The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study.

BACKGROUND: This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel. METHODS: Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m(-2) docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated. RESULTS: In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of > or =6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of >or =3 mg kg(-1). Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had > or =5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from > or =5 to <5 CTCs and 9 out of 10 (90%) had a > or =30% decline in CTCs after therapy. CONCLUSIONS: Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.

Development of the human Achilles tendon enthesis organ.

The attachment of the Achilles tendon is part of an 'enthesis organ' that reduces stress concentration at the hard-soft tissue interface. The organ also includes opposing sesamoid and periosteal fibrocartilages, a bursa and Kager's fat pad. In addition, the deep crural and plantar fasciae contribute to Achilles stress dissipation and could also be regarded as components. Here we describe the sequence in which these various tissues differentiate. Serial sections of feet from spontaneously aborted foetuses (crown rump lengths 22-322 mm) were examined. All slides formed part of an existing collection of histologically sectioned embryological material, obtained under Spanish law and housed in the Universidad Complutense, Madrid. From the earliest stages, it was evident that the Achilles tendon and plantar fascia had a mutual attachment to the calcaneal perichondrium. The first components of the enthesis organ to appear (in the 45-mm foetus) were the retrocalcaneal bursa and the crural fascia. The former developed by cavitation within the mesenchyme that later gave rise to Kager's fat pad. The tip of the putative fat pad protruded into the developing bursa in the 110-mm foetus and fully differentiated adipocytes were apparent in the 17-mm foetus. All three fibrocartilages were first recognisable in the 332-mm foetus--at which time adipogenesis had commenced in the heel fat pad. The sequence in which the various elements became apparent suggests that bursal formation and the appearance of the crural fascia may be necessary to facilitate the foot movements that subsequently lead to fibrocartilage differentiation. The later commencement of adipogenesis in the heel than in Kager's pad probably reflects the non-weight environment in utero. The direct continuity between plantar fascia and Achilles tendon that is characteristic of the adult reflects the initial attachment of both structures to the calcaneal perichondrium rather than to the skeletal anlagen itself.

Follow-up schedules after treatment for malignant melanoma.

BACKGROUND: Existing follow-up guidelines after treatment for melanoma are based largely on dated literature and historical precedent. This study aimed to calculate recurrence rates and establish prognostic factors for recurrence to help redesign a follow-up schedule. METHODS: Data were retrieved from the Sydney Melanoma Unit database for all patients with a single primary melanoma and American Joint Committee on Cancer (AJCC) stage I-II disease, who had received their first treatment between 1959 and 2002. Recurrence rates, timing and survival were recorded by substage, and predictive factors were analysed. RESULTS: Recurrence occurred in 18.9 per cent (895 of 4748) of patients overall, 5.2 per cent (95 of 1822) of those with stage IA disease, 18.4 per cent (264 of 1436) with IB, 28.7 per cent (215 of 750) with IIA, 40.6 per cent (213 of 524) with IIB and 44.3 per cent (86 of 194) with IIC disease. Overall, the median disease-free survival time was 2.6 years, but there were marked differences between AJCC subgroups. Primary tumour thickness, ulceration and tumour mitotic rate were important predictors of recurrence. CONCLUSION: A new follow-up schedule was proposed: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB-IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.

Cutaneous melanomas that defy conventional prognostic indicators.

Tumor thickness is usually an accurate prognostic indicator for the patient with melanoma. However, very thin primary melanomas occasionally recur locally or metastasize, whereas some patients with very thick primary melanomas survive far longer than expected. There is also a group of patients with primary melanomas of various thicknesses who relapse after a very long disease-free interval. The large database of the Sydney Melanoma Unit which now contains comprehensive long-term follow-up on more than 13,000 patients treated over a 45-year period, has provided a unique opportunity to study melanomas that defy conventional prognostic indicators. Recurrence developed in 2.8% of melanoma patients classified as stage I (pTNM staging system) and with very thin lesions (< 0.50 mm). These recurrences developed more frequently in women than men and histologically were found to be associated with ulceration, high mitotic activity, and invasion to Clark's level IV, but not with regression. Concurrent lymph node metastases (stage III) were present in 3.1% of patients with very thin lesions (< 0.50 mm). In this group, most patients were men, and every lesion displayed regression. Total survival exceeded 15 years in 15.7% of stage II and III patients with very thick lesions (> 5.5 mm). In 1.7% of patients with lesions of any thickness, the disease-free interval before relapse was > 15 years. Neither in patients with very thick lesions surviving for > 15 years, nor in those with a disease-free interval of > 15 years was it consistently possible to show the presence or absence of any of the histological features usually considered to be of prognostic significance.

