BCG immunotherapy for recurrent malignant melanoma

Summary A study was made of immunologic parameters obtained from patients with stage IIIB malignant melanoma who were treated with BCG. Patients with the longest disease-free interval and survival times were those who had small initial skin test reactions and developed larger reactions during the course of BCG treatment. Of these patients, those with less than five involved nodes had the longest disease-free interval and survival times. Patients who had increases in skin test reactivity generally showed these increases by the first visit after initiation of BCG therapy.     

Adjuvant BCG immunotherapy for stage I and II malignant melanoma.

Initial adjuvant immunotherapy trials have demonstrated a greater disease-free interval in patients treated with bacille Calmette-Guérin (BCG) compared with historical controls. In this study 149 patients at high risk of recurrence after surgical treatment of local or regional malignant melanoma were given BCG for 2 years and were followed up for a median of 28 months from the start of immunotherapy. The 36 patients in the comparison group had a higher rate of recurrence than the patients treated with BCG, and the rate in the treatment group was close to that reported from a similar study at the University of California at Los Angeles. The relatively long disease-free interval for the high-risk comparison patients in this study suggests that the control groups at other centres may have included patients with unrecognized additional risk. The rates of survival in the Canadian treatment group were also comparable to those reported by other centres. However, reports of a favourable BCG-mediated pattern of recurrence could not be confirmed. Therefore, the routine use of adjuvant BCG immunotherapy is not recommended.     

Prognostic significance of TP53 mutations in oral squamous cell carcinoma with human papilloma virus infection

PURPOSE: The aim of this study was to analyze the prognostic impact of mutated TP53 in patients with oral squamous cell carcinoma (OSCC) whose tumors were infected with human papillomavirus (HPV). METHODS: Thirty-two HPV-positive OSCC patients were included. Most of them were clinically classified as stage III (n=29). All patients underwent postoperative radiotherapy (follow-up from 12 to 60 months, median 32). There were 21 relapses. DNA was isolated by phenol extraction from tumor tissue. HPV DNA (type 16, 18, 31, 33) was detected in genomic DNA of the tumors by the PCR-PAGE method. TP53 mutations (exons 4-8) were detected by the PCR-SSCP method. RESULTS: A statistically significant difference in the number of relapses in HPV-infected (13/21) versus HPV-infected and TP53-mutated (8/8) patients was observed. Patients with both TP53 mutation and HPV infection had a significantly shorter disease-free interval than patients with HPV infection only (median 6 versus 31 months, respectively). CONCLUSIONS: TP53 mutations are associated with a higher risk of relapse and contribute to an even worse prognosis of patients with OSCC when the tumors are HPV infected. The shorter disease-free interval in patients with TP53 mutations indicates that the response to postoperative radiotherapy may be influenced by TP53 status. The presence of both HPV infection and TP53 mutations may define a particular group of tumors with a more aggressive phenotype in advanced OSCC.     

Efficacy of adjuvant Immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials

The benefits of immunochemotherapy employing the biological response modifier polysaccharide K (PSK) for patients with curatively resected colorectal cancer was reassessed by means of a meta-analysis of data with center randomization from 1,094 patients enrolled in three clinical trials. In all three trials, patients were followed up for at least 5 years after surgery and enrollment of the last patient and outcomes for standard chemotherapy were compared with those for chemotherapy plus PSK. The endpoints were overall survival and disease-free survival; and intent-to-treat analysis was performed without patient exclusion. Data were analyzed using the weighted average of the individual log hazard ratios. The overall survival risk ratio for all eligible patients was 0.71 (95% confidence interval (CI) : 0.55–0.90; P=0.006), and the disease-free survival risk ratio was 0.72 (95% CI: 0.58–0.90; P=0.003). The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK can improve both survival and disease-free survival of patients with curatively resected colorectal cancer.     

大肠癌组织中TS和COX-2的表达及其与患者无病生存期的关系

目的:探讨大肠癌患者癌组织中环氧化酶-2(COX-2)、胸苷酸合成酶(TS)的表达及其与患者无病生存期的关系。方法:筛选我院收治的大肠癌根治术患者,选择无病生存期大于48个月者30例和无病生存期小于48个月者29例。采用免疫组化法检测大肠癌组织中COX-2和TS的表达,并分析其与患者无病生存期的关系。结果:49例结直肠癌患者中,TS的阳性表达率为91.84%,COX-2的阳性表达率为77.55%。不同无病生存期的大肠癌患者TS的表达水平比较无统计学差异(P=0.646)。COX-2在无病生存期48个月的患者癌组织中表达水平明显低于无病生存期48个月的患者,差异有统计学意义(P=0.033)。结论:COX-2与大肠癌患者的无病生存期显著相关,可能成为预测大肠癌预后的参考指标。     

Mesothelin Expression in Triple Negative Breast Carcinomas Correlates Significantly with Basal-Like Phenotype,Distant Metastases and Decreased Survival

Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients’ race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.     

