This study aims to provide reasons for the poor sarcoma-related survival in patients with radiation-induced sarcoma (RIS).
We performed a case–control study comparing sarcoma-related survival of 98 patients with RIS to that of 239 sporadic high-grade malignant sarcomas.
The cumulative sarcoma-related 5-year survival was 32% (95% confidence interval (CI): 22–42) for patients with RIS vs 51% (95% CI: 44–58) for controls (P<0.001). Female gender, central tumour site and incomplete surgical remission were significantly more frequent among RIS patients than in controls. In multivariate analysis incomplete surgical remission (hazard ratio (HR) 4.48, 95% CI: 3.08–6.52), metastases at presentation (HR 2.93, 95% CI: 1.95–4.41), microscopic tumour necrosis (HR 1.88, 95% CI: 1.27–2.78) and central tumour site (HR 1.71, 95% CI: 1.18–2.47) remained significant adverse prognostic factors, but not sarcoma category (RIS vs sporadic).
The poor prognosis of RIS patients are not due to the previous radiotherapy per se, but related to the unfavourable factors – central tumour site, incomplete surgical remission, microscopic tumour necrosis and the presence of metastases, the two former factors overrepresented in RIS.
radiation; radiation-induced; sarcoma; secondary malignancies; prognosis; treatment-related morbidity
Hodgkin's lymphoma survivors (HLSs) have an elevated risk for cardiovascular diseases that appear several years after radiotherapy. This study examined the time-dependent development and evolution of valvular and myocardial function related to treatment with mediastinal radiotherapy and anthracyclines in HLSs.
Patients and methods:
In 1993, echocardiography was performed in 116 HLSs median 10 years (range 6–13 years) after treatment with mediastinal radiotherapy. None of the 116 patients had valvular stenosis in 1993 whereas 36 (31%) had moderate valvular regurgitation. In 2005–2007, 51 of 57 invited patients were included in a second echocardiographic study – median 22 years (range 11–27 years) after treatment. Of these patients, 28 (55%) had also received anthracyclines. The patients were selected on the basis of the presence or absence of moderate valvular regurgitation in 1993.
The second echocardiographic study demonstrated that 10 out of 27 (37%) patients with only mild or no aortic or mitral regurgitation in 1993 had developed moderate regurgitation in either or both the aortic or mitral valve. Of the 24 patients with moderate (n=23) or severe (n=1) regurgitation in the aortic or mitral valve in 1993, 8 (33%) had progressed to severe regurgitation, developed moderate regurgitation in a previously normal or mild regurgitant valve or had received valvular replacement. In total, of all patients, 20 (39%) had developed mild to severe aortic stenosis and 3 patients had received valvular replacement. In a multiple linear regression the use of anthracyclines predicted left ventricular remodelling between ECHO 1993 and 2005 as demonstrated by increased left ventricular end systolic diameter (β =0.09 (95% CI 0.01–0.17), P=0.04) and reduced thickness of the left ventricular posterior wall (β =−0.18 (95% CI −0.33 to −0.03), P=0.02) and interventricular septum (β =−0.16 (95% CI −0.30 to −0.03), P=0.02).
Given the progressive nature of valvular dysfunction and left ventricular remodelling 20–30 years after diagnosis, we recommend life-long cardiological follow-up of HLSs treated with mediastinal radiotherapy.
