Extramedullary relapse of acute lymphoblastic leukemia in childhood to the prostate

A 6-year-old boy presented with the chief complaints of miction pain and pollakisuria. He had a past history of acute lymphoblastic leukemia (ALL), which subsided in response to chemotherapy at 3 years of age. Ultrasonography revealed urinary retention associated with bilateral hydronephrosis secondary to the prostate enlargement. Computed tomography and magnetic resonance imaging showed no other abnormal finding. Transrectal needle biopsy showed infiltration of leukemic cells in the prostate. Bone marrow puncture and cerebrospinal fluid aspiration revealed no leukemic cells, resulting in a diagnosis of extramedullary relapse of ALL in the prostate. Although he was successfully treated by chemotherapy, irradiation and his voiding function was improved, ALL relapsed in the left testis 1 year later. In spite of left orchiectomy, irradiation and additional chemotherapy, he died of bone marrow relapse and multiple organ failure. Extramedullary relapse of ALL in the prostate is very rare. To our knowledge, our case is the first well-documented report in the published work.     

Relapsing membranous nephropathy. Response to therapy of relapses compared to that of the original disease.

BACKGROUND: Although controversial, treatment of membranous nephropathy appears to yield a reduction in the degree of proteinuria and conservation of renal function. METHODS: We report herein our experience with the treatment with steroids alone (group II, n = 13), or in combination with immunosuppressants (group III, n = 19) of patients with membranous nephropathy and the nephrotic syndrome, with a mean follow-up of 8.37 years. RESULTS: All patients underwent a first remission, with 24-hour urine protein excretion falling to 0.63 +/- 0.25 g in group II and 0.62 +/- 0.26 g in group III (p = NS) after 12.69 +/- 10.94 months of treatment in group II and 18.95 +/- 13.17 months in group III (p = NS). Three patients from group II (23%) and seven patients from group III (36.8%) experienced four and eight relapses, respectively (proteinuria in 24 h 4.0 +/- 0.80 g in group II relapsers and 4.4 +/- 0.87 in group III relapsers; p = NS). On treatment, all relapses remitted (second remission) after 7 +/- 6.93 months of therapy for group II and 8.6 +/- 6.70 months of treatment for group III (p = NS). Thereafter, no patients from group II, but 3 patients from group III (33.3%) had a second relapse. After treatment, all relapses remitted (third remission) in 3.3 +/- 1.53 months of therapy. CONCLUSIONS: These studies show that relapses, which occur in one-third of patients, respond favorably to treatment albeit remitting in approximately half the time, and that the duration of remission gets progressively longer in the later compared to the earlier remission.     

Surveillance for stage I non-seminomatous germ cell tumours of the testis: the optimal protocol has not yet been defined

Forty-six patients with clinical stage I testicular non-seminomatous germ cell tumours were followed up according to a protocol of active surveillance between 1979 and 1987. The median follow-up time was 40+ months. Thirteen patients (28%) relapsed, predominantly in retroperitoneum and/or lung. Ten of these relapses (76%) occurred within 8 months of orchiectomy. Relapses occurred in 7/35 T1 tumours and 5/10 T2 to T4 tumours. No correlation was detected between the histological type and relapse rate. Three late relapses were diagnosed at 23, 29 and 36 months. Eleven of the relapsed patients remain in prolonged complete remission after PVB chemotherapy +/- surgery; one patient, who initially refused treatment at the time of relapse, has died. Another relapsed with predominant elements of rhabdomyosarcoma intermingled with malignant teratoma in a bone metastasis. He had a partial response to PVB chemotherapy but subsequently died. Thirty-four patients (74%) did not undergo lymphography (LG) and had a higher relapse rate (11/34) than those who had LG (2/12); this was not a statistically significant difference in this small series. The policy of active surveillance is not yet the "state of the art" and should be under constant scrutiny with respect to safety and practice.     