Cytoreductive surgery with intraperitoneal chemotherapy in patients with colon cancer and peritoneal carcinomatosis]

The efficacy of cytoreductive approach for colon cancer with carcinomatosis was assessed. 34 patients (the main group) underwent colon resections, peritonectomy, omentectomy and intraperitoneal chemotherapy (mitomycin and 5-fluorouracil). 22 patients (control group) underwent palliative colon resections only. The spread of peritoneal dissemination was assessed in all patients, basing on Peritoneal Cancer Index (PCI). It was found, that the rate of postoperative morbidity is higher in the main group, but it was not accompanied by enhanced postoperative mortality. It was also detected, that cytoreductive approach permits to prolong the survival (17.0 +/- 3.5 months in main group vs. 7.5 +/- 2.1 months in controls). The main prognostic factor in these patients was the PCI. The most favorable prognosis is identified if PCI < 5 (few discrete implants are present); the survival in this group was 23.0 +/- 4.5 months and disease-free interval was 14.0 +/- 2.5 months. When PCI was higher then 5, the survival was 14.5 +/- 2.5 months and disease-free interval was 7.0 +/- 1.3 months.     

Vascular endothelial growth factor (VEGF) and other common tissue prognostic indicators in breast cancer: a case-control study

VEGF is a specific mitogen and survival factor for endothelial cells and a key promoter of angiogenesis in physiological and pathological conditions. Nevertheless, VEGF tissue evaluation in cancer patients as a prognostic factor compared to the conventional histological and biological parameters is still controversial. In this case-control study, tissue VEGF was retrospectively determined by immunohistochemistry and related to T, N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 in 129 breast cancer patients. Seventy-four of these patients had developed distant metastases postoperatively. The remaining 55 patients had remained disease-free >10 years after surgery. In 17 (13%) of the 129 patients (six with distant metastases and eleven disease-free) tissue and plasma VEGF were concomitantly evaluated. In univariate analysis no significant differences in VEGF and tumor size were found between metastatic and disease-free patients, whereas there were significant differences in N, ER, PgR, c-erbB-2, p53, MIB-1 and cyclin D1 (p ranging from 0.001 to 0.0001). In multivariate analysis VEGF showed less significance than N, ER, c-erbB-2, MIB-1 and cyclin D1 (p = 0.012, p = 0.007, p = 0.005, p = 0.005, p = 0.002 and p = 0.001, respectively). VEGF was a significant unfavorable prognostic indicator only in the N+ subset (p = 0.015), while ER (p = 0.05 and p = 0.021) and MIB-1 (p = 0.031 and p = 0.022) were significant in both the N+ and N- subgroups. In multivariate analysis in the 74 metastatic cases VEGF did not show any significance in relation to disease-free interval and overall survival from the time of mastectomy and from the time of relapse, whereas N and PgR did (p ranging from 0.018 to 0.001). In conclusion, tissue VEGF does not seem a suitable candidate to replace conventional histological and other common biological prognostic factors in breast cancer.     

Internal auditory canal metastasis mimicking a vestibular schwannoma at presentation – a case report and review of the literature

Metastasis to the internal auditory canal from breast carcinoma is extremely rare and difficult to diagnose. It radiologically mimics vestibular schwannoma and can occur as a first manifestation of systemic relapse after a long disease-free interval in patients previously treated for early breast cancer. The diagnosis is usually made retrospectively and the optimal management of such metastasis following complete resection remains undefined.     

Repeat hepatectomy justified in patients with early recurrence of colorectal cancer liver metastases: A systematic review and meta-analysis