lymphoma; cardiac valves; cardiomyopathy
Gonadal function was assessed in male lymphoma survivors based on serum hormone levels (LH, FSH, testosterone, SHBG), and was related to treatment, age and observation time. Male patients ⩽50 years at diagnosis treated for Hodgkin's (HL) and/or non-Hodgkin's lymphoma (NHL) at the Norwegian Radium Hospital from 1 January 1980 to 31 December 2002 were included. Five treatment groups were defined: 1: radiotherapy only and/or low gonadotoxic chemotherapy (both HL and NHL)(‘No/low'), 2: medium gonadotoxicity chemotherapy for NHL (‘med-NHL'), 3: medium gonadotoxicity chemotherapy for HL (‘med-HL'), 4: highly gonadotoxic chemotherapy for NHL (‘high-NHL'), 5: highly gonadotoxic chemotherapy for HL (‘high-HL'). Gonadal hormone levels were categorised into three groups: 1: All gonadal hormones within normal range (normal), 2: Isolated elevated FSH, with LH, SHBG and testosterone within normal range (exocrine hypogonadism), 3: Testosterone below and/or LH above normal range (endocrine hypogonadism). One hundred and forty-four (49%) of the patients had normal gonadal hormones, 60 (20%) displayed exocrine hypogonadism and almost one-third (n=90, 30%) had endocrine hypogonadism. Compared to those treated with no/low gonadotoxic chemotherapy patients from all other treatment groups had significantly elevated risk for exocrine hypogonadism. Patients from the other treatment groups, except those in the med-NHL group, also had significantly elevated risk for endocrine hypogonadism compared with the group treated with no/low gonadotoxic chemotherapy. Men aged above 50 years at survey were about five times more likely to have endocrine hypogonadism compared with those less than 40 years. Because of the adverse health effects following long-lasting endocrine hypogonadism, gonadal hormones should be assessed regularly in male lymphoma survivors, especially after treatment with alkylating agents and high-dose chemotherapy with autologous stem cell support and in male patients who are 50 years and older.
male lymphoma survivors; chemotherapy; gonadal function
Attempted and achieved post-treatment parenthood, with or without use of assisted reproduction techniques (ARTs), was assessed in Hodgkin's lymphoma survivors treated from 1971–1998, aged below 50 (females) or 65 (males) at diagnosis, aged 18 to 75 at survey. Four treatment groups were constructed: radiotherapy only, low -, medium - and high gonadotoxic chemotherapy (with or without radiotherapy in the three chemotherapy groups). Using Kaplan–Meier estimates, log-rank tests and Cox regression analyses, factors influencing post-treatment parenthood were investigated, with birth of the first child after treatment as the end point. Forty-five per cent (120/269) of males and 50% (91/184) of females reported attempted post-treatment parenthood. Of these, 76 (63%) males and 68 (75%) females had a child without use of ARTs. In addition 10 males and one female achieved post-treatment parenthood with use of ARTs. Treatment group was significantly associated with post-treatment parenthood, with highest probabilities after radiotherapy only and low gonadotoxic chemotherapy. In univariate analyses, age at diagnosis was a significant factor related to post-treatment parenthood in females.
Hodgkin's lymphoma; chemotherapy; radiotherapy; post-treatment parenthood
The purpose of this study was to explore the incidence of late relapse in patients with malignant germ cell tumour (MGCT) in a population-based series, with emphasis on the mode of detection, survival, and the relevance of histological findings. The clinical records from a population-based cohort of patients with seminoma (n=1123) or non-seminoma (n=826) were evaluated for late relapses. Twenty-five patients developed a late relapse. The cumulative 10-year incidence rate was 1.3%. All 10 seminoma patients, but only eight of 15 non-seminoma patients relapsed with vital malignant tumour (P=0.02). Teratoma or necrosis was found in seven of nine primarily chemotherapy-treated non-seminoma patients with normal tumour markers at late relapse. Six of nine patients operated with limited retroperitoneal lymph node dissection as part of the primary treatment had relapsed retroperitoneally outside the original operation field. The 10-year cause-specific survival was 68% in all patients, 50% in patients relapsing with vital malignant tumour and 100% in those with teratoma/ necrosis before or after salvage chemotherapy. The 10-year incidence rate of late relapses of 1.3% might reflect the true incidence rate in a population-based cohort of MGCT patients, with cure in at least half of them.
late relapse; late recurrence; testicular cancer; extragonadal germ cell cancer; EGGCT; seminoma; non-seminoma; retroperitoneal lymph node dissection
New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP.
