Optimising primary molecular profiling in non-small cell lung cancer.

INTRODUCTION: Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. METHODS: This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. RESULTS: Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. CONCLUSION: This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.

Role of CMR-derived atrial deformation analysis in the prediction of atrial fibrillation recurrence rate after pulmonary vein isolation.

PURPOSE: Left atrial (LA) dimensions have been identified as anatomical predictors for atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). The value of LA function compared to pure LA anatomical risk prediction for AF recurrence after PVI is not well investigated. Cardiovascular magnetic resonance (CMR) is able to simultaneously assess LA anatomical, tissue and functional markers within one examination. The hypothesis of this explorative study was that CMR-derived LA strain has incremental value for the prediction of AF recurrence after PVI. METHOD: Fifty-two patients with paroxysmal or persistent AF were retrospectively enrolled for CMR (1.5T) prior to PVI. Strain-analysis was derived from standard cine images in 4-, 3- and 2-chamber view. LA function was divided into LA reservoir strain and strain rate (εs and SRs), LA conduit (εe and SRe) and LA booster pump function (εa and SRa). The primary endpoint was recurrence of AF within one year after PVI. RESULTS: Twelve patients (23 %) presented with AF recurrence. There was no difference in age, LA size as well as LA sphericity index between the groups. Patients with AF recurrence (68.3 ± 5.5 years, 66 % male) showed significantly reduced LA booster pump function compared to the patients without AF recurrence (66.3 ± 10.5 years, 50 % male) (εa: p = 0.015; SRa: p = 0.036). In binomial logistic regression analyses, the only predictor for AF recurrence after PVI was εa (p = 0.033). CONCLUSIONS: In this descriptive study, impaired LA booster pump function predicted AF recurrence one year after PVI. Compared to further LA strain and anatomical parameters, LA booster pump might serve as additional predictor of AF recurrence.

Association of molecular status and metastatic organs at diagnosis in patients with stage IV non-squamous non-small cell lung cancer.

OBJECTIVES: Biological predisposition for specific metastatic organs might differ between molecular subgroups of lung cancer. We aimed to assess the association between molecular status and metastatic organs at diagnosis in a nationwide stage IV non-squamous non-small cell lung cancer ((ns)-NSCLC) cohort. METHODS: All ns-NSCLC from 2013 that were stage IV at diagnosis were identified from the Netherlands Cancer Registry, which records information on metastatic organs at diagnosis. Tumors were matched to the Dutch Pathology Registry (PALGA) from which data on molecular status established in routine practice was extracted. Four molecular subgroups (EGFR+, KRAS+, ALK+, triple-negative) were identified. For each metastatic organ, proportions of tumors metastasized to this organ were, per molecular subgroup, compared to triple-negative tumors by multivariable logistic regression analyses (adjusted odds ratios (OR) with 95% confidence intervals (CI)), taking clinicopathological variables into account. RESULTS: 160 EGFR+ (exon 19 del, exon 21 L858R), 784 KRAS+, 42 ALK+, and 1008 triple-negative tumors were identified. Most frequent metastatic organs were the bone (34%), pleura (24%), lung (23%), and brain (22%). Compared to triple-negatives, EGFR+ tumors had more often metastases to the bone (31.5 vs 53.8%; OR 2.55 (95% CI 1.80-3.62)) and pleura (24.1 vs 37.5%; OR 2.06 (1.42-2.98)), and less often to the brain (22.0 vs 12.5%; OR 0.53 (0.32-0.88)) and adrenal glands (19.1 vs 7.5%; OR 0.46 (0.28-0.75)). Compared to triple-negatives, KRAS+ and ALK+ tumors had at diagnosis metastasized more often to the lung (20.3 vs 26.7%; OR 1.40 (1.12-1.76)) and the liver (13.1 vs 23.8%; OR 2.07 (1.00-4.32)), respectively. CONCLUSION: NSCLC molecular status was associated with metastatic pattern at diagnosis. 54% of stage IV EGFR+ ns-NSCLC patients had bone metastases at diagnosis. These observational results are hypothesis generating, and call for a prospective study where EGFR+ patients are screened for bone metastases, and treated to prevent skeletal related events.

