Successful implementation of handheld reflectance confocal microscopy as the standard of care in the (surgical) management of lentigo maligna (melanoma).

BACKGROUND: Reflectance confocal microscopy (RCM) has shown promise in predicting surgical outcomes by non-invasively detecting subclinical lentigo maligna (melanoma) (LM/LMM). OBJECTIVES: To assess the effects of presurgical mapping using handheld RCM (HH-RCM) on surgical treatment, follow-up outcomes and management decisions. METHODS: A total of 117 consecutive LM/LMM cases (2015-2023) were included. The diagnostic accuracy of HH-RCM in detecting subclinical LM and invasive components was evaluated. The primary endpoints included histological margin status and changes in management based on the outcomes of the HH-RCM mapping procedure. Margin and follow-up outcomes were compared to a historical cohort before HH-RCM was introduced in our center (n = 94) (2003-2014). RESULTS: HH-RCM detected subclinical LM in 60% (n = 60) of cases. The median mapping duration was 14 min (range 4-50). In 27% (n = 33), the mapping procedure resulted in modified management, the majority consisting of limited surgery with adjuvant imiquimod (n = 15) or imiquimod monotherapy (n = 14). The remaining cases (n = 84) underwent HH-RCM-assisted surgery. Histological margins were cleared in 96.5% of the patients with a median histological margin of 3.0 mm, significantly higher than 81% in the historical cohort (median 2.0 mm) (p = 0.001). The sensitivity and specificity for detecting the extent of subclinical LM were 94% (95% CI 80.4-99.3) and 84% (95% CI 70.3-92.7), respectively. The negative predictive value for the detection of LMM was 94% (95% CI 84.4-97.7), and 75% of the initially missed LMM (n = 12) were identified during the HH-RCM mapping procedure. The study cohort had a 1.6% local recurrence rate compared with 25% in the historical cohort. CONCLUSIONS: Integrating HH-RCM as the standard of care could lead to more personalized treatment strategies for LM/LMM and allows for the selection of patients suitable for nonsurgical treatment.

Lentigo maligna (melanoma): A systematic review and meta-analysis on surgical techniques and presurgical mapping by reflectance confocal microscopy.

Because of an increased risk of local recurrence following surgical treatment of lentigo maligna (melanoma) (LM/LMM), the optimal surgical technique is still a matter of debate. We aimed to evaluate the effect of different surgical techniques and reflectance confocal microscopy (RCM) on local recurrence and survival outcomes. We searched MEDLINE, Embase and PubMed databases through 20 May 2022. Randomized and observational studies with ≥10 lesions were eligible for inclusion. Bias assessment was performed using the Methodological Index for Non-Randomized Studies instrument. Meta-analysis was performed for local recurrence, as there were insufficient events for the other clinical outcomes. We included 41 studies with 5059 LM and 1271 LMM. Surgical techniques included wide local excision (WLE) (n = 1355), staged excision (n = 2442) and Mohs' micrographic surgery (MMS) (n = 2909). Six studies included RCM. The guideline-recommended margin was insufficient in 21.6%-44.6% of LM/LMM. Local recurrence rate was lowest for patients treated by MMS combined with immunohistochemistry (<1%; 95% CI, 0.3%-1.9%), and highest for WLE (13%; 95% CI, 7.2%-21.6%). The mean follow-up varied from 27 to 63 months depending on surgical technique with moderate to high heterogeneity for MMS and WLE. Handheld-RCM decreased both the rate of positive histological margins (p < 0.0001) and necessary surgical stages (p < 0.0001). The majority of regional (17/25) and distant (34/43) recurrences occurred in patients treated by WLE. Melanoma-associated mortality was low (1.5%; 32/2107), and more patients died due to unrelated causes (6.7%; 107/1608). This systematic review shows a clear reduction in local recurrences using microscopically controlled surgical techniques over WLE. The use of HH-RCM showed a trend in the reduction in incomplete resections and local recurrences even when used with WLE. Due to selection bias, heterogeneity, low prevalence of stage III/IV disease and limited survival data, it was not possible to determine the effect of the different surgical techniques on survival outcomes.

Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials.

BACKGROUND: Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. PATIENTS AND METHODS: In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2× ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n = 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3 mg/kg q3w; n = 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n = 26) followed by surgery. RESULTS: The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. CONCLUSIONS: Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma.