BackgroundThe benefit of repeat hepatectomy in patients with early recurrence of colorectal cancer liver metastases (CRLM) is questioned, in particular in those suffering from recurrence within three to six months following initial hepatectomy. The aim of this review was therefore to assess whether disease-free interval was associated with overall survival in patients undergoing repeat hepatectomy for recurrent CRLM.MethodsA systematic review and meta-analysis was conducted, according to PRISMA guidelines. PubMed, Embase and Cochrane Library databases were searched from database inception to 6th June 2020. Observational studies describing results of repeat hepatectomy for recurrent CRLM, including (disease-free) interval between hepatic resections and overall survival were included. Patients undergoing repeat hepatectomy within three months or additional resection of extrahepatic disease were excluded from meta-analysis.ResultsThe initial search identified 2159 records, of which 28 were included for qualitative synthesis. A meta-analysis of 15 cohort studies was performed, comprising 1039 eligible patients. Median overall survival of 54.0 months [95 %-CI: 38.6–69.4] was observed after repeat hepatectomy in patients suffering from recurrent CRLM between three to six months compared to 53.0 months [95 %-CI: 44.3–61.6] for patients with recurrent CRLM between seven to twelve months (adjusted HR = 0.89, 95 %-CI: 0.66–1.18; p = 0.410), and 60.0 months [95 %-CI: 52.7–67.3] for patients with recurrent CRLM after twelve months (adjusted HR = 0.70, 95 %-CI: 0.53−0.92; p = 0.012).ConclusionsDisease-free interval is considered a prognostic factor for overall survival, but should not be used as selection criterion per se for repeat hepatectomy in patients suffering from recurrent CRLM.     

Clinical characteristics of melanoma metastasis

Approximately one third of clinical Stage I melanoma patients will experience disease recurrence. The author reviews the main prognostic factors predicting the outcome of melanoma patients, the incidence, pattern and time of first metastases. Of all recurrences, two third will occur earlier by the lymphatic, and one third later by the hematogenous pathway. 75-80% of recurrences develop in the first 3 years, 3-4% of metastases occur after 10 years of disease-free interval. The data emphasize the value of lifelong follow-up.     

Dynamics of plant mosaic disease propagation and the usefulness of roguing as an alternative biological control

In this research article, an epidemiological model is formulated for mosaic disease considering plant and vector populations. Plant host population has been divided into three compartments namely healthy, latently infected and infected ones, and vector population is divided into two compartments: non-infective and infective vectors. The system possesses three equilibria: plant-only, disease-free and endemic equilibrium. Plant-only equilibrium is always unstable; disease-free equilibrium is stable when the basic reproduction number, R₀, is less than unity and unstable for when it crosses unity, and ensure existence of an endemic equilibrium which may be stable or can undergo a Hopf bifurcation. Finally, impulse periodic roguing with varied rate and time interval is adopted for cost effective and eco-friendly disease control and future direction of agriculture management. The dynamics of the impulsive system has also been analysed. Detailed numerical simulations are employed to support the analytical results. We found that roguing is most cost effective and useful management for mosaic disease eradication of plants if applied at proper rate and interval.     

Quantitative pathologic analysis of first and second primary cancers in double tumors of the lung

In spite of the frequent occurrence of double tumors of the lung, pathologic reports on these tumors are rare. In this study, 34 patients with double tumors (10 metachronous and 24 synchronous) were quantitatively analyzed; in all cases, both the first and second tumors had been completely resected and had adequate archival material. One aim of the study was to investigate whether there was a difference in the malignancy of the first and second tumors, as evaluated from their pathologic features. A second question was whether the length of the disease-free interval between the first and second tumors or the survival could be predicted on the basis of any of the investigated features. It was found that the first and second tumors, whether synchronous or metachronous, were strikingly similar: there was no difference in any of the quantitative pathologic features studied (epithelial percentage, DNA index, mean nuclear area and standard deviation of the nuclear area). It was not possible to predict by either univariate or multivariate analysis from any of the parameters either the length of the disease-free interval between the first and second tumors or the survival. These quantitative pathologic similarities suggest that the malignancy of the second tumor (synchronous as well as metachronous) is not higher than that of the first tumor. Thus, in the case of metachronous tumors, the fact that most of the second tumors (60%) are detected at a higher (inoperable) stage is probably caused by inadequate follow-up and not by increased malignancy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase II study of recombinant interferon alpha-C in patients with metastatic renal cell carcinoma

Recombinant interferon alpha-C is a new strain of the alpha interferon family. It was given to 33 patients with measurable metastatic renal cell carcinoma of whom 31 were evaluable. Protocol consisted of 3 million U/d for 2 weeks, then 3 million U/m2 every other day until progression. No complete response was observed. Three patients (9.7%) had partial response for a mean duration of 5.6 months and eight patients (25.8%) were stabilized for a mean of 4.3 months. Responsive sites were mainly lung, bone, and kidney, while side effects were generally mild. better results were observed in previously nephrectomized patients who had not received chemotherapy or hormonotherapy for recurrent or metastatic disease (p less than 0.05), and also in patients with a brief disease-free interval and short delay from presenting symptoms of the primary tumor until interferon treatment (p less than 0.05). Median survival was significantly longer in responders than in progressors (p less than 0.05). We suggest that the efficacy of recombinant interferon alpha-C in a low-dose regime versus other types of interferon as first-line therapy for inoperable, metastatic, or locally recurrent renal cell carcinoma should be investigated in a prospective, controlled, randomized study.     