Epidemiologic data on vulvar cancer: comparison of hospital with population-based data.

Data on vulvar cancer are subject to a possible selection bias because older patients with vulvar cancer are sometimes not referred to specialized centers. The aim of this study was to compare the variables obtained from the population as a whole with variables obtained from referral and nonreferral hospitals. Population-based data on age, stage, histological type, and treatment modality were registered for 138 patients with vulvar cancer. The characteristics of the patients who were referred to a gynecologic oncology center were compared with those of the patients treated in nonreferral hospitals. The age-adjusted incidence was 2.3 per 100,000 women. Basal cell cancer was less common in the referral center than in the nonreferral centers (3% versus 28%). No difference was found in FIGO stage distribution in the different subgroups. Groin node dissection was omitted in 80% of the patients not referred to a center. Omission of groin node dissection was more common in patients older than 74 years (P = 0.002). Population-based data on vulvar cancer differ significantly from hospital-based data and give better insight into the real characteristics of patients with vulvar cancer.

Wound healing after radical vulvectomy and inguino-femoral lymphadenectomy: experience with granulocyte colony stimulating factor (filgrastim, r-metHuG-CSF).

After radical vulvectomy, infection and wound breakdown occurs in approximately 40-60% of patients resulting in significant morbidity and increased hospital stay. Wound breakdown is primarily due to infection of and tension on the wound. Post-operative defects in the immune system and neutrophil dysfunction may contribute to the high rate of this complication. To investigate this phenomenon in patients with a known high risk for postoperative infection, we studied the effect of filgrastim on primary or secondary wound healing (surgical wound breakdown)--per incisional side--in women requiring radical vulvectomy and inguino-femoral lymphadenectomy (RVIFL). The results were compared with a historical control group and indicate a reduction in the rate of surgical wound breakdown. Besides the clinical importance of decreasing the incidence of wound infection and tissue breakdown on patients quality of life, the benefits in terms of social-economic impact (days of hospitalization, post-operative nursing care health care budget) should also be taken into account.

Extracapsular growth of lymph node metastases in squamous cell carcinoma of the vulva. The impact on recurrence and survival.

BACKGROUND: Patients with squamous cell carcinoma of the vulva who present with multiple positive groin lymph nodes have poor survival. Growth of cancer through the capsule of the groin lymph nodes recently has been identified as an important prognostic factor for survival in that patient group. The objective of this study was to determine the influence of several clinicopathologic parameters on the pattern of recurrence and survival. METHODS: A review of 71 patients with squamous cell carcinoma of the vulva and positive lymph nodes was performed to assess the independent prognostic value of a number of variables for survival. Variables analyzed included tumor size, stage, number of positive lymph nodes, extracapsular growth of lymph node metastasis, the greatest dimension of tumor in the lymph nodes, the percentage of replacement of the lymph nodes by tumor, clinical lymph node status, and laterality of positive lymph nodes. RESULTS: Using the Mantel-Cox test, extracapsular growth of lymph node metastases (P = 0.00), two or more positive lymph nodes (P = 0.02), and greater than 50% replacement of lymph nodes by tumor (P = 0.03) were predictors of poor survival. No difference was found between the groups with two positive lymph nodes and those with three or more. Extracapsular growth of lymph node metastases was the most significant independent predictor for survival. Distant metastases occurred in 7 of 15 patients (48%) who had a combination of extranodal spread, lymph node replacement greater than 50%, and three or more positive lymph nodes. CONCLUSION: Extracapsular growth of lymph node metastases in the groin is the most important predictor for poor survival in patients with squamous cell carcinoma of the vulva. Because of the predominant distant failure pattern in a subgroup of patients who have a combination of extranodal spread, multiple positive lymph nodes, and lymph nodes replaced by tumor greater than 50%, a future study of the effectiveness of systemic therapy for vulvar cancer must include these patients.

Surgical support and suspension of genital prolapse, including preservation of the uterus, using the Gore-Tex soft tissue patch (a preliminary report).