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.

From reactive to proactive tube feeding during chemoradiotherapy for head and neck cancer: A clinical prediction model-based approach.

OBJECTIVES: Feeding tubes are placed unnecessarily in a proportion of head and neck cancer (HNC) patients treated with chemoradiotherapy (CRT) when prophylactic tube placement protocols are used. This may have a negative impact on the risk of long-term dysphagia. Reactive tube placement protocols, on the other hand, might result in weight loss and treatment interruption. The objective of this study is to identify patients at risk for prolonged tube dependency in order to implement a personalized strategy regarding proactive tube placement. MATERIALS AND METHODS: A retrospective study was performed in a consecutive cohort of HNC patients treated with primary CRT for whom a reactive tube placement protocol was used. A prediction model was developed to predict prolonged (> 90 days) feeding tube dependency. Model performance and clinical net benefit of the model were assessed. RESULTS: Of the 336 included patients, 229 (68%) needed a feeding tube during CRT and 151 (45%) were prolonged feeding tube dependent. The prediction model includes the predictors pretreatment BMI, weight loss, Functional Oral Intake Scale and T-stage. Discriminatory ability is fair (area under the ROC-curve of 0.69) and calibration is adequate (Hosmer and Lemeshow test p = .254). The model shows net benefit over current practice for probability thresholds from 35 to 80%. CONCLUSION: The developed model can be used to select patients for proactive feeding tube placement during primary CRT for HNC. The nomogram with easily obtainable parameters is a useful tool for clinicians to support shared decision making regarding proactive tube placement.

The best of both worlds: a hybrid approach for optimal pre- and intraoperative identification of sentinel lymph nodes.

PURPOSE: Hybrid image-guided surgery technologies such as combined radio- and fluorescence-guidance are increasingly gaining interest, but their added value still needs to be proven. In order to evaluate if and how fluorescence-guidance can help realize improvements beyond the current state-of-the-art in sentinel node (SN) biopsy procedures, use of the hybrid tracer indocyanine green (ICG)-99mTc-nancolloid was evaluated in a large cohort of patients. PATIENTS AND METHODS: A prospective trial was conducted (n = 501 procedures) in a heterogeneous cohort of 495 patients with different malignancies (skin malignancies, oral cavity cancer, penile cancer, prostate cancer and vulva cancer). After injection of ICG-99mTc-nanocolloid, SNs were preoperatively identified based on lymphoscintigraphy and SPECT/CT. Intraoperatively, SNs were pursued via gamma tracing, visual identification (blue dye) and/or near-infrared fluorescence imaging during either open surgical procedures (head and neck, penile, vulvar cancer and melanoma) or robot assisted laparoscopic surgery (prostate cancer). As the patients acted as their own control, use of hybrid guidance could be compared to conventional radioguidance and the use of blue dye (n = 300). This was based on reported surgical complications, overall survival, LN recurrence free survival, and false negative rates (FNR). RESULTS: A total of 1,327 SN-related hotspots were identified on 501 preoperative SPECT/CT scans. Intraoperatively, a total number of 1,643 SNs were identified based on the combination of gamma-tracing (>98%) and fluorescence-guidance (>95%). In patients wherein blue dye was used (n = 300) fluorescence-based SN detection was superior over visual blue dye-based detection (22-78%). No adverse effects related to the use of the hybrid tracer or the fluorescence-guidance procedure were found and outcome values were not negatively influenced. CONCLUSION: With ICG-99mTc-nanocolloid, the SN biopsy procedure has become more accurate and independent of the use of blue dye. With that, the procedure has evolved to be universal for different malignancies and anatomical locations.

[A man with an anomaly in his ear]. / Een man met een afwijking in het oor.

A 65-year-old man presented with an anomaly in his left ear. He had no complaints, but was ashamed of the lesion. On physical examination a pigmented, pedunculated, polypoid tumour of approximately 2 x 2.5 cm was seen, which filled the whole cavum conchae. After excision, histopathological examination showed a verruca seborrhoica.

Recurrent oropharyngeal cancer after organ preserving treatment: pattern of failure and survival.