Lymphoscintigraphy in high-risk melanoma of the trunk: predicting draining node groups, defining lymphatic channels and locating the sentinel node.

Lymphoscintigraphy was performed in 209 patients with high-risk melanoma of the trunk referred to the Sydney Melanoma Unit and considered for lymph node dissection. Lymphoscintigraphy accurately defined the draining lymph node groups and was 94% sensitive in detecting draining sites that contained metastases. When combined with the clinical finding of palpable lymph nodes, the sensitivity rose to 98%. Most patients showed lymph drainage to one or two node groups and only 22 patients showed drainage to 3 or more node groups. The major lymph channels could also be marked on the skin prior to incontinuity dissection. Most patients had multiple draining lymph channels and these often diverged significantly from each other in the path to the draining node group. The number and location of interval nodes could be determined and marked on the skin. These and the major lymph channels could thus be excised at the time of surgery. Unusual drainage patterns were sometimes seen; for example, three patients displayed a new lymph pathway with direct drainage from the back anteriorly to the para-aortic nodes. The location of the sentinel nodes in each draining lymph-node group could also be marked on the skin prior to surgery, enabling quick and accurate identification of this node, using the blue-dye technique if biopsy were to be performed. These findings lead us to recommend lymphoscintigraphy prior to wide local excision in patients with truncal melanoma who are candidates for surgery. Lymphoscintigraphy results will help plan surgery and lead to minimum surgical intervention, consistent with effective surgical management.

Lymphatic drainage to triangular intermuscular space lymph nodes in melanoma on the back.

METHODS: Lymphoscintigraphy with 99mTc-antimony sulphide colloid was performed on patients with cutaneous melanoma of the back to define draining node fields and sentinel nodes before surgery. RESULTS: One patient was found to have drainage from the back to sentinel lymph nodes in the triangular intermuscular spaces bilaterally, above and lateral to the scapula. Subsequently, drainage to this node field has been found in 26% of 42 consecutive patients who have had lymphoscintigraphy performed for melanoma on the back. CONCLUSION: When performing lymphoscintigraphy to locate draining node fields and sentinel nodes in patients with melanoma on the back, it is important to look for drainage to the triangular intermuscular space node field by obtaining posterior and lateral scans. Any sentinel lymph nodes found in this field should be marked prior to surgery in the same way as nodes in other node fields are delineated so that they may be removed at surgery.

Thin malignant melanomas and recurrence potential.

Of 846 patients with stage I malignant melanoma that was less than 0.76-mm thick who were followed up for two to 31 years, 61 (7.2%) developed a recurrence. For those patients who did not initially undergo an elective lymph node dissection, the majority of first recurrences were at regional lymph nodes. Attempts have been made to identify those patients at risk of relapsing. Axial lesions, particularly those on the scalp, had the highest recurrence rate, with 15% of all thin scalp lesions recurring compared with only 4% of all thin extremity lesions. Three histological features proved to be useful prognostic indicators when analyzed by single-factor analysis. Evidence of ulceration in the primary lesion increased the recurrence rate from 6.7% to 26.1%. While only 4.3% of lesions displaying low mitotic activity recurred, this rate rose to 23.8% for those lesions of a high mitotic grade. Only 5% of Clark's level II lesions recurred, compared with about 12% of lesions at either level III or IV. Evidence of regression in thin lesions had no deleterious effect on prognosis. This study defines a small subset of patients who may benefit from elective lymph node dissection.

Late relapse from cutaneous stage I malignant melanoma.

In 1,283 patients with cutaneous stage I malignant melanoma who had ten or more years of follow-up, the incidence of late recurrence (first evidence of metastases occurring ten or more years after melanoma diagnosis) was 2.7%. None of the factors of prognostic importance (anatomic site, tumor thickness, ulcerative state of primary lesion, or initial surgical treatment) proved useful in predicting those patients with late recurrence. There was no sex or age difference in either incidence of late recurrence or prognosis subsequent to recurrence. Prognosis subsequent to late recurrence depended on the site of the recurrence. Survival after distant metastases became evident was extremely short. However, in the majority (53%) of patients, late recurrence was local and survival subsequent to treatment of these metastases was often protracted, emphasizing the importance of long-term follow-up in all patients with cutaneous melanoma.

