Evidence that treatment with vaccinia melanoma cell lysates (VMCL) may improve survival of patients with stage II melanoma

Summary A total of 80 patients with melanoma metastases in regional lymph nodes were treated by i.d. injections with a vaccine prepared from a vaccinia virus-infected allogeneic melanoma cell line; 39 patients have been followed for a 2-year period. Interim results from comparison of the treated group with 151 historical controls treated without the vaccine from September 1978 to December 1981 at the same institution and 56 non-randomized concurrent controls suggest that survival was significantly prolonged in the vaccinated group. At the 2-year period overall survival was 75% in the treated compared to 57% in the historical control group. Subset analysis showed a greater apparent benefit of vaccine therapy among patients who had metastases detected at the time of treatment of the primary melanoma (synchronous metastases), while therapy appeared less effective in patients with metastases detected at some time after treatment of the primary (delayed metastases). In the latter only those with one lymph node appeared to benefit from the treatment whereas in patients with synchronous metastases patients with three or more nodes as well as one node appeared to have improved survival. The survival rates at 2 years for treated patients with synchronous metastases in one, two, three or more lymph nodes was 100%, 83% and 79% respectively compared with that of 82%, 86% and 47% respectively in the equivalent control groups. Survival rates in treated patients with delayed metastases in one, two, three or more lymph nodes was 70%, 70% and 65% compared with 47%, 42% and 35% in the equivalent control groups. Treatment and control groups appeared well matched for a number of known prognostic features, including number and size of involved nodes, sex and thickness of primary tumor. Multivariate analysis indicated the effect of treatment was independent of these factors. Despite the empiricism of this approach the present results suggest that this form of therapy warrants further evaluation in a randomized controlled trial.     

Adjuvant therapy after radical surgery of cervical cancer: Zagreb experience

The results of the analysis of the treatment of 72 patients with carcinoma of the uterine cervix are presented. Seventy-two patients with Stage IB1 carcinoma of the cervix underwent a radical hysterectomy and pelvic lymphadenectomy. The low-risk group includes the patients without unfavourable prognostic factors that were treated by surgery alone. The high-risk group included women with pelvic node metastases, clinical tumour size greater than 3.0 cm, depth of stromal invasion greater than 1/3 of the cervical wall, Grade 3 tumours and the presence of lympho-vascular space involvement. High-risk patients received whole pelvic radiotherapy between two and four weeks following surgery. Thirty-four patients (47.2%) were in the low-risk group and thirty-eight patients (52.8%) were in the high-risk group. Locoregional recurrences were diagnosed in three cases (8.8%) in the surgery group and in four patients (10.5 %) assigned to postoperative radiotherapy. The incidence of distant metastases was 2.9% in the group treated by surgery alone and 5.3% in the group treated by surgery and radiotherapy. Overall survival at five years was 91.2% in the low-risk group and 89.5% in the high-risk group of patients. Five-year overall survival, locoregional and distant metastases were similar in the low-risk and high-risk groups of patients, which emphasizes the value of whole pelvic radiation in patients with one or more unfavourable prognostic factors after radical surgery in Stage IB1 cervical cancer     

Phase I pilot clinical trial of human IgM monoclonal antibody to ganglioside GM3 in patients with metastatic melanoma