The objectives is to thoroughly analyze the pattern of failure and oncologic outcome in recurrent oropharyngeal cancer (OPC) after (chemo)radiotherapy and correlate the site of failure to the planned radiation dose. Between January 2010 and April 2014, 57 patients with recurrent OPC after (chemo)radiotherapy were analyzed. Endpoints were pattern of failure and overall survival (OS). Local (LF) and regional failure (RF) were classified as in-field [>50% within gross tumor volume (GTV)], marginal [<50% within GTV but >50% within clinical target volume (CTV)], or out-of-field (>50% outside CTV) recurrences. In the whole group, 70 recurrences were reported. Of the 31 LF, 29 (93.5%) were in-field and 2 (6.5%) were marginal. No out-field LF was reported. Of the 21 RF, 13 RF (62%) were in-field, 6 (28.5%) marginal, and 2 (9.5%) out-of-field recurrences. Forty-three percent of RF was developed in an electively treated neck level, and 2 of them were contralateral. OS at 2 years in recurrent HPV positive, compared to HPV-negative OPC, were 66 and 18%, respectively (p = 0.011). OS was also significantly better in patients that were salvage treatment which was possible (70 vs. 6%, p < 0.001). Median survival after distant failure was 3.6 months. The great majority of LFs were located within the GTV and 43% of RFs developed in an electively treated neck level. The currently used margins and dose recipe and the indication for bilateral nodal irradiation need to be reevaluated. OS was significantly better in recurrent HPV-positive OPC and in patients, where salvage treatment was possible.

Quality of life after different procedures for regional control in oral cancer patients: cross-sectional survey.

OBJECTIVES: To examine health utilities in patients with cT1-2 oral cavity squamous cell carcinoma following different diagnostic and treatment modalities for the neck and to investigate the relation between shoulder morbidity and health utility. DESIGN: Cross-sectional survey. SETTING: Two Dutch hospitals. PARTICIPANTS: Four subgroups of patients with oral cavity cancer who underwent watchful waiting, sentinel lymph node biopsy, elective supraomohyoid neck dissection or therapeutic modified radical neck dissection. MAIN OUTCOME MEASURES: Patients received the EuroQol-5D-3L questionnaire and the shoulder disability questionnaire. Mean health utility, visual analogue scale and shoulder disability scores were calculated. RESULTS: A total of 181 patients (62%) returned the questionnaires. Mean health utilities, adjusted for age, gender and time since treatment were 0.804, 0.863, 0.834 and 0.794 for the watchful waiting, sentinel lymph node biopsy, supraomohyoid neck dissection and modified radical neck dissection subgroups, respectively. Mean shoulder disability scores (higher score means more shoulder complaints) for these subgroups were 8.64, 10.57, 18.92 and 33.66. Patients with shoulder complaints had a mean utility of 0.78 while patients without shoulder complaints had a mean utility of 0.90. CONCLUSIONS: This study shows that more invasive procedures appear to result in lower health utility. The high health utility for patients after sentinel lymph node biopsy supports a role for this procedure in patients with oral cancer.

Merkel cell carcinoma of the head and neck: emphasizing the risk of undertreatment.

Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma. It occurs predominantly in the head and neck area and often behaves aggressively. In this single-institution retrospective observational cohort study, we describe the results of a treatment strategy that we developed over the past decades. Endpoints of this study were local, regional and distant control, disease-specific survival and overall survival. In total 47 patients with head and neck MCC, diagnosed in the Netherlands Cancer Institute-Antoni van Leeuwenhoek (NKI-AvL) between 1984 and 2012, were included in this study. Local tumor control was 82 % (95 % CI 71-95 %) at 5 years. Regional lymph node metastases were found at the moment of diagnosis in 13 cases (28 %). In the group of patients who were initially cN0, the 5-year regional control was 80 % (68-95 %). The 5-year metastasis-free interval probability was 80 % (68-94 %). The disease-specific survival (DSS) at 5 years was 70 % (56-86 %). An overall survival of 54 % (40-72 %) was found at 5-year follow-up and of 37 % (23-59 %) at 10-year follow-up. Univariable Cox regression analysis of many clinical and pathological variables did not identify any predictors for DSS. The MCC has a high propensity for locoregional and distant spread in the head and neck region. Undertreatment, especially of the lymph nodes in the neck, is a serious problem as regional (micro)metastasis are common even in T1 tumors. Future research will have to elucidate the role of the sentinel lymph node procedure versus the elective selective node dissection and standardized elective local and regional radiotherapy in the head and neck area.