Multimodality Treatment May Improve the Survival Rate of Patients with Metastatic Nasopharyngeal Carcinoma with Good Performance Status

The aim of the present study was to evaluate the benefit of chemotherapy, combined with palliative radiotherapy (PRT) and other local treatments to the metastatic sites, for patients with metastatic nasopharyngeal carcinoma (NPC) who had a performance status 0–2. We conducted a retrospective review of available data from 197 biopsy-proven NPC patients who developed metastasis after their initial definitive treatment. These patients were grouped into three categories according to the different treatment paths that were followed: the best supportive care (64 patients), chemotherapy alone (55 patients), and multimodality treatment with chemotherapy combined with PRT and other local treatments to metastatic sites (78 patients). The 2-year metastatic survival rate of patients in the multimodality treatment group was 57.7%, which was significantly better than that of the patients in both the chemotherapy alone group and the best supportive care group (32.7% and 1.6%, respectively). The independent significant factors affecting survival were the disease-free interval prior to the detection of metastatic disease, the number of metastases, the number of chemotherapy cycles and the biological effective dose of PRT. In conclusion, multimodality treatment may improve survival of select patients with recurrent NPC with distant metastases.     

The need for immune evaluation prior to thymosin-containing chemoimmunotherapy for melanoma

Summary In an attempt improve the response to BCG or BCG + DTIC therapy in Stage IIIB melanoma patients, we added thymosin treatment with repeated doses of 4 mg/m² or 40 mg/m². Twenty-eight patients were clinically and immunologically evaluable. Pretreatment immunological evaluation consisted of determination of delayed-type hypersensitivity to recall antigens, enumeration of E-rosettes in blood, and measurement of blood lymphocyte response to phytohemmagglutinin (PHA) and concanavalin A (Con-A). The disease-free interval was correlated with thymosin dose and parameters of immunocompetence. Immunocompetent melanoma patients treated with a high thymosin dose and BCG relapsed earlier than those treated with a low thymosin dose and BCG. Thus, 72% of the melanoma patients who had a PHA SI50 and were treated with 4 mg thymosin/m², were disease-free at 9 months, compared with only 31% of those treated with 40 mg/m² (P=0.02). When the dermatophytin delayed hypersensitivity response (>10 mm induration) was used as a parameter of immunocompetence, 86% of the patients treated with 4 mg/m², were disease-free at 9 months, as against 28% of patients treated with 40 mg thymosin/m² (P=0.07). None of the immunoincompetent patients on high thymosin dose relapsed (0/3). The results suggest that while a high thymosin dose (40 mg/m²) may be detrimental to immunocompetent patients, it may have a beneficial effect in immunoincompetent patients. A low thymosin dose is probably not detrimental to immunocompetent melanoma patients in this study. Monitoring of the immune status prior to and during the use of thymosin in cancer immunotherapy is mandatory.This paper was presented at the Thirteenth Annual Meeting of the American Society for Clinical Oncology, Denver, 1977     

Combined analysis of tumor growth pattern and expression of endogenous lectins as a prognostic tool in primary testicular cancer and its lung metastases

The aim of this study was to glyco- and immunohistochemically analyze expression of distinct growth/adhesion-related markers of primary testicular carcinomas and their lung metastases in relation to the risk of developing lung metastases and survival of patients, and to correlate immunohistochemical staining profile and syntactic structure analysis in order to delineate new prognostic parameters for this tumor type. Clinical features of 50 patients with primary testicular carcinomas and their corresponding lung metastases were evaluated and compared to those of a control cohort of 25 cases. The set of eight probes including labeled galectins-1 and -3, specific non-cross-reactive antibodies against galectins-1, -3, and -8 as well as anti-Ki-67, anti-bcl-2, and anti-p53 was applied to formalin-fixed, paraffin-embedded tumor sections of both primary and metastatic lesions. Syntactic structure analysis computed staining intensities and structural features of the tumor cells. These parameters were set into relation separately and in combination to clinical data including tumor stages, smoking habits, applied cytostatic therapy, disease-free interval, and survival. The risk of testis cancer patients to develop lung metastases depends in descending order on the tumor cell type (non-seminoma versus seminoma), tumor cell heterogeneity (mixed versus monomorphous cell type), age of patients, and pT stage. The extent of differential expression of galectin-related features between primary and secondary lesions was pronounced. Prognostic correlations for distinct galectin-related features were delineated in combination with data from syntactic structure analysis, for example cluster radius of galectin-3-positive tumor cells and post-surgical and total survival. Lengths of disease-free interval and total survival of patients were also correlated to characteristics obtained by syntactic structure analysis and their combination with galectin data in the first place, then to smoking habits, percentage of proliferating cells in the primary and secondary tumors, and finally to expression of certain galectins and of p53. Patients with non-seminoma testicular cancer should be thoroughly controlled for lung metastases. Regarding marker selection, our study underscores that further investigation of the growth-regulatory network of galectins is clearly warranted.     