Abdominal-retroperitoneal sacral genito-colpopexy using the expanded polytetrafluoroethylene (ePTFE) soft tissue patch has been found to be highly effective for repair of genito-vaginal prolapse. We treated 61 patients in this way, including patients who had failed multiple previous attempts at repair. At a mean of 32 months of follow-up, more than 95% of patients were still classified as successfully treated. To preserve the uterus in cases of complete genito-vaginal prolapse, we have developed a new surgical technique, which we describe in this paper.

Prophylactic oophorectomy.

The risks and benefits of prophylactic bilateral oophorectomy (BO) accompanying hysterectomy are reviewed. The potential reduction in the risk of subsequent ovarian cancer is quantified using literature data and a mathematical model. The risks of subsequent breast cancer from low-dose ERT are estimated using a comprehensive mathematical model. It is hypothesized that BO may have a substantial protective effect on breast cancer risk despite subsequent low-dose or non-low-dose ERT, when BO is performed at an early age. In women with a family history of ovarian cancer or breast cancer, the individual risks must be assessed on the basis of a pedigree analysis. In conclusion, a decision on BO must be based on weighing the potential benefits of reduced ovarian and breast cancer risks against the psychological importance of retaining the ovaries and the risk of osteoporosis and cardiovascular disease when compliance with ERT is less than perfect. The provided quantitative data may help in making the right decision.

A stage Ia vulvar carcinoma with an inguinal lymph node recurrence after local excision. A case report and literature review.

A patient with a stage Ia vulvar squamous cell carcinoma (< 1 mm invasion) is reported in which an inguinal recurrence one and a half years after partial radical vulvectomy and superficial inguinal lymph node sampling was noted. After the initial biopsy showing a tumor invading 0.3 mm into the stroma, residual tumor could not be shown in the vulvectomy specimen nor in the superficial lymph nodes. A review of the literature indicates that this is only the second reported case of stage Ia vulvar carcinoma with lymph node metastases.

Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer.

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

Single-dose prophylaxis with broad-spectrum penicillins (piperacillin and mezlocillin) in gynecologic oncological surgery, with observation on serum and tissue concentrations.

Serum, fat and pelvic tissue levels of piperacillin or mezlocillin (patients randomly selected to receive one of both) were measured during surgery of 48 patients (mean age 55 years) with gynecologic cancer and related to the minimal inhibitory concentrations (MIC). Only during the first 3 hours the fat and pelvic tissue levels of these antibiotics were above the MIC levels (3 to 5 mg/l), while the serum reached marginal levels after 4 to 5 hours. Excessive blood loss (more than 1.500 ml) decreases the serum and fat levels; however, during the first 3 hours not below the MIC values. Single-dose prophylaxis with both antibiotics appeared fully effective in debulking surgery, total abdominal hysterectomy and radical hysterectomy. However, out of a group of 12 patients who underwent radical vulvectomy, 8 patients had postoperative infections.

Malignant mixed müllerian tumour of the fallopian tube.

We report two cases of primary heterologous malignant mixed Müllerian tumour of the Fallopian tube. One of these was bilateral, a finding which, as far as we know, has not been reported before.

Piperacillin for prophylaxis in gynecological surgery.

The effectiveness of perioperative Piperacillin for prevention of operative-site infection after gynaecological surgery was studied in a total of 100 patients. In an open randomized clinical trial of 52 women undergoing abdominal or vaginal hysterectomy Piperacillin was compared to the combination Gentamicin/Metronidazole. Piperacillin was well-tolerated. Surgical-site infection was diagnosed in the Piperacillin group in two patients and in the Gentamicin/Metronidazole group in one patient. The occurrence of postoperative febrile morbidity was also similar between the two group. In 48 patients undergoing complicated gynecological surgery of long duration, only Piperacillin was administered perioperatively. Thirty-five of these 48 women underwent oncological operations and the mean operative length was 3.3 h. One patient developed a transient rash after the administration of Piperacillin. No other adverse side-effects were observed. Nine of these 48 patients developed a surgical-site infection postoperatively, and this was found to be significantly more often than in the first group of 52 patients. It was concluded that Piperacillin seems to be a valuable alternative for perioperative prophylaxis in gynecological surgery. Its effectiveness in vaginal and abdominal hysterectomy is similar to the combination of Gentamicin/Metronidazole, but after complicated surgery of long duration a decreased effectiveness should be reckoned with.