intermediate and poor prognosis metastatic germ cell tumours; bleomycin; carboplatin; vincristine; cisplatin; etoposide
KIT; testicular germ cell tumours
malignant germ cell tumours; mortality; nongerm cell cancer; cardiovascular diseases
prostatic neoplasms/receptor; epidermal growth factor/receptor; erbB-2/receptor; erbB-3
testicular cancer; treatment; BMI
Four different genes were identified by immunoscreening of a cDNA expression library from the human prostate cancer cell line DU145 with allogeneic sera from four prostate cancer patients. A cDNA encoding the nucleolar protein No55 was further analysed and shown to be expressed at the mRNA level in several normal tissues, including ovaries, pancreas and prostate and in human prostate cancer cell lines PC-3, PC-3m and LNCaP. By reverse transcriptase/polymerase chain reaction, expression of No55 was several-fold higher in two out of nine prostate cancer primary tumours and two out of two metastatic lesions, compared to normal prostate tissue. Antibodies to No55 were detected in sera from seven out of 47 prostate cancer patients but not in sera from 20 healthy male controls. Sequence analysis of the No55 open reading frame from normal and tumour tissues revealed no tumour-specific mutations. The No55 gene was located to chromosome 17q21, a region reported to be partially deleted in prostate cancer. Considering the immunogenicity of the No55 protein in the tumour host, the expression profile and chromosomal localization of the corresponding gene, studies evaluating No55 as a potential antigen for immunological studies in prostate cancer may be warranted. © 2000 Cancer Research Campaign
SEREX; prostate cancer; No55
The intention was to explore the relationship between fertility and testicular cancer, including the possibly treatment-induced changes over time in the post-diagnostic fertility. Data are from the Norwegian Cancer Registry, The Norwegian Population Register and the Population Censuses. By estimating Poisson regression models, birth rates among testicular cancer patients were compared with those of other men who had the same age, parity and duration since previous birth. Poisson regression models were also estimated to check whether men's parity has an effect on the cancer incidence. Fertility rates among testicular cancer patients born after 1935 and treated before 1991 decreased by roughly 30% when compared with the normal population. The introduction of cisplatin chemotherapy and of nerve-sparing RPLND in the 1980s seems to have enabled more patients with non-seminoma to father a child after treatment, or at least shortened the time to conception. Moreover, the risk of being diagnosed with seminoma is reduced with increasing parity. This suggests that the relatively low fertility after diagnosis may be partly due to the continuing inherent influence of a sub- or infecundity that also had a bearing on the development of the disease. © 2000 Cancer Research Campaign
fecundity; incidence; infecundity; infertility; parity; treatment
germ cell malignancy; relapse; cisplatin-based chemotherapy; survival
Residual retroperitoneal masses may remain after chemotherapy for metastatic non-seminomatous testicular cancer, which harbour residual tumour or totally benign tissue (necrosis/fibrosis). These residual masses may be effectively removed by a surgical resection. We evaluated current selection criteria and tried to develop alternative criteria in a data set of 544 patients, who had retroperitoneal lymph node dissection of residual masses. Six resection policies were identified from the literature. Two alternative policies were developed with logistic regression analysis. Evaluation of the policies focused on the true-positive rate (resection in case of tumour), and the false-positive rate (resection in case of necrosis). It appeared that most current policies use the size of the residual mass (> or = 10 mm or > or = 20 mm) as the predominant selection criterion. This resulted in high true-positive rates (most > 90%), but false-positive rates between 37% and 87%. The alternative policies included five well-known predictors of necrosis in addition to residual mass size (primary tumour histology, prechemotherapy levels of the three tumour markers alphafetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH) and mass shrinkage during chemotherapy). This strategy resulted in improved true- and false-positive rates, even when categories of the predictors were simplified for practical application. We conclude that a simple statistical model, based on a limited number of patient characteristics, provides better guidelines for patient selection than those currently used in clinical practice.