Acute leukemia: Diagnosis and management of testicular involvement

Contemporary therapy of acute leukemia frequently achieves long-term continued complete remission (CCR) of bone marrow disease and prevents central nervous system relapse. However, accompanying improved survival is an increasing incidence of overt testicular relapse either during CCR or associated with bone marrow relapse. In 7 boys testicular abnormalities developed during CCR, 6 had open biopsy and 5 had histologically confirmed leukemic infiltration. Despite local therapy of orchiectomy or irradiation and chemotherapy reinduction, 2 of 6 had testicular relapse and 4 of 6 died. Three boys with coexistent overt testicular and systemic relapse died. Nine boys with normal testes had testicular biopsy during CCR prior to discontinuation of chemotherapy. Results of all biopsies were benign, but one boy had a relapse. The diagnosis of occult testicular leukemia prior to discontinuation of chemotherapy allows selection of high-risk boys requiring prolonged, intensive, and possibly alternative therapy. The indication for testicular biopsy in boys with acute leukemia is documented, and appropriate clinical management of testicular leukemia is presented.     

Medulloblastoma: freedom from relapse longer than 8 years--a therapeutic cure?

Seventy-seven patients presenting with medulloblastoma between 1958 and 1986 were treated at Stanford University Medical Center and studied retrospectively. Multimodality therapy utilized surgical extirpation followed by megavoltage irradiation. In 15 cases chemotherapy was used as adjunctive treatment. The 10- and 15-year actuarial survival rates were both 41% with an 18-year maximum follow-up period (median 4.75 years). There were no treatment failures after 8 years of tumor-free survival. Gross total removal of tumor was achieved in 22 patients (32%); the surgical mortality rate was 3.9%. No significant difference was noted in the incidence of metastatic disease between shunted and nonshunted patients. The classical form of medulloblastoma was present in 67% of cases while the desmoplastic subtype was found in 16%. Survival rates were best for patients presenting after 1970, for those with desmoplastic tumors, and for patients receiving high-dose irradiation (greater than or equal to 5000 cGy) to the posterior fossa. Although early data on freedom from relapse suggested a possible beneficial effect from chemotherapy, long-term follow-up results showed no advantage from this modality of treatment. The patterns of relapse and survival were examined; 64% of relapses occurred within the central nervous system, and Collins' rule was applicable in 83% of cases beyond the period of risk. Although patients treated for recurrent disease could be palliated, none were long-term survivors. The study data indicate that freedom from relapse beyond 8 years from diagnosis can be considered as a cure in this disease. Long-term follow-up monitoring is essential to determine efficacy of treatment and to assess survival patterns accurately.     

Isolated testicular leukemic relapse. Response to radiation therapy

Between January, 1975, and December, 1984, at the University of Michigan Medical Center, 17 boys with leukemia presented with overt or occult isolated testicular relapse. Diagnosis was obtained by bilateral open-wedge biopsies of the testes. All the patients were treated with combined local testicular irradiation and systemic chemotherapy. In only 1 of the 17 patients (6%) testicular leukemia developed as the only site of relapse. It appears that doses in the range of 2,000 to 2,400 cGy in 10 to 12 fractions achieve optimum control of leukemic infiltration of the testes.     

Avascular necrosis in children with acute lymphoblastic leukemia

This study describes the prevalence and demographics of avascular necrosis (AVN) in children with acute lymphoblastic leukemia (ALL). With improving survival of ALL patients on modern chemotherapy regimens, an increasing number of children with AVN will be presenting to orthopaedists. From 1991 to 1996, 202 patients were treated for ALL at a major tertiary pediatric cancer referral center. Eight patients (4.0%) subsequently developed AVN at an average of 30.0 months after beginning chemotherapy. A total of 27 documented joints were involved, with an average of 3.4 joints affected per patient diagnosed with AVN. The subset of patients with high-risk ALL who underwent an aggressive chemotherapy protocol was particularly susceptible to developing AVN. Six of 58 high-risk ALL patients (10.3%) developed AVN at an average of 18.5 months. As ALL patients now frequently survive into adulthood, orthopaedists will be increasingly called on to manage AVN affecting multiple joints in children and young adults.     