Purpose: A human monoclonal antibody (L612 HuMAb) that binds to ganglioside GM3 has been developed in our laboratory. L612 HuMAb is a 100% human IgM protein. L612 HuMAb binds to cell surface of melanoma and can kill the cells in the presence of complement. The primary objective of this study was to test the toxicity and pharmacokinetics associated with administration of L612 HuMAb to melanoma patients whose tumor cells expressed GM3. Experimental design: Nine patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered in the study. Eight had failed previous treatments that included chemotherapy, radiation therapy, melanoma cell vaccine, and/or biological therapy. All patients received a 48-h continuous infusion of L612 HuMAb at a dose of 960 mg, 1,440 mg, or 1,920 mg. Five of these patients received a second infusion and one patient received a third infusion, all with the previous dose. Results: Toxicity was limited to transient and mild pruritus and skin rash. One patient complained of pain at the site of subcutaneous metastases. Serum antibody levels peaked 24 to 48 h after starting the infusion. Two patients, one receiving a single course of 960 mg (612 mg/m²) and the second receiving two courses of 1,440 mg (911 mg/m²) followed by surgical therapy, are without evidence of disease >5 years after antibody infusion. Conclusions: The human IgM monoclonal antibody, L612 HuMAb, was well tolerated. Infusion of L612 HuMAb appears to produce significant antitumor activity in melanoma patients.Dr. Ollila is currently affiliated with the University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.Supported by grant CA 30647 from the National Institutes of Health, National Cancer Institute.     

Late recurrence of localized cutaneous melanoma: its influence on follow-up policy

This paper reports 11 cases of recurrence 10 years or more after primary treatment of clinically local cutaneous melanoma at the Peter MacCallum Cancer Institute. Using the product-limit method for estimating recurrence-free survival, two late recurrence rates have been calculated. The estimated late recurrence rate among all treated patients is 5 percent (95 percent confidence interval: 2 to 8 percent), and the estimated late recurrence rate for the group who survived the first 10 years without recurrence is 7 percent (95 confidence interval: 3 to 11 percent). No prognostic factors were found that could identify a patient subgroup significantly at risk of late recurrence. Recurrence-free survival curves show that most recurrences have presented by the end of 6 years, but later recurrences are seen, the latest in this series being 18.2 years following treatment. While patients probably do not require long-term follow-up in specialist clinics provided they are adequately educated in the nature of their disease, this paper shows the value of long-term statistical surveillance.     

Prognostic Factors of Melanoma Patients with Satellite or In-Transit Metastasis at the Time of Stage III Diagnosis

Background

Prognosis of patients with loco-regional skin metastases has not been analyzed in detail and the presence or absence of concurrent lymph node metastasis represents the only established prognostic factor thus far. Most studies were limited to patients already presenting with skin lesions at the time of initial diagnosis. We aimed to analyze the impact of a broad penal of prognostic factors in patients with skin metastases at the time of first metastatic spread, including patients with synchronous lesions already present at the time of initial diagnosis, stage I/II patients with loco-regional recurrence and patients initially presenting with skin metastasis but unknown primary melanoma.

Patients and Methods

We investigated disease-specific survival of 380 patients treated at our department between 1996 and 2010 using Kaplan Meier survival probabilities and Cox-proportional hazard analysis.

Results

Five-year survival probability was 60.1% for patients with skin metastases only and 36.3% for those with synchronous nodal metastases. The number of involved nodes and a tumor thickness of at least 3 mm had independent negative impact on prognosis. A strong relationship was identified between the risk of death and the number of involved nodes. Neither ulceration nor the timing of the first occurrence of metastases as either in stage I/II patients, at the time of excision of the primary melanoma or initially in patients with unknown primary tumor, had additional effects on survival.

Conclusion

Lymph node involvement was confirmed as the most important prognostic factor for melanoma patients with loco-regional skin metastasis including those with unknown primary tumor and stage I/II patients with skin recurrence. Consideration of the tumor thickness and of the number of involved lymph nodes instead of the exclusive differentiation into presence vs. absence of nodal disease may allow a more accurate prediction of prognosis for patients with satellite or in-transit metastases.     