The aim of the present retrospective study was to assess long-term survival after cisplatin-based chemotherapy in 398 patients with advanced urothelial transitional cell carcinoma (TCC) treated at seven international oncological units. Various combinations of cisplatin, methotrexate, vinblastine (or vincristine) and doxorubicin were used. The complete response rate according to the WHO criteria was 17%. Partial responses were obtained in 42% of the patients. The overall cancer-related 2 year and 5 year survival rates were 21% and 11% respectively. Based on multivariate analyses, a good prognosis group could be identified comprising patients with a good performance status with disease confined to lymph nodes (14%) or patients with T4b disease only. These patients had a 28% 5 year survival rate, which, in part, has to be related to post-chemotherapy consolidation treatment in patients with pelvis-confined disease (radiotherapy, 26%; total cystectomy, 11%). Fifteen patients died of chemotherapy-related complications and in 16% of the patients toxicity led to discontinuation of treatment. Modern cisplatin-based chemotherapy leads to long-term survival and cure of selected patients with advanced urothelial transitional cancer. In routine clinical practice, chemotherapy should be offered to good prognosis patients; those presenting with a good performance status and a non-metastasising T4b tumour or with metastases confined to lymph nodes. Post-chemotherapy consolidation treatment by surgery or radiotherapy should always be considered. Such chemotherapy requires oncological expertise in order to avoid unnecessary toxicity.
The aims of the trial were to establish the response rate and determine the toxicity of combination chemotherapy with ifosphamide, vincristine and cisplatin (HOP regimen) in advanced metastatic seminoma and to study the role of post-chemotherapy consolidation treatment. Patients with bulky metastatic non-alpha-fetoprotein-producing seminomas were eligible for this phase II study [serum human chorionic gonadotropin < 200 U l-1 (< 40 ng l-1)] if they presented with abdominal masses > or = 10 cm or had extra-gonadal seminoma or had relapsed after previous radiotherapy. The HOP regimen consisted of four 3-weekly cycles of the following drug combination: ifosphamide (days 1-5, 1.2 mg m-2 day-1), vincristine (day 1, 2 mg) and cisplatin (days 1-5, 20 mg m-2 day-1). Residual masses persisting 6 months after chemotherapy could be considered for consolidation surgery or radiotherapy. Maximal response to the HOP chemotherapy (evaluated at any time) was based on the WHO criteria. The median observation time was 2.5 years (range 1.8-5.5 years). Thirteen institutions treated 42 eligible patients within the study (testicular cancer stage > or = IID, 25; extragonadal, 5; relapse after previous radiotherapy, 12). Two patients were not evaluable for response owing to premature treatment discontinuation. Maximal response was as follows: complete remission (CR), 26 (65%); partial remission (PR) 11 (28%); no change (NC), 2 (5%); progressive disease (PD), 1 (3%). Four patients have died, three from their malignancy (two without previous irradiation and one with prior radiotherapy). The fourth patient died of treatment-related toxicity. The 3 year survival for all 42 eligible patients was 90%. Dose reduction and treatment postponement were necessary in 25 and 14 patients respectively. Ten patients experienced granulocytic fever. Previously irradiated patients tolerated chemotherapy as well as non-irradiated patients. Immediately after HOP chemotherapy a mass persisted in 16 of 17 patients with retroperitoneal masses of > or = 100 mm at presentation. Three of these residual lesions were resected within the following 6 months showing complete necrosis. Four lesions dissolved spontaneously during the first year of follow-up. Nine lesions persisted for > or = 1 year (one after consolidation radiotherapy) without leading to relapse. Four of seven patients with mediastinal lesions achieved CR and three a PR after HOP chemotherapy. The HOP chemotherapy regimen is highly effective in patients with advanced metastatic seminoma or those relapsing after previous radiotherapy, but is associated with a high risk of toxicity, in particular myelotoxicity.
