewees reported that children and parents find their GP's office a safe place to come, whereas going to the CAMHS at the hospital can seem frightening to some of them. Both focus groups reported that many families are happy that things can be solved at the GP's practice, so they need not be referred and undergo what is often a time-consuming process.

GP: 'Cause they had the abilities in the family to handle this. Right? So that was very good. The alternative would have been to refer. And that would have been a lot more hassle.

GPs' learning effects

The GPs said that they had learned a great deal from seeing how the specialists talked with the children-that they could be quite direct with them.

GP: The short version is that they are quite direct. (…) They call a spade a spade.

The GPs said that their diagnostic skills had improved and that they had learned how to explore for different problems, so they could better sort which patients to refer and which not to refer. The specialists agreed with the GPs self-evaluations.

CAMHS: Learning to sift. It's obvious that we achieve that with Svingen Health Centre.

The GPs said they had also received concrete advice and learned strategies to use when treating such conditions as phobias and sleeping disorders.

GP: Next time I can try that for myself.

Benefits for the child and adolescent psychiatry clinic

The GPs were not sure what the specialists can learn from them, other than gaining insight into the way a GP works, seeing a broader range of patients, and obtaining some somatic knowledge. As the psychologist confirms:

CAMHS: I think it's been a benefit to the clinic to have somatic medicine tied closer to us. Probably it's been useful to me, who doesn't have a medical education.

The GPs said they think the CAMHS specialists enjoy this way of working, which the specialists confirm.

CAMHS: We meet the GP as consultants. That is to say, we're not responsible for the things that are brought up, all the documentation. In a way, taking care of the patients, that's the GPs' responsibility.

The specialists also found that there were now fewer referrals from Svingen Health Centre, and that the referrals that did come, were more appropriate.

CAMHS: And they get it, the GPs at Svingen. Later, with a similar case, you don't refer this. You can handle it yourself. "

The value of meeting each other

The GPs stressed the importance of meeting the CAMHS specialists in person, for learning effects, for the good of the specific patient, and for an opportunity for a short, informal consultation about other patients.

GP: There's so little contact between us and the specialist health services, face to face. Right? We never meet. So, having such meeting points is important.

The CAMHS specialists also agreed that meeting their colleagues in primary health care was important, for both sets of health care workers and for the patients.

CAMHS: The function of getting together early and looking at things together…An unbeatable team, when the GP and someone from the child psychiatry meet, I think, having some experience, there's a lot of power in that meeting.

Is there no downside?

Both GPs and specialists mentioned the possibility that the joint consultation could lead GPs to cut down on referrals of children and adolescents who should have been referred. The GPs were aware that one of the clinic's reasons for suggesting the collaboration was to reduce the number of referrals. Some of the GPs were concerned that they could lead the consultation in the wrong direction and miss important information.

GP: And then I've thought sometimes, if I've been thinking wrong to start with and lead things in a wrong direction, then we miss.

Some GPs expressed discomfort with the responsibility they were expected to assume after they had decided not to refer.

GP: I've been thinking of the first consultation, the first joint consultation, that, well, I felt I got a little too much responsibility.

At the same time, they went on to explain how these issues were counteracted so as not to constitute major problems. The CAMHS specialists pointed to their prioritizing guidelines, which state that the more severe disorders are their responsibility. The GPs stressed that by following up on their patients, they'll be able to see if other measures need to be taken.

GP: Even if [the psychologist] said not to refer, you think, yes, well, it's your right to refer anyway.

When to use the joint consultation?

The GPs and the specialists agreed that a joint consultation is not suitable if the child's parents are in conflict and some GPs said that they would be reluctant to participate if severe psychiatric symptoms were in question.

CAMHS:

The worst is when children experience their parents screwing up, to put it simply. I don't want to witness that.

Everyone saw the joint consultations as useful for sorting the problems. Is this a normal reaction? Should it be referred to the pedagogic-psychological service? Can the GP handle this, or should the CAMHS take over?

CAMHS: I think that to take part and sort, trying to separate the wheat from the chaff, there, I believe, our two disciplines have much to gain from each other.

Both groups also mentioned concrete problems like phobias and encopresis as suitable issues for joint consultation.

CAMHS: Everything to do with poop, pee, head, stomach, everything to do with psychosomatics for example, is brilliant [for joint consultation].

How to make it work in practice?