Ovarian cancer: PCD and brain metastases

Paraneoplastic cerebellar degeneration (PCD), the one of the most common paraneoplastic syndromes, refer to clinical disorders associated mostly with lung, ovarian and breast cancer, but not directly caused by the cancer or its metastases. Pathologic finding is an extensive loss of Purkinje cells in the cerebellum. Immunohistochemically, the auto-antibodies on the Purkinje cells had been detected. Clinically, PCD is characterized by sub-acutely evolving pancerebellar symptoms. Neurological dysfunction may appear before the detection of the underlying cancer. Therefore, the surgical exploration is necessary for the final diagnosis. The patient undergoes specific therapy. Soon, neurological status of the patient gets irreparable worse. Death come usually 2-3 years after the first symptoms of the PCD occurs. Case of a 63-years old woman with PCD as the first evidence of her cancer is reported. The patient developed brain metastases and died almost 3 years after the first symptoms of PCD occur     

Primary mucosal sinonasal melanoma—Case report and review of the literature. The role of complex treatment-surgery and adjuvant radiotherapy

Aim

The place of adjuvant radiotherapy in the treatment of sinonasal melanoma.

Background

Sinonasal mucosal melanoma is a rare disease with poor prognosis and requires a complex treatment. Elective neck dissection in patients with N0 and adjuvant radiotherapy has been a source of controversy. High late regional recurrence rates rise questions about elective irradiation of the neck nodes in patients with N0 stage disease.

Methods

We present our two years’ follow up in a case of locally advanced sinonasal melanoma and literature review of the treatment options for mucosal melanoma.

Results

In locally advanced sinonasal melanoma treated with surgical resection, postoperative radiotherapy and chemotherapy we had local tumor control. Two years later, a regional contralateral recurrence without distant metastasis occurred.

Conclusions

Literature data for frequent neck lymph nodes recurrences justify elective neck dissection. Postoperative elective neck radiotherapy for patients with locally advanced sinonasal melanoma and clinically N0 appears to decrease the rate of late regional recurrences.     

A Statistical Review of Malignant Testicular Tumours Based on the Experience of the Ontario Cancer Foundation Clinics, 1938-1961

For the 827 patients with malignant testicular tumours registered at the Ontario Cancer Foundation''s regional clinics in the period 1938-1961, the probability of surviving for five years after treatment was 59.8%; for the 731 patients who received all or part of their initial treatment at the clinics or were not treated anywhere, five-year survival probability was 62.7%. Most deaths from testicular cancer took place in the first two years after treatment, and 90% of recorded recurrences were diagnosed before the third anniversary. Survival rates were strongly influenced by histological type and extent of disease, and to some degree by age. Survival did not seem to be closely correlated with delay after first symptom, site or size of primary lesion, ectopia, surgical treatment of the abdominal nodes, site or dosage of radiation, or chemotherapy. The survival rates in this series of cases compare favourably with those of other large series.     

Long-term follow-up of patients treated with radical surgery for rectal cancer

In developed societies colorectal cancer (CRC) is the second most frequent malignant tumor which causes more than 5000 deaths yearly in Hungary. We have attempted to answer the question how to improve the above mentioned data by the long-term follow-up of patients operated upon for rectal cancer at our department. Of the patients operated on for rectal cancer at our department between March 1990 and April 2006, we have conducted regular follow-up of 297 patients according to a protocol developed by us. We have examined the length of time between the rectum operation and the diagnosis and the number of local recurrences, distant metastases, tumor progression in more than one organ as well as second tumors (independent of the rectal cancer). During this period we found 24 local recurrences, 32 distant metastases, 43 tumor progressions in more than one organ, and 21 second tumors. In two patients, in addition to distant metastases, we found a second CRC independent of the original rectal cancer, and in one patient with tumor progression in more than one organ we also detected breast cancer. In one patient we found 3 second tumors (CR, lung and urinary bladder) independent of the original rectal cancer. Altogether we found tumors in 117 out of 297 patients. During the same period, we performed 69/117 operations and 31/117 patients were alive at the end of our study with a median survival of 60.4 (3-184) months. In summary, we can state that this work is beneficial for curing the recurrence of rectal cancer, making the patients' life longer or making the quality of life better for the patients operated on for rectal cancer.     