In patients with clinical stage I non-seminomatous testicular cancer only limited information is available about the administrative problems with the surveillance programme, in particular if this policy is to be implemented in a geographically extended country with limited computerised tomography (CT) resources. One hundred and two patients with non-seminomatous testicular cancer clinical stage I and low-risk histology (MRC criteria, UK) were followed by the surveillance policy for at least 1 year after orchiectomy (median 47 months, range 21-81 months). Twenty-two patients (22%) relapsed after a median time of 5 months (range 2-18 months), 14 of them in the retroperitoneal space. Serum alpha-fetoprotein and/or human chorionic gonadotrophin were elevated in eight of the 22 relapsing patients. The progression-free and cancer-corrected survival rates were 78% and 99% respectively. Patient non-compliance did not represent a major problem, whereas the regular and adequate performance of necessary CT examinations yielded some administrative difficulties. One and 3 years after orchiectomy about 50% of the relapse-free patients had no psychological problems and were satisfied with the surveillance programme, whereas 46% reported minor and 4% major psychological distress. Despite non-negligible administrative difficulties in geographically extended countries, surveillance is feasible and safe in compliant patients with low-risk non-seminomatous testicular cancer stage I. The responsible cancer centre and the local hospitals should establish a high degree of cooperation and enable adequate follow-up examinations in these patients.
Tissue specimens from 150 patients with localised prostatic carcinomas and 116 patients with prostatic carcinomas with distant metastases were analysed for histological grade (WHO and Gleason) and immunoreactivity for prostate acid phosphatase (PAP), prostate-specific antigen (PSA), neurone-specific enolase (NSE), p53 protein, c-erbB-2 protein, cytokeratins (AE1/AE3) and vimentin. After stratification for the presence or absence of distant metastases, multivariate regression analysis revealed that WHO grading was the most powerful independent prognosticator, followed by age and prostate acid phosphatase expression. There was a trend towards reduced survival with decreasing prostate-specific antigen reactivity. The Gleason system showed poor prognostic ability. The analysis predicted reduced survival in the presence of extensive neurone-specific enolase reactivity, mostly because of one case of small-cell carcinoma.
DNA ploidy and S-phase fraction (SPF), determined by flow cytometry were studied in 118 patients with muscle-invasive transitional cell carcinoma (TCC) of the urinary bladder, scheduled for cystectomy after pre-operative radiotherapy (20 Gy/1 week) with or without systemic cisplatin-based neo-adjuvant chemotherapy. The correlation between these parameters and immunohistochemically demonstrated p53, c-erbB-2 and HCG was also investigated. There were 16 DNA diploid and 102 DNA non-diploid tumours. DNA ploidy was not related to the T (all 118 patients) or pN (58 patients) category, occurrence of stage reduction or cancer-related 5 years survival. Patients with high SPF tumours tended, however, to have a better prognosis than those with low SPF TCC reaching the level of significance (P < 0.05) for those patients who had high SPF tumours and received neo-adjuvant chemotherapy. Fifty-one of the tumours were p53 positive. p53 positive tumours were significantly more often found in TCC with low SPFs than in those with high SPFs. Respectively 12 and 9% of the tumours were HCG and c-erbB-2 positive, without correlation to DNA ploidy or SPF. We conclude that DNA ploidy does not represent a prognostic parameter in muscle-invasive operable bladder carcinomas. A high SPF, determined by FCM, may be helpful to identify patients with chemotherapy-sensitive TCC of the urinary bladder.
A follow-up study of pulmonary function in two groups of patients with testicular cancer was performed 6-12 years after treatment. Both groups, 47 patients in each, had undergone retroperitoneal lymph node dissection (RPLND). Patients with pathological stage (ps) II had also received bleomycin (median 270 mg) and cisplatin (median 540 mg) in three or four courses which included vinblastine or etoposide. Patients in ps I and II were similar with respect to age, general health, observation period, inspired oxygen fraction (FiO2) and maximal arterial oxygen pressure (pO2) at RPLND, but four (8.2%) with psII disease developed densities on chest X-ray during chemotherapy. At the long-term follow-up the groups were similar with respect to physical exercise, smoking pattern, present drug treatment and history of cardiopulmonary disease. In both groups forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and single breath transfer factor for carbon monoxide (TLCO) were within normal limits, and no difference was found between the groups. The combined data for both groups showed that smoking was highly associated with impairment in TLCO (P = 0.005), and smoking frequency was negatively correlated to TLCO (P = 0.002). We conclude that 3-4 courses with bleomycin, cisplatin and etoposide/vinblastine in testicular cancer patients do not lead to long-term impairment of pulmonary function.