Interval nodes: the forgotten sentinel nodes in patients with melanoma.

BACKGROUND: Any sentinel lymph node that receives lymph drainage directly from a primary melanoma site, regardless of its location, may contain metastatic disease. This is true even if the sentinel node does not lie in a recognized node field. Interval (in-transit) nodes that lie along the course of a lymphatic vessel between a primary melanoma site and a recognized node field are sometimes seen during lymphatic mapping for sentinel node biopsy. If drainage to such interval nodes is ignored by the surgeon during sentinel node biopsy, metastatic melanoma will be missed in some patients. HYPOTHESIS: When lymph drains directly from a cutaneous melanoma site to an interval node, that sentinel node has the same chance of harboring micrometastatic disease as a sentinel node in a recognized node field. DESIGN: Preoperative lymphoscintigraphy with technetiumTc 99m antimony trisulfide colloid was performed to define lymphatic drainage patterns and, since 1992, to locate the sentinel lymph nodes for surgical biopsy or for permanent skin marking of their location with point tattoos. SETTING: Melanoma unit of a university teaching hospital. PATIENTS: A total of 2045 patients with cutaneous melanoma were studied in 13 years. RESULTS: Interval nodes were found in 148 patients (7.2%). The incidence of interval nodes varied with the site of the primary melanoma. Interval nodes were more common with melanomas on the trunk than with those on the lower limbs. Micrometastatic disease was found in 14% of interval nodes that underwent biopsy as sentinel nodes. This incidence is similar to that found in sentinel nodes located in recognized node fields, confirming the potential clinical importance of interval nodes. CONCLUSIONS: Interval nodes should be removed surgically along with any additional sentinel nodes in standard node fields if the sentinel node biopsy procedure is to be complete. In some patients, an interval node will be the only lymph node that contains metastatic disease.

Hereditary melanoma in Australia. Variable association with dysplastic nevi and absence of genetic linkage to chromosome 1p.

Hereditary cutaneous malignant melanoma in association with the presence of multiple precursor lesions termed the dysplastic nevus syndrome (DNS) has been reported to display autosomal dominant inheritance with high penetrance. The gene for this disease was recently assigned to the distal short arm of chromosome 1 on chromosomal band 1p36, 7.6 centimorgans distal to the locus for the pronatrodilatin (PND) gene. We assessed 119 family members of eight newly described Australian families, 30 of whom had cutaneous malignant melanoma. Only eight of these affected individuals also had dysplastic nevi (DN). An additional 15 family members had DN alone. Pedigrees fell into three groups: 1) hereditary melanoma alone with no associated DN, 2) hereditary melanoma with occasional DN-affected individuals, and 3) hereditary melanoma with DN. All families displayed an autosomal dominant pattern of inheritance. An analysis of the cosegregation of the cutaneous malignant melanoma/DN trait with eight polymorphic DNA markers on the short arm of chromosome 1, including the distally located DNA markers D1S47 and PND yielded a strongly negative probability of linkage. The putative gene for susceptibility to melanoma in these families was effectively excluded from this region of the short arm of chromosome 1. No evidence for linkage was found at any of the other chromosome 1 markers examined. These findings suggest that hereditary melanoma is heterogeneous in relation to the genetic basis and its association with the DNS.

The surgical treatment of primary melanoma.

Local control is paramount to the clinical management of melanoma. A general consensus has been reached regarding the surgical treatment of primary malignant melanoma. By means of well-designed, multi-institutional, prospective, and randomized trials, the margins of excising the primary melanoma have been reduced considerably since the initial guidelines set out by W. S. Handley in 1907. The margins of excision now recommended are designed to limit the risk of local recurrence with its potential effect on survival and achieve the optimal cosmetic outcome. These margins are modified according to particular anatomic site constraints.

Elective lymph node dissection in patients with primary melanoma of the trunk and limbs treated at the Sydney Melanoma unit from 1960 to 1991.