Infiltration of primary and metastatic melanomas with macrophages of the 25F9-positive phenotype

Summary In order to gain insight into the role of macrophages in human melanoma, we studied fresh-frozen material from 15 dysplastic nevi, 199 primary melanomas, 107 melanoma metastases, and paraffin sections from 98 primary melanomas with the monoclonal antibody 25F9 which recognizes an 86×10³ dalton protein present on a subset of mature human macrophages. Considerable infiltration of tumors with 25F9-positive macrophages was observed in 2 dysplastic nevi (13%), 87 primary melanomas (44%), and 45 metastases (42%). The degree of intratumoral macrophage infiltration correlated with expression of class II HLA-DR antigens on tumor cells, in primary melanoma with a tumor thickness above 0.75 mm, and with the occurence of metastases within 2 years. In paraffin sections, intratumoral 25F9-positive macrophages also correlated with metastatic spread of primary tumors after longer follow-up. Metastases revealed a higher degree of macrophage infiltration following systemic or local immunotherapy, compared with untreated metastases, or metastases removed during chemotherapy. Of 38 patients who died within an observation period of 1 year, 19 (50%) had considerable infiltration of metastases with 25F9-positive macrophages, whereas this was found in only 4 of 12 patients (33%), who survived for longer than 2 years following metastases removal. A higher degree of 25F9-positive macrophages correlated with a shift towards the T8-positive subsets within the T cell compartment of the infiltrate. Our results suggest that accumulation of 25F9-positive macrophages in melanomas indicates more aggressive tumor properties.     

Surgical considerations in the management of malignant melanoma of the ear

Malignant melanomas of the external ear are rare and are difficult lesions to treat because of the cosmetic importance and the reconstructive difficulty of their location. The literature suggests that these lesions have a worse prognosis than melanomas occurring elsewhere and that radical resection is the "correct" treatment. To clarify this issue, we examined 21 consecutive patients (19 male, 2 female) with malignant melanoma of the ear seen at the Yale-New Haven Hospital over the last 10 years. Nineteen patients had a diagnosis of primary malignant melanoma of the ear, one had a local recurrence, and one had an in-transit melanoma from an unknown primary site. The mean thickness of the lesions was 2.7 mm. Two patients had palpable nodes, which in both cases turned out to be histologically positive for tumor. All patients underwent local excision and reconstruction using chondrocutaneous or fasciocutaneous flaps or skin grafts. There was one local recurrence (0.5 mm original thickness); there were two patients with regional recurrences, both of whom died within a year with disseminated disease. Forty-three percent have been followed for 5 or more years and all are alive and free of disease. This suggests that malignant melanoma of the ear may be safely treated by conservative excision and reconstruction.     

The Significance of Regional Lymph Node Metastases in Breast Carcinoma

The significance traditionally attached to regional lymph node metastases has been questioned following a retrospective review of 922 patients with early breast cancer.Conservative surgical removal of axillary lymph node metastases and conservative irradiation of internal mammary lymph node metastases did not prejudice the five- and 10-year survival rates of patients so treated.Axillary lymph node recurrences had an ominous prognosis and occurred more commonly in the conservatively treated patients, yet survival rates were the same as those following radical mastectomy. Many axillary lymph node recurrences occurred more than five years after primary therapy, or with or after other evidence of reactivation of the breast cancer.It is suggested that breast cancer patients do not do poorly because they have regional lymph node metastases, but rather they have these metastases when they do poorly.     

Prognostic value of serial determinations of circulating immune complex levels in malignant melanoma