Pre- and post-treatment specimens from 47 patients with hormone resistant prostatic carcinoma were compared with each other regarding histological grade and immunoreactivity for p53 protein, neuron specific enolase and c-erbB-2 protein. Significantly more specimens expressed a high malignancy grade when the tumour had become hormone resistant than at the time of initial diagnosis (Gleason P: < 0.0001, WHO P:0.0003). p53 protein immunoreactivity increased significantly with disease progression (P:0.006), while tissue PSA immunoreactivity was reduced in post-treatment specimens (P:0.011). p53 protein expression did not correlate with histological grade or PSA expression and seems to be an independent parameter which participates late in the neoplastic transformation. Thirty-two percent of the tumours were neuron specific enolase positive, but this parameter did not correlate with development of hormone resistance. c-erbB-2 protein reactivity was not recognised.
Aspects of sexuality were assessed by questionnaires in 76 testicular cancer patients after orchiectomy before further treatment and, respectively, 6, 12 and 36 months after therapy. Before treatment 11% of the patients reported dissatisfaction with sexual life. About 20% of the patients sometimes experienced reduced libido and erectile difficulties. Six months after therapy significantly more patients (27%) recorded an unsatisfactory sexual life as compared to the pretreatment situation. At the 36 months' evaluation 22 of 76 evaluable patients (18%) still stated that their sexual life was inferior to the pretreatment experience. Libido and erectile function decreased transiently during the first year after treatment in most patients. Twelve patients reported permanent 'dry ejaculation' after bilateral retroperitoneal lymph node dissection. Other sexual disturbances could not be related to specified treatment modalities. Increased age at the time of diagnosis and psychological distress tended to correlate with the incidence of sexual problems. For about 60% of the patients the discussion of expected and experienced sexual life problems was an important issue to be discussed before their treatment for testicular cancer and during follow-up. The high frequency of any kind of long-lasting sexual problems (30%), though often of minor degree, warrants an adequate counselling of these patients before and after treatment.
The outcome of salvage treatment was reviewed in 55 patients relapsing during or after their primary chemotherapy for advanced malignant germ cell tumours. Fifty-two patients had been given cisplatin-based chemotherapy as their primary treatment, whereas three patients had received carboplatin-based chemotherapy. The median time to relapse was 2 months (range: 0-96 months) from discontinuation of the primary treatment. Two patients underwent radical surgery only, and one patient had radiotherapy to a brain metastasis as his only curatively intended salvage treatment. Six patients did not receive any treatment for their recurrent malignancy (refusal, terminal condition) except for purely palliative measures. The disease-free survival for the total group was 27% at 5 years. Complete response to primary treatment lasting for > or = 6 months was the only parameter which significantly predicted a favourable outcome (45% 5 year disease-free survival in 12 eligible patients).
Hematological and biochemical parameters were evaluated in 31 patients receiving 150 MBq 89Strontium (89Sr) intravenously due to painful skeletal metastases from hormone resistant prostate cancer. Two and 3 months after the injection prostate specific antigen (PSA) had increased by a median of 36% and 100%, respectively, as compared to the pretreatment value whereas alkaline phosphatase (APHOS) had decreased by about 20% (median). The leucocyte and platelet counts were reduced by about 20-35%, without reaching grade greater than or equal to 2 toxicity. Pain relief was reported in 14 of 29 evaluable patients at 2 months and in 11 of 23 patients at 3 months. It is concluded that 89Sr represents a worthwhile therapeutic modality in the palliation treatment of patients with hormone resistant prostate cancer, though the biological significance of frequently increasing PSA and decreasing APHOS is not yet completely understood.