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia during first complete remission

Patients with acute lymphoblastic leukemia who have poor prognostic features at diagnosis usually have a short disease-free survival in spite of successful remission induction. Those poor risk features are: age over 30 years, a white blood cell count over 25,000/microliter, certain translocations of chromosomes, and requirement for more than six weeks of induction chemotherapy to attain a complete remission. We have used high-dose radiochemotherapy to prepare 39 patients with acute lymphoblastic leukemia in first complete remission (1 infant and 38 adults; median age 23 years) for bone marrow transplantation from histocompatible sibling donors. Thirty-one of the 39 patients in this study had one (n = 23) or more (n = 8) poor risk features: age (n = 7); high white blood cell count (n = 19); translocations (n = 4), or resistance to initial induction therapy (n = 11). Currently, 26 patients are surviving for 4-72 months (median 18 months) following marrow grafting and are in complete remission. One of the surviving patients had two marrow transplant procedures because of recurrent leukemia. Actuarial survival in complete remission is 63% for the entire group of 39 patients and is 60% if the eight patients who had no poor risk features are excluded from analysis. The following causes for failure were observed: leukemic relapse was encountered in four patients between 3 and 17 months after BMT for an actuarial relapse rate of 16%; bacterial sepsis was the cause of death in two patients; graft-versus-host disease and/or interstitial pneumonia led to the demise of seven patients, and one patient died with leukoencephalopathy. It appears that high-dose radiochemotherapy followed by bone marrow transplantation from a histocompatible sibling donor during first complete remission can result in a high disease-free survival rate for younger adults with poor-risk acute lymphoblastic leukemia. This concept needs to be tested in prospective trials comparing bone marrow transplantation with chemotherapy.     

Clinical study of six cases showing late relapse of germ cell tumors

Late relapse of germ cell tumors has been considered rare. We report six patients treated at our institution with relapses of germ cell tumors more than 2 years after first successful management. Median time to late relapse for pure seminomas and non-seminomatous germ cell tumors was 30.0 and 75.5 months, respectively. The sites of the late relapses in two cases of pure seminoma were located out of the fields of irradiation. After systematic chemotherapy, both these patients remain disease free. Two patients with non-seminomatous germ cell tumors received salvage chemotherapy at the time of late relapse, but tumor markers did not normalize in either case. A complete resection of relapsed masses was performed in three cases of non-seminomatous germ cell tumors. All three patients are without evidence of disease. The incidence of late relapse in patients with pure seminomas and non-seminomas was 2.4% and 3.3%, respectively, which suggests the necessity for long-term follow up.     

Is surveillance for stage 1 germ cell tumours of the testis appropriate outside a specialist centre?

OBJECTIVE: To assess the results of treatment for stage 1 germ cell tumours of the testis, outside a specialist centre. PATIENTS AND METHODS: From May 1984 until March 1996, 123 patients with stage 1 disease were treated at our institution. Sixty patients with seminoma and 31 with teratoma were treated with orchidectomy only and surveillance; 32 patients with stage 1 seminoma elected for orchidectomy and adjuvant radiotherapy. The mean ages were 40, 31 and 35 years, and the median follow-up 52, 47 and 49 months, respectively. RESULTS: There were no disease- or treatment-related deaths. However, 18 (30%) patients with seminoma treated by orchidectomy only relapsed (median time 8 months, range 3-19); 14 of these responded to radiotherapy, three to radiotherapy and chemotherapy for second relapses outside the irradiated fields, and one to chemotherapy initially, for large-volume relapse. Fifteen (48%) patients with teratoma relapsed (median time 3 months, range 1-12); all responded to 4-6 courses of bleomycin/etoposide/cisplatin chemotherapy. One patient had a second relapse and is currently disease-free 3 years after surgical excision of a lung metastasis. CONCLUSION: These results show that stage 1 testis tumours can be managed successfully in a district general hospital. However, we are concerned about the high relapse rates and are now attempting to identify patients at greater risk of recurrence, to consider adjuvant therapy in this group.     