BACKGROUND: The value of elective lymph node dissection (ELND) in melanoma remains controversial. Published prospective and retrospective studies can be criticized, and results from two ongoing randomized trials are not yet available. A previous retrospective review from the Sydney Melanoma Unit (SMU) showed apparent survival benefit from ELND, especially in tumors of intermediate thickness. STUDY DESIGN: We undertook a retrospective analysis of all patients treated at the SMU since 1960 for melanoma of the trunk or limbs measuring 1.5 mm or more in thickness, without clinical lymph node metastases, whose definitive wide excision (WE) with or without ELND was performed at the SMU within 60 days of initial diagnosis. RESULTS: There were 1,278 patients who fulfilled these criteria. Of these, 845 (66 percent) were treated with ELND and the remaining 34 percent were treated with WE alone. The median follow-up period was 58 months. Patients with thicker tumors and younger age more commonly underwent ELND. Among patients with thinner tumors, males underwent ELND more commonly than females. A multivariate proportional hazard model of melanoma-specific survival stratified by tumor thickness was chosen to allow for the imbalances between the two groups. With or without allowance for covariates, no benefit from ELND was found in the whole group or any subset. In contrast to previous studies from the SMU, we deliberately excluded from the present study patients referred only after WE with or without ELND elsewhere, because these might have been a selectively biased poor prognostic group. CONCLUSIONS: This study does not indicate a benefit from ELND for melanomas of the trunk or limbs measuring over 1.5 mm in thickness.

Location of sentinel lymph nodes in patients with cutaneous melanoma: new insights into lymphatic anatomy.

BACKGROUND: Accurate staging of melanoma patients by sentinel node (SN) biopsy can be achieved only if all SNs draining a given melanoma site are identified and removed for detailed histologic examination. Lymphoscintigraphy with a radiolabeled colloid provides an objective and reliable method of locating SNs and demonstrates that confident prediction of their location is not possible on clinical grounds. STUDY DESIGN: Lymphatic drainage pathways demonstrated by preoperative lymphoscintigraphy for 1,759 patients with primary cutaneous melanomas were reviewed, and locations of SNs in these patients were documented. An SN was defined as any node receiving direct lymphatic drainage from a primary melanoma site. RESULTS: In many instances the cutaneous lymphatic drainage pathways were found to be at variance with longheld concepts of lymphatic anatomy. Several new pathways were identified, draining to SNs in unexpected sites. These included triangular intermuscular space SNs (from upper back and, rarely, upper limb primaries), paraaortic and retroperitoneal SNs (from upper and lower back primaries), and costal margin SNs with onward drainage to internal mammary nodes (from periumbilical primaries). Occasional drainage to node fields on the opposite side of the body was noted from head, neck, and trunk primaries, and drainage to interval nodes (by definition, SNs) outside recognized lymph node fields was also observed. CONCLUSIONS: Knowledge of the possibility of these unusual lymphatic drainage patterns and SN sites should help to ensure the accuracy and completeness of SN identification. Preoperative lymphoscintigraphy to definitively locate SNs is recommended for every patient undergoing an SN biopsy procedure.

Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma.

Lymphoscintigraphy (LS) has been performed for 8 years in patients of the Sydney Melanoma Unit, to define lymphatic drainage patterns. Over the past 2 years, LS has also been used to locate the sentinel lymph node prior to surgery. Our technique for LS and subsequent sentinel node biopsy has an accuracy of 97%. All sentinel nodes must be marked to ensure the successful application of the sentinel biopsy technique. We have found that the axilla and groin average just over one sentinel node per draining node group for lesions on the trunk and upper limb, but have noted that drainage to the groin differed when lower limb lesions were studied. Because of the anastomosis of lymph vessels in the upper thigh, multiple sentinel nodes are identified in the groin in some patients. We have found an average of three sentinel nodes in the groin when lymph drainage from lower limb lesions was studied with LS. This difference demands a modification of the LS technique, with early imaging of the groin nodes to identify all sentinel nodes in each patient. The depth of the sentinel nodes can also be measured and the location of all interval nodes marked on the skin. This ensures that all sentinel nodes and interval nodes can be removed at the time of surgery.

Prediction of potential metastatic sites in cutaneous head and neck melanoma using lymphoscintigraphy.