Summary A total of 50 melanoma patients free of distant metastatic disease and 54 healthy controls were analyzed for circulating immune complexes (cIC) and complement split product (C3d), using solid-phase C1q-anti-IgG radio-immunoassay (RIA), C1q-protein A RIA, and anti-C3d anti-IgG RIA for cIC detection. No significant differences in cIC and C3d levels could be demonstrated between the controls and the 31 patients with primary malignant melanoma analyzed before surgery. To evaluate the prognostic value of serial measurements, samples from the 50 patients were taken at regular intervals for 4 to 27 months (median, 20 months). Surgery was the only treatment given. Significant changes in the cIC and C3d levels were defined by reference to the changes that occured in 23 of the 54 healthy controls observed for a period of 6 to 55 months (median, 23 months). During the period of serial sampling, recurrent disease developed in 8 of the patients. In only 3 of these 8 patients (versus 10 of 42 patients without recurrence) did significant changes occur, and the changes occurred either at the same time or after the clinical diagnosis of recurrence. During the entire clinical observation period of 6 years, a total of 11 patients developed recurrences. Significant changes were only observed in 4 of these 11 patients versus 8 of 37 patients without recurrence. In conclusion, changes in cIC and/or C3d levels were not found to be indicative of early or long-term recurrence of malignant melanoma.     

Cardiac metastasis of malignant melanoma: a case report

The heart is regularly involved in metastatic neoplasms with cardiac metastases being found in up to 20 % of autopsies. We present a case about a 42-year-old Caucasian female with a fatal metastatic melanoma to the heart. The five- year survival rate for stage IV melanoma (melanoma with metastases to other organs) is 15 to 20 %. If patients with malignant melanoma present with new onset of cardiac symptoms, clinicians should always be aware of the possibility of cardiac metastases and perform further investigations.     

PD‐L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti‐PD‐1/PD‐L1 clinical trials

This study evaluated the expression of PD‐L1 in immunotherapy‐naïve metastatic melanoma patients to determine longitudinal intrapatient concordance and correlate PD‐L1 status with clinicopathologic characteristics and outcome. PD‐L1 expression was assessed by immunohistochemistry in 58 patients (43 primary tumors, 96 metastases). Seventy‐two percent of patients had at least one specimen expressing PD‐L1 in ≥1% of tumor cells. Median positive tumor cell count overall was low (8% in nonzero specimens). PD‐L1 expression was frequently discordant between primary tumors and metastases and between intrapatient metastases, such that 23/46 longitudinal patient specimens were discordant. PD‐L1 was associated with higher TIL grade but not with other known prognostic features. There was a positive univariate association between PD‐L1 expression in locoregional metastases and melanoma‐specific survival, but the effect was not observed for primary melanoma. In locoregional lymph node metastasis, PD‐L1+/TIL+ patients had the best outcome, and PD‐L1+/TIL? patients had poor outcome.     

Clinicopathologic Predictors of Survival in Patients with Desmoplastic Melanoma

Background and Objectives

Desmoplastic melanoma is a unique subtype of melanoma which typically affects older patients who often have comorbidities that can adversely affect survival. We sought to identify melanoma-specific factors influencing survival in patients with desmoplastic melanoma.

Methods

Retrospective review from 1993 to 2011 identified 316 patients with primary desmoplastic melanoma. Clinicopathologic characteristics were correlated with nodal status and outcome.

Results

Fifty-five patients (17.4%) had nodal disease: 33 had a positive sentinel lymph node biopsy and 22 developed nodal recurrences (no sentinel lymph node biopsy or false-negative sentinel lymph node biopsy). Nodal disease occurred more often in younger patients and in cases with mixed compared with pure histology (26.7% vs. 14.6%); both of these variables significantly predicted nodal status on multivariable analysis (p<0.05). After a median follow-up of 5.3 years, recurrence developed in 87 patients (27.5%), and 111 deaths occurred. The cause of death was known in 79 cases, with 47 deaths (59.5%) being melanoma-related. On multivariable analysis, Breslow thickness, mitotic rate ≥1/mm² and nodal status significantly predicted melanoma-specific survival (p<0.05).

Conclusions

Nodal status predicts melanoma-specific survival in patients with desmoplastic melanoma. However, since patients with desmoplastic melanoma represent an older population, and a considerable proportion of deaths are not melanoma-related (40.5%), comorbidities should be carefully considered in making staging and treatment decisions in this population.     