Long-term outcome in patients harboring intracranial ependymoma

OBJECT: The prognostic significance of tumor grade and resection and the efficacy of prophylactic radiation remain controversial in the management of intracranial ependymoma. The outcomes in patients with intracranial ependymoma treated at the Kyoto University Hospital were reviewed retrospectively, and prognostic significance was analyzed. METHODS: Between 1972 and 2002, 29 patients were seen at the authors' institution. Eighteen cases involved a Grade II lesion according to the World Health Organization classification of ependymoma and 11 involved a Grade III lesion. Postoperative radiation was applied in 24 cases and chemotherapy was administered in nine. Overall survival and progression-free survival rates were significantly higher in patients with Grade II ependymoma (p = 0.006 and 0.004, respectively) and in patients who had undergone gross-total resection of the tumor (p = 0.002 and 0.04, respectively). Fourteen patients relapsed from 10 to 120 months (median 39 months) after diagnosis. In nine patients the ependymoma recurred only at the original tumor site. Three patients experienced both local and distant relapse, whereas two others had only a distant relapse. All relapses of the Grade II ependymoma initially occurred at the primary tumor site. Histological grade and extent of resection were significantly associated with tumor dissemination (p = 0.0034 and 0.0011, respectively). The field of postoperative radiation had no impact on patient survival or lesion recurrence. CONCLUSIONS: Tumor grade and resection are the two important prognostic factors with respect to patient survival, tumor recurrence, and tumor dissemination. Considering that relapses were predominantly local and that there was no apparent benefit from prophylactic radiation, the authors concluded that postoperative radiation should be focused on local control, especially for Grade II ependymomas.     

Survival Benefit of Hyperthermic Intraperitoneal Chemotherapy for Recurrent Ovarian Cancer: A Multi-institutional Case Control Study

Background

Hyperthermic intraperitoneal chemotherapy (HIPEC) and complete surgical removal of the tumor, in relapsing patients may provide a clinical benefit. There is no consensus considering the place of HIPEC for patients who had first ovarian cancer relapse. To assess for possible efficacy of HIPEC on overall survival (OS) rates in this situation, we performed a multi-institutional study.

Methods

The current study was a retrospective case control multi-institutional study comparing a group of patients treated with HIPEC to a group of patients treated without HIPEC. Inclusion criteria were first relapse of a serous ovarian carcinoma and >6 months after the end of initial treatment. Exclusion criteria were another pathological subtype of ovarian cancer, a relapse at <6 months after initial treatment, and a second relapse or more. We aimed to assess OS, morbidity, and mortality rates and prognostic factors.

Results

From June 1997–July 2011, 42 patients were included, 23 in the HIPEC group and 19 in the control group. Each patient from the two groups had a complete secondary surgery at the time of the first relapse. At 4 years OS was 75.6 % in the HIPEC group and 19.4 % in the control group (p = 0.013). In a multivariate analysis, HIPEC and interval-free before the end of initial treatment were both independent prognostic factors.

Conclusion

When compared to the control group, complete secondary surgery and HIPEC appear to afford a better OS rate than complete secondary surgery alone, in case of first ovarian cancer relapse. Further randomized trials are warranted to confirm these results.     

Acute lymphocytic leukemia recurring in the spinal epidural space

A 27-year-old man presented with a very rare spinal epidural mass associated with recurrence of acute lymphocytic leukemia (ALL) manifesting as acute progressive neurological deficits. The patient presented with shoulder pain and ambulatory difficulties 3 years after remission of ALL treated by bone marrow transplantation. Magnetic resonance imaging revealed an epidural mass extending from C-7 to T-3, which compressed the cord and extended to the intervertebral foramen along the roots. After decompression surgery, the symptoms dramatically improved. Histological examination showed clusters of immature lymphocytes consistent with recurrence of leukemia, so chemotherapy and radiation therapy were carried out. At 1 year after the operation, no local mass expansion or systemic progression of leukemia had occurred. Leukemic mass must be considered in the differential diagnosis of spinal epidural mass, even in patients with ALL.     

Management of testicular cancer--16 years' experience from southwest Finland

OBJECTIVE: This study investigated the outcome of testicular cancer treatment in Finland. MATERIAL AND METHODS: Data on 88 testicular cancer patients treated in Turku University Central Hospital between 1976 and 1992 were studied to analyse outcome and survival. RESULTS: The histological diagnosis was seminoma for 39 patients and non-seminoma for 49 patients. Two seminoma patients relapsed (5%) and one patient died of progressive disease (3%; initially stage II seminoma). Eleven non-seminoma patients relapsed (22%), nine of whom were cured with chemotherapy. Four non-seminoma patients died of progressive disease (8%; initially one stage I non-seminoma and three stage III non-seminomas). The median time to relapse after the completion of treatment was 9 months (range 3-50 months). Non-seminoma patients had significantly more relapses than seminoma patients (p = 0.03). Most relapses (73% of the non-seminoma relapses) were found among the stage I non-seminoma patients who had not received adjuvant chemotherapy, while none of the stage I seminoma patients relapsed (p = 0.007). CONCLUSIONS: Close surveillance is important for all non-seminoma patients to guarantee the early detection and treatment of recurrent disease. Treatment and surveillance should be covered by national guidelines and be conducted in centres with special interest in this rare but mostly curable cancer.     