Total abdominal irradiation in stage I and II carcinoma of the ovary.

In the period from 1981 to 1986, 85 patients with ovarian carcinoma stage I and II were treated in a prospective study. All patients underwent primary surgery: bilateral salpingo-oophorectomy, hysterectomy and omentectomy followed by a staging procedure. In 46 patients, the staging was completed by a retroperitoneal lymph-node dissection, whereas in 39 patients, this procedure was omitted. Total abdominal irradiation (25 Gy/1.50 Gy per fraction) was followed by a pelvic boost dose (25 Gy/1.75 Gy per fraction). Patients with stage I and IIa well differentiated tumours received no adjuvant radiotherapy and are not reported here. The 5-year actuarial recurrence-free survival rate for the irradiated group was 75%. Stage according to FIGO appeared to be of significant prognostic influence. There was no difference in survival between completely and incompletely staged patients. Serious (small) bowel complications occurred however in 6 out of 45 patients who had undergone complete staging.

The role of cytoreduction in ovarian cancer.

Whether or not cytoreduction improves the outlook of ovarian cancer patients is not yet clear from data from Literature. Maybe not the successful procedure itself, but the favourable tumor characteristics of these tumors determine the prognosis. New studies are necessary to define the role of surgery in the overall management of ovarian cancer more precisely. In this article a Dutch study is presented, to answer the question about the influence of attempted cytoreductive surgery prior to, during chemotherapy on survival time and remission rates. All patients are treated with either combination chemotherapy and/or an attempt to cytoreduction prior to or during chemotherapy. With this strategy ethical problems concerning undertreatment are avoided. The study is currently activated but it is too early to draw any conclusions.

A review of prognostic factors in early-stage carcinoma of the cervix (FIGO I B and II A) and implications for treatment strategy.

Several prognostic factors in stages I B and II A cervical carcinoma have been widely studied to define groups of patients with a poor prognosis. Most of these factors are interrelated. The characteristics which should be regarded as main factors have not yet been defined, because the studies reported were based on mainly retrospective and non-randomized analysis. Reviewing the literature, lymph node metastasis, differentiation grade, tumor size, parametrial extension, lymph-blood vessel invasion and cervical invasion seem to be prognostically important factors, which suggests that the subdivision of patients according to the FIGO classification alone is inaccurate. It seems useful to define subgroups of patients according to tumor characteristics, determined after surgical treatment and accurate histologic examination of the surgical specimen. Patients with one or more of these tumor features need additional treatment to improve survival. The current treatment modalities, such as postoperative radiotherapy, have not been thoroughly evaluated, but doubt exists as to their efficacy. Data in the literature suggest that particularly patients with para-aortic or multiple pelvic lymph node metastasis (greater than 3) have already developed distant metastases at the time of primary treatment and therefore need adjuvant systemic therapy. Patients with tumors larger than 4 cm in diameter, differentiation grade III, lymph-blood vessel invasion or cervical invasion (of more than 70%) seem to have high recurrence rates at both pelvic and distant sites, indicating that there is also a need for better pelvic control.

DNA flow cytometry, histological grade, stage, and age as prognostic factors in human epithelial ovarian carcinomas.

The prognostic value of parameters as determined by DNA flow cytometry, in combination with other parameters, was assessed in 75 patients with ovarian carcinomas (20% in stage I and II). DNA- index of the tumours appeared to predict mainly the degree of differentiation, since the DNA-index only tended to affect prognosis and low grade tumours were mainly diploid. However, with ascites a non-diploid DNA-index was associated with a significantly lower survival in short-term follow-up. Subgroups with a favourable prognosis were defined by an age of patients less than or equal to 40 years, grade 1 tumours, and tumours in stage I or II. Particularly favourable was the combination of a grade 1 tumour, or a tumour in stage I or II, with percentage of cells in G1 greater than 85%. Prognostically poor subgroups were defined by an age greater than 60 years, by grade 2 or 3 tumours and by a clinically advanced stage. The combination of grade 2 or 3, or a clinically advanced stage, with G1-phase fraction less than or equal to 85% identified subgroups with a particularly poor prognosis.