Characteristics and outcomes of advanced melanoma patients with complete response and elective discontinuation of first-line anti-programmed death-1 monotherapy: A real-world multicentre observational cohort study

Anti-programmed death-1 (anti-PD1) treatment has significantly improved outcomes of advanced melanoma with a considerable percentage of patients achieving complete response (CR). This real-world study analyzed the feasibility of elective anti-PD1 discontinuation in advanced melanoma patients with CR and evaluated factors related to sustained response. Thirty-five patients with advanced cutaneous or primary unknown melanoma with CR to nivolumab or pembrolizumab from 11 centers were included. Mean age was 66.5 years, and 97.1% had ECOG PS 0–1. 28.6% had ≥3 metastatic sites with 58.8% having M1a-M1b disease; 8.6% had liver and 5.7% had brain metastases. At baseline, 80% had normal LDH, and 85.7% had a neutrophil-to-lymphocyte ratio ≤3. 74.3% of patients had CR confirmed in PET-CT. Median duration of anti-PD1 was 23.4 months (range 1.3–50.5). 24 months after therapy discontinuation, 91.9% of patients were progression-free. Estimated PFS and OS at 36, 48, and 60 months from the start of anti-PD1 were 94.2%, 89.9%, 84.3%, and 97.1%, 93.3%, 93.3%, respectively. Antibiotics use after anti-PD1 discontinuation increased the odds of progression (OR 16.53 [95% CI 1.7, 226.03]). The study confirms the feasibility of elective anti-PD1 discontinuation in advanced melanoma patients with CR and favorable prognostic factors at baseline.     

Pamidronate in the treatment of bone metastases from breast cancer

Bone metastases afflict over 70% of patients with advanced breast cancer, resulting in impaired quality of life and significant clinical problems. Until appearance of the bisphosphonates there was no specific therapeutic treatment available to manage the symptoms of osteolytic bone metastases. Bisphosphonates are stable chemical analogues of pyrophosphate, and inhibit osteoclast-mediated bone resorption, the treatment is effective in reducing skeletal morbidity in breast cancer with fewer skeletal related events, reduced pain and analgesic consumption, and improved quality of life. As a result, bisphosphonates should now be part of the routine management of metastatic bone disease and multiple myeloma. Promising data have resulted in considerable interest in the possible adjuvant use of bisphosphonates. Pamidronate is an easy to use potent inhibitor of osteolysis, given in conjunction with standard anticancer therapies effectively relieves bone pain and improves performance status. Monthly pamidronate infusions for one or two years in addition to standard anticancer therapy reduce by more than one third the yearly frequency of skeletal-related events. The authors report their practice in which 119 breast cancer patients metastatic to bone received 90-120 mg pamidronate infusion/cycle in addition to standard breast cancer therapy every 3-4 weeks.     

Failure to detect intra-abdominal metastases from breast cancer: a case for staging laparotomy

Two studies were performed to assess the accuracy of non-invasive methods in detecting intra-abdominal metastases from breast cancer. Firstly, the sites of spread detected at the time of first presentation with metastases were compared with the sites of spread shown at necropsy in the same patients. Although about two-thirds of the patients with bone and lung metastases at necropsy had had metastases detected at these sites when they first presented with metastases, only a third of the patients with liver metastases and none of those with other intra-abdominal metastases had had evidence of disease at first presentation with metastases. The second study confirmed a poor detection rate of liver and other intra-abdominal metastases in patients with breast cancer undergoing laparotomy and oophorectomy who were staged immediately before operation.Pre-mastectomy staging laparotomy should be considered in those patients with primary breast cancer who are most likely to have disseminated disease beyond the regional nodes. In the presence of occult gross metastases detected by staging laparotomy, mastectomy will not provide additional protection against loca recurrence of disease. Patients with occult gross metastases should also be excluded from studies on adjuvant chemotherapy (designed to treat micrometastases). Aggressive methods of staging are justified to protect the patient as far as possible against unnecessary mastectomy and to identify those patients who should be treated by therapeutic chemotherapy rather than adjuvant chemotherapy.