Late relapse of metastatic testicular nonseminomatous germ cell cancer: surgery is needed for cure

OBJECTIVE: To identify patients with late relapse of metastatic, nonseminomatous germ cell tumour (NSGCT) and to evaluate the patterns of relapse, treatment and outcome, as such relapse at >2 years after complete remission to treatment for metastatic disease (late relapse) is uncommon, but with prolonged follow-up is becoming increasingly recognized. PATIENTS AND METHODS: Between 1980 and 2004, 1405 patients with testicular GCTs were identified who presented to Southampton University Hospital; 742 had NSGCTs or combined testicular GCTs, of whom 405 received primary chemotherapy for metastatic disease. In all, 329 (81%) patients achieved a complete response (CR) to initial treatment, with 101 of them (31%) requiring surgical resection of residual masses after chemotherapy. Any patient relapsing at >2 years after a CR to initial treatment (late relapse) was assessed in detail. RESULTS: In all, 20 patients had a late relapse, 17 of whom received initial treatment locally and three of whom were initially treated elsewhere. Most (65%) late relapses were asymptomatic and detected by routine cross-sectional imaging or rising levels of tumour markers. Late relapse occurred at a median (range) of 108 (26-217) months (approximately 9 years) after CR. Fifteen (75%) patients underwent only surgery for late relapse, including five who had invasive malignant germ cell cancer within the resected specimens. Fourteen of 15 surgically treated patients remained alive at a median of 44 (9-184) months from initial treatment for late relapse; one had died with progressive recurrent germ cell/epithelial malignancy. Five (25%) patients were initially treated with chemotherapy for late relapse; three of them died from progressive germ cell cancer and the two survivors both had surgical excision of residual abnormalities after salvage chemotherapy. Overall, 15 of 20 (75%) men remain alive with no evidence of disease; one further patient is currently undergoing salvage treatment for his third relapse. CONCLUSION: Late relapse is uncommon after modern therapy for metastatic GCTs. Surgical treatment for localized disease, where possible, is associated with prolonged disease-free and overall survival. By contrast, chemotherapy is associated with a low response rate and a poor outcome.     

A clinical study of prostatic carcinoma

Seventy seven patients with prostatic carcinoma were treated in our clinic between 1977 and 1986. Most of them were treated by a hormonal agent as the first therapy. None of the 9 stage A1 cases showed any reactivation, but 4 of the 5 stage A2 cases relapsed to metastatic disease. The chemotherapy performed in 3 of the 4 reactivated cases had no obvious effect on the disease. Seven of the 8 patients with stage B disease were alive without relapse. Relapse was seen in the other patient who had poorly differentiated carcinoma and chemotherapy in this case resulted in stable disease for the present. Four of the 15 stage C cases including 3 poorly differentiated carcinomas were hormone resistant or reactivated. For these resistant cases radiotherapy and/or the chemotherapy were performed, but a response was seen in only one case. Consequently, the first therapy for stage A2, B and C of poorly differentiated carcinoma must be improved. Of the 40 stage D cases, 4 patients who were treated by an early combination of hormonal therapy and chemotherapy had a better prognosis than the others. These 4 patients had poorly differentiated carcinomas with multiple bone metastases. Two of these 4 patients were alive without relapse for 17 and 72 months, and one of the 2 patients with relapse was also alive for 75 months. We believe that early chemotherapy is the key for better prognosis in stage D cases.     