Intrapatient diversity and its correlation with viral setpoint in human immunodeficiency virus type 1 CRF02_A/G-IbNG infection

The human immunodeficiency virus type 1 (HIV-1) viral setpoint during the disease-free interval has been strongly associated with future risk of disease progression. An awareness of the correlation between viral setpoint and HIV-1 genetic evolution over time is important in the understanding of viral dynamics and infection. We examined genetic diversity in HIV-1 CRF02_A/G-IbNG-infected seroincident women in Dakar, Senegal; determined whether a viral setpoint kinetic pattern existed for CRF02_A/G-IbNG during the disease-free interval; and correlated viral load level and diversity. Samples were drawn during the disease-free interval from consenting CRF02_A/G-IbNG-infected, antiretroviral therapy-na?ve female commercial sex workers in Dakar, Senegal. Based on sequential plasma RNA values, low and high viral setpoint groups were established. Intrapatient diversity and divergence over time was determined from earlier and later time point DNA samples from each person. Most individuals followed the viral setpoint paradigm. For each 1/-/log(10) copy/ml of plasma increase in viral load, intrapatient diversity increased by 1.4% (P = 0.028). A greater diversification rate was observed in the high viral setpoint group than in the low viral setpoint group (P = 0.01). Greater nucleotide (P = 0.015) and amino acid (P = 0.048) divergences and a greater nucleotide divergence rate (P = 0.03) were found in the high viral setpoint group. There was no difference between the groups in the ratio of the number of nonsynonymous substitutions per nonsynonymous site to the number of synonymous substitutions per synonymous site. The greater intrapatient diversity, divergence, and diversification rates observed in the high viral setpoint group supports the notion that diversity is driven by cycles of viral replication resulting in accumulated mutations. Recognizing diversity potential based on viral load levels in individuals may inform the design of vaccines and therapies.     

Adjuvant specific immunotherapy of resectable squamous cell lung carcinoma analysis at the eighth year

From June 1976 to June 1981, 86 patients with resectable (Stage I and II) squamous cell lung carcinoma were entered into a randomized controlled study with three arms: Control Group - no treatment postoperatively. Specific Immunotherapy Group - three monthly doses of 500 micrograms of tumor associated antigen (TAA) emulsified with complete Freund's adjuvant (CFA). Nonspecific Immunotherapy Group - three monthly doses of CFA emulsified in saline. All the patients in the study received skin tests with PPD (5TU) and 100 micrograms of the same TAA used for the immunotherapy at 1, 4, 6, 9, and 12 months postoperatively. Patients in both immunotherapy groups showed a tendency for a better disease-free interval and overall survival compared to those of the control, but these interval and beneficial therapeutic effects were statistically significant only in the Group III patients who had no hilar lymph node metastasis (T1N0 and T2N0). Although Group III was originally designated as a nonspecific immunotherapy group, retrospectively, it should be called a lowdose specific immunotherapy group because these patients actually received a total of 500 micrograms of TAA (as skin tests) and three doses of CFA at separate sites.     

Adjuvant immunotherapy with levamisole in resectable lung cancer

Summary Levamisole (1.1–3.8 mg/kg daily) or a placebo was given in a randomized, double-blind study to 211 patients undergoing curative surgery for primary lung cancer. The treatment, in a fixed dose of one tablet (containing 50 mg or a placebo) t.i.d., was given for 3 days before the operation, and such 3-day courses were repeated every 2 weeks thereafter for 2 years.A significant reduction of the cancer mortality was observed at 18 and 21 months post surgery in the levamisole group. There was also a nonsignificant increase of the disease-free interval.In patients who had received more than 2 mg/kg (or more than 80 mg/m²) daily, the crude recurrence rates had been halved and the death rates reduced to one-third. No beneficial effect could be observed in the patients who had been given a lower dose. In the former, adequately dosed patients, the beneficial effect was more marked if the tumor had been more advanced at the time of surgery. In addition, the incidence of hematogenous secondaries was significantly reduced in the same group of patients.Professor Swierenga died in late 1977, shortly before completion of the work