The GPs mentioned several practical issues that were necessary to make this work in a busy practice. There must be fixed, sufficiently frequent appointments that are easy for the GPs to book. Both groups also stated that a successful collaboration depends a great deal on the specialists; not everyone would be comfortable or do a good job in such a setting.

GP: But I believe the main success factor is personal. One must bear that in mind, right? [They are] confident, very experienced specialists who dare go straight to the core of the problems, you know, so that people feel that what's happening is important, and that you get help.

Discussion

Statement of principal findings

We found that the specialists and the GPs shared the impression that the collaboration is useful; its benefits clearly outnumbering negative effects. They described benefits for the patients, the GPs, and the CAMHS. Both groups expressed the belief that patients find it easier to come to the GP than to the specialist clinic, that it feels safe, that it is a low-threshold service, and that many families are happy not to be referred. One model for collaboration is "meeting between experts" and another is "transference of competence from one level to another". We find that the experiences from the present project are more like the last. Although the CAHMS specialists say that they benefit from coming closer to somatic medicine, both GPs and CAMHS specialists describe more learning effects for the GPs than for the CAMHS specialists. GPs reported themselves as being more confident now when talking to children and adolescents about difficult issues and that their diagnostic skills in child and adolescent psychiatry had improved. The psychiatrist and the psychologist have the impression that there are now fewer and more adequate referrals. Both GPs and CAMHS specialists are aware of the fact that one motivation of CAMHS for entering the collaboration is a reduction in the number of referrals, and that this could lead to patients not receiving the help they need. To counteract this potential problem, the GPs say that they can detect through follow-up if the situation is not improving, and then take action. The CAMHS specialists point to the priority guidelines to which they should adhere. The two groups agreed upon the issues that are more suitable for these joint consultations, and that it is especially useful for sorting the wheat from the chaff. They also agreed that the mental health specialists must be confident and experienced for the collaboration to be successful.

Strength and weaknesses of the study

In the GP focus group, one of the GPs had had only one joint consultation and participated little in the focus group discussion; the other four were all active during the discussion. The youngest of the GPs had approximately 6 months' experience and was substituting during that time for the first author, who had participated in the consultation project since its start in 2008 and was an observer to the discussion. A possible weakness of this study is that one the GPs who had taken part in the collaboration from the beginning (i.e. the first author) did not participate in the discussion. Another problem is her being biased from being a part of the collaboration, and analysing the discussion between her colleagues. To minimize this potential bias all four authors have read the interviews, and the coding was discussed between them during the analysis. The interview was performed by a GP from a neighbouring health centre that is not part of the collaboration in question and who is also a researcher with experience from focus group interviews.

There were only two CAMHS specialists involved in the collaboration. Although focus groups usually consist of more than two persons, we chose to do a group interview also with the psychiatrist and the psychologist, reckoning that this after all would make the discussion more comparable to the one in the GP group than if we had done individual interviews. A better option might have been to divide the GP group in two, to make the groups more comparable in size, or to conduct individual interviews with all participants. Still, the dynamics in the groups were similar and the results were largely coincidental.

A limitation of focus groups is the extent to which participants (usually strangers) are willing to reveal their feelings and opinions to the rest of the group and the facilitator. In this study, the participants in both groups were colleagues who knew each other well. The first author was present and observed both interviews, and had a clear impression that the participants were open and talked freely about the issues that arose.

The transferability of our findings may be limited by the fact that only one health centre and one speciality clinic was involved in the collaboration. As the participants argue, the success of this model depends largely on personal factors-on the participants being comfortable with an interdisciplinary collaboration. Further research on a broader and more representative group of GPs and child and adolescent psychiatry clinics is needed to determine if this would be a suitable collaboration in other contexts.

The health care providers argue that the collaboration is helpful for the patients, but the researchers did not have the resources to interview children and their families. This addition to the study would have provided greater insight into the experiences of the patients.