Study of consolidation chemotherapy in advanced epithelial ovarian carcinoma

Objective:A prospective randomized study was designed to evaluate the role of consolidation chemotherapy in advanced epithelial ovarian carcinoma.Methods:50 patients with advanced epithelial ovarian carcinoma treated in our hospital during the period from March 2000 to October 2005 were enrolled in this study.All patients had achieved clinical complete remission by means of standard treatments,and were randomly divided into consolidation chemotherapy group and control group.Relapse rate,and disease-free survival(DFS)time were analyzed in both groups.Results:24 patients were assigned in consolidation chemotherapy group,and 26 patients in control group.Tumor relapse interval in consolidation group was(26.5±7.4)months,vs.(16.8±7.0)months in control group respectively,P=0.001.Time to relapse(TTR)in consolidation group was(19.2±6.8)months,vs.(10.0±6.9)months in control group,P=0.002.Analysis of DFS time and overall survival time,Log Rank test:P=0.042 and P=0.062,respectively.Conclusions:Consolidation chemotherapy could be the relevant factor that postpones tumor relapse interval and prolongs DFS time in advanced epithelial ovarian carcinoma patients who had achived chlinical complete remission.But so far the statistic result of our clinical study is beyond the conclusion that consolidation chemotherapy can decrease relapse rate or increase survival rate.Multicenter randomized clinical trial should be performed to confirm the role of consolidation chemotherapy in advanced epithelial ovarian carcinoma.     

Results of treatment for metastatic osteosarcoma with neoadjuvant chemotherapy and surgery

The purpose of the current study was to define the survival outcome variables for the 85 patients with Stage IIB osteosarcoma treated with neoadjuvant chemotherapy at the authors' institution from 1982 to 1997. A minimum 4-year followup or death was a requisite for inclusion. Forty-three patients were relapse-free survivors and 14 had no evidence of disease at followup for an overall survival of 67%. Twenty-nine patients had thoracotomy and nine have no evidence of disease with a minimum 4-year followup from last thoracotomy. The mean time to metastasis after diagnosis for patients presenting with Stage IIB disease was 12.8 months. There was no difference in the survival for any of the three chemotherapy protocols, used during the 15 years included in this analysis. There was a significant relation between length of time to relapse and survival. For each additional year without relapse, there is an 18% increase in chance of survival. In patients who were treated with thoracotomy, the number of metastatic nodules was a significant predictor of survival; specifically, each nodule increased the risk of death by 43%. A favorable outcome in this cohort of patients is related to the length of time between initiation of therapy and diagnosis of metastasis, and the number of metastatic foci.     

Testicular biopsy and occult tumor in acute lymphocytic leukemia

Testicular biopsy has become a routine procedure before discontinuing chemotherapy in male children being treated for acute lymphocytic leukemia (ALL). Before a decision can be made to discontinue multiple drug therapy, all possible sites of occult tumor such as the testis, cerebrospinal fluid, and bone marrow must be sampled. Between December, 1978, and November, 1981, 25 male children underwent testicular biopsies after two or more years of combination chemotherapy at the Babies Hospital, Columbia-Presbyterian Medical Center. Only 3 of the 25 patients (12%) were found to have leukemic infiltrates on histologic sections. Two of 3 patients, however, were noted preoperatively to have either irregular testicular contours or testicular enlargement and induration. Occult testicular infiltration discovered after two or more years of chemotherapy is rare. Most children with a histologically positive biopsy result were at least suspected preoperatively to have testicular involvement.     

Patients with osteosarcoma with a single pulmonary nodule on computed tomography: a single-institution experience

Background/PurposeThe purpose of this study is to determine if patients with osteosarcoma (OS) with metachronous metastatic pulmonary disease presenting with a single pulmonary nodule (SPN) on computed tomography (CT) were found to have other lesions at the time of thoracotomy.MethodsData were collected retrospectively on consecutive patients with OS treated at our institution from 1982 to 2007. Patients with no evidence of disease at the end of initial therapy who subsequently relapsed in the lung were identified.ResultsIn our study, 16 (8%) of 198 patients with OS with metachronous metastatic pulmonary disease presented with a SPN on CT scan. In all patients, only 1 metastatic nodule for OS was found at the time of thoracotomy. The median time between diagnosis and first lung relapse was 23.8 months (range, 4-80 months). Eleven patients (68.7%) subsequently had a second lung relapse, but only 3 patients had involvement of the ipsilateral lung (mean time interval between first and second pulmonary relapses of 17 months; range, 2-44 months). Five-year overall survival from diagnosis was 56.2%. Seven patients (43.8%) died of disease progression.ConclusionsIn our experience, patients with OS with metachronous metastatic pulmonary disease presenting with a SPN on CT were not found to have additional malignant lesions at the time of thoracotomy. Consideration should be given in this group of selected patients to use a minimally invasive approach to nodule removal with image-guided localization, if needed, rather than open thoracotomy because ipsilateral metastases are not likely to be found.