BACKGROUND: The technique of lymphoscintigraphy may allow a more selective approach to the management of clinically negative neck nodes among patients with cutaneous head and neck melanoma. PATIENTS AND METHODS: A group of 97 patients with cutaneous head and neck melanoma had preoperative lymphoscintigraphy using intradermal injections of technetium 99m antimony trisulfide colloid to identify sentinel nodes. Fifty-one patients were eligible for clinical analysis after initial definitive treatment by wide excision only (n = 11), wide excision and elective dissection of the neck (n = 19) or axilla (n = 1), or wide excision and a sentinel node biopsy procedure (n = 20). RESULTS: Sentinel nodes were identified in 95 of 97 lymphoscintigrams, and 85% of patients had multiple sentinel nodes. In 21 patients (22%), sentinel nodes were identified outside the parotid region and the 5 main neck levels, mostly in postauricular nodes (n = 13). Lymphoscintigrams were discordant with clinical predictions in 33 patients (34%). Lymph nodes were positive in 4 elective dissections and 4 sentinel node biopsies. Among 16 patients evaluable after wide excision and a negative sentinel node biopsy, 4 patients subsequently developed metastatic nodes; however, confident identification of all nodes marked as sentinel nodes on lymphoscintigraphy was not achieved at the original biopsy procedure in 3 of these patients. CONCLUSIONS: Lymphoscintigraphy and sentinel node biopsy are more difficult to perform in the head and neck than in other parts of the body. The reliability of sentinel node biopsy based on lymphoscintigraphy may be improved by identifying and marking all nodes that are considered to receive direct lymphatic drainage from the primary melanoma, and by use of a gamma probe intraoperatively.

Histogenesis of malignant melanoma with an adjacent component of the superficial spreading type.

There has been a world-wide exponential increase in the incidence of thin malignant melanoma. At the Sydney Melanoma Unit, the proportion of patients diagnosed as having superficial spreading melanoma has more than doubled from 33% prior to 1960 to 78% during 1980-83. A study was made of the non-invasive component of malignant melanoma with an adjacent non-invasive component of the superficial spreading type in an attempt to elucidate the pathogenetic mechanisms involved in these changing trends. In this study on 723 cases of melanoma with a superficial spreading component, there was evidence that 39% originated in a precursor lesion. In the remaining 61%, the adjacent superficial spreading component consisted of melanoma in situ, suggesting that these were melanomas from the beginning. The latter lesions were thinner and had a lower degree of mitotic activity than melanomas commencing in a precursor lesion. Despite the large increase in incidence of superficial spreading melanomas and the shift to thinner lesions over time, there appeared to be no difference in the proportion of lesions commencing de novo to those commencing in a precursor lesion. This suggests that the precursor lesion may be of genetic origin.

Prognostic histopathological factors in malignant melanoma.

An analysis of prognostic factors in 4000 patients with cutaneous malignant melanoma at the Sydney Melanoma Unit and the University of Alabama in Birmingham has demonstrated that the histological features of the primary melanoma become less predictive of survival the more advanced the disease becomes. Thus, whilst 4 features of primary lesions were independent predictors in localized disease (tumour thickness, ulceration, level of invasion and regression), only one of the stronger ones (ulceration) remained predictive in patients with regional lymph node metastases. Once distant spread was evident, there were no parameters of the primary lesion that predicted survival. Thus, in patients with advanced disease prognosis was dictated by the extent of metastatic involvement: the number of positive lymph nodes in stage II patients and the number and location of metastatic sites in stage III patients.

Lymphatic drainage from peri-umbilical skin to internal mammary nodes.

While performing lymphoscintigraphy to define draining lymph node groups and sentinel nodes in patients with melanoma, the authors have discovered a new lymphatic channel in two patients with tumors in the peri-umbilical area. This channel passes over the right costal margin to an interval node before passing toward the midline, where it passes through the chest wall to reach the internal mammary lymph node chain. Appreciating the possible presence of this channel in patients with periumbilical lesions has important implications for the surgical management and follow-up of these patients.

Afatinib use in non-small cell lung cancer previously sensitive to epidermal growth factor receptor inhibitors: the United Kingdom Named Patient Programme.

INTRODUCTION: Afatinib prolongs progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) who were previously sensitive to erlotinib or gefitinib. This study investigated experience of afatinib under a Named Patient Use (NPU) programme. PATIENTS AND METHODS: Retrospective data for 63 patients were collected, including demographics, dose, toxicity and clinical efficacy. RESULTS: Response rate and median PFS were 14.3% and 2.6months, respectively. Diarrhoea and rash were the most common toxicities; 46% of patients required a dose reduction and 41% had a dose delay. CONCLUSIONS: Efficacy and safety in the NPU programme are consistent with the LUX-Lung 1 trial.