Findings in relation to other studies

There are some examples of consultation-liaison psychiatry for children and adolescents, the most similar to ours being a pilot study by Neira-Munoz, wherein GPs were assisted by a primary mental health care worker who provided expert support and advice and specialist consultations [26]. Similar to the impression in our study, this programme resulted in fewer referrals to child and adolescent mental health services by the GPs in the intervention group, and the referrals were more likely to be assessed as appropriate. A Canadian study describes how the integration of mental health teams in a primary care setting has improved access to mental health care for children and expanded the capacity of primary care physicians to deliver mental health care [32]. As in our study, they mention the advantages of a low-threshold service and argue that secondary and tertiary mental health service efficiency is improved because of better triaging of patients in primary care before referral. This project involved several health professions and had central management, as opposed to our small-scale collaboration with virtually no administration. Studies from paediatrics and adult psychiatry support the findings from our study. Both Macaulay and Montgomery-Taylor find that a model with joint consultations with GPs and paediatricians provides learning for the participating GPs [16,17]. Mouland states that patients often receive sufficient help from one joint consultation with the GP and the psychiatrist [20] and Saillant's study suggests that joint consultation is an effective way of transferring skills and building confidence in primary care physicians regarding care of patients with mental health problems [21]. Saillant discusses the limitation that they, as we, were unable to explore the experiences of the patients. This would be a key area for further research.

In general, the value of meeting face to face is a common finding in studies about collaboration between primary and secondary health care professionals, a finding that is in agreement with our results. Compared to other examples, our model involves few persons and little administration, which makes it easy to implement.

Conclusions

There are several collaboration models involving GPs and other mental health professionals, but we have found no other studies evaluating joint consultations between GPs and child and adolescent psychiatry specialists. Therefore, although our study is a small-scale collaboration, we think it is an interesting addition to what is already published, and we hope it can encourage others to new collaborations and further research. Norwegian guidelines for mental health services for children and adolescents state that outpatient clinics should collaborate closely with primary health care, and joint consultation could be an effective way of doing so.

Abbreviations GP: general practitioner; CAMHS: child and adolescent mental health services.

Authors' contributions TS, MB and ORH planned the study together. IT facilitated the focus groups, TS was listening in and transcribed the focus group discussions. All authors read the transcriptions and discussed the analysis, which was mainly done by TS. TS wrote the initial draft of the article, which was then reviewed and structured by MB and ORH. All authors read and approved the final manuscript.

Table 1
1Interview guideQuestion
Comment

1
How have you experienced having
joint consultations with CAMHS spe-
cialists in your office? / How have
you experienced visiting the GP's
office for the joint consultations?

Focus on the emotional
aspect of having a con-
sultation with another
professional. Has it felt
difficult or uncomfort-
able? If yes, why? If no,
why?

2
Have you learnt something from the
joint consultations? If yes, can you
describe what you have learnt. Do
you think the CAMHS specialists/
the GPs have learnt anything? If yes,
what?

3
Can you tell us about an especially
successful consultation? When
the child wasn't referred? When
the child was referred? How do
you think the family felt about the
consultation?

Not necessarily all exam-
ples from everyone, but
try to get all alternatives
covered

4
Can you tell us about a not so suc-
cessful consultation? When the child
wasn't referred? When the child was
referred? How do you think the fam-
ily felt about the consultation?

Not necessarily all exam-
ples from everyone, but
try to get all alternatives
covered

5
For what kind of problems do you
find the joint consultation especially
useful?

6
Are there problems that are not suit-
able for joint consultations?

7
What factors are important for such a
collaboration to work?

8
Would you recommend joint consul-
tations to other GPs/CAMHS clinics?

9
Anything else you want to mention?

Table 2 76
2children seen in joint consultations-gender and ageGirls
Boys

Table 3
3Age of children seen in 100 joint consultationsAge group (years)
Percentage of consultations (%)

<5
10

6-9
30

10-13
40

14-17
19

>18
1

GP: I believe the fact that we are confident in [the specialists], affects the patients. They know us, right, and they see that we trust and like the company of the person from the child and adolescent psychiatry clinic, which makes it easier for them to relax and open up too, it's astonishing, you know, to see how people are able to open up faced with a person they never met before. It's pretty good. And there, I believe we have kind of a catalyst role, just by being there.
AcknowledgementsNot applicable.Competing interestsThe authors declare that they have no competing interests.Availability of data and materialsThe data consists of two focus group interviews that have been recorded digitally, then transcribed verbatim. The participants did not consent to have the transcripts made publicly available.Consent for publicationThe participants in the focus groups have consented to publication of the article.Ethics approval and consent to participate The Regional Committee for Medical and Health Research Ethics found the project not covered by the Health Research Act, and hence not in need of ethical approval. The Data Protection Official for Research has granted its approval. The participants gave their informed consent to take part in the focus group discussions. Consent was written.FundingFunding was provided by The Research Fund in General Practice (AMFF). The funding body has had no role in the design of the study, nor in the collection, analysis, and interpretation of data or in writing the manuscript.Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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