An innovative multimodality approach for sentinel node mapping and biopsy in head and neck malignancies.

PURPOSE: Recent innovations such as preoperative SPECT/CT, intraoperative imaging using portable devices and a hybrid tracer were evaluated in a multimodality approach for sentinel node (SN) mapping and biopsy in head and neck malignancies. MATERIAL AND METHODS: The evaluation included 25 consecutive patients with head and neck malignancies (16 melanomas and 9 oral cavity squamous cell carcinomas). Patients were peritumorally injected with the hybrid tracer ICG-(99m)Tc-nanocolloid. SNs were initially identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT/CT) 2 hours after tracer administration. During surgery a portable gamma camera in combination with a near-infrared fluorescence camera was used in addition to a handheld gamma ray detection probe to locate the SNs. RESULTS: In all patients the use of conventional lymphoscintigraphy, SPECT/CT and the additional help of the portable gamma camera in one case were able to depict a total of 67 SNs (55 of them visualized on planar images, 11 additional on SPECT/CT and 1 additional with the portable gamma camera). A total of 67 of the preoperatively defined SNs together with 22 additional SNs were removed intraoperatively; 12 out of the 22 additional SNs found during operation were located in the vicinity of the injection site in anatomical areas such as the periauricular or submental regions. The other 10 additional SNs were found by radioguided post-resection control of the excision SN site. CONCLUSION: In the present series 26% additional SNs were found using the multimodal approach, that incorporates SPECT/CT and intraoperative imaging to the conventional procedure. This approach appears to be useful in malignancies located close to the area of lymphatic drainage such as the periauricular area and the oral cavity.

Evaluation of lasersurgery and radiotherapy as treatment modalities in early stage laryngeal carcinoma: tumour outcome and quality of voice.

For treatment of early stage (Tis-T2) laryngeal cancer the main choice is between microlaryngoscopy with carbon dioxide laser resection (laser surgery) and radiotherapy. Because both treatments provide excellent tumour control, secondary outcome variables such, as quality of voice may be of importance in treatment preference. In this study tumour outcomes and quality of voice were analysed for a cohort of patients with early stage (Tis-T2) laryngeal (glottic) carcinoma. The "physical subscale" of the voice handicap index questionnaire (VHI) and a validated five-item screening questionnaire were used. Analysis of 89 patients treated with laser surgery and 159 patients treated with radiotherapy revealed a 5-year local control of 75 and 86 % (p = 0.07). Larynx preservation (5-year) was, however, superior in patients treated with laser surgery, 93 vs 83 % (p < 0.05). Tumour outcomes were also analysed per tumour stage and none were of significant difference. Quality of voice was analysed in 142 patients. VHI scores were 12.4 ± 8.9 for laser surgery and 8.3 ± 7.7 for radiotherapy (p < 0.05), with a higher score reflecting a worse outcome. VHI scores per tumour stage for laser surgery and radiotherapy were, respectively, 12.0 ± 9.9 and 7.9 ± 7.5 in T1a (p = 0.06), 16.7 ± 9.0 and 4.9 ± 6.6 in T1b (p < 0.05). Outcomes of the five-item questionnaire showed voice deficiency in 33 % for laser surgery and 23 % for radiotherapy in T1a (p = 0.330) and 75 and 5 % for T1b (p = 0.001). Oncologic outcomes of laser surgery and radiotherapy were comparable. Larynx preservation is, however, preferable in patients initially treated with laser surgery. According to subjective voice analysis, outcomes were comparable in T1a lesions. Depth of laser resection is of influence on voice deficiency displayed by a significantly higher percentage of voice deficiency in patients treated with laser surgery for T1b lesions.

Photodynamic therapy of early stage oral cavity and oropharynx neoplasms: an outcome analysis of 170 patients.

The indications of photodynamic therapy (PDT) of oral cavity and oropharynx neoplasms are not well defined. The main reason is that the success rates are not well established. The current paper analyzes our institutional experience of early stage oral cavity and oropharynx neoplasms (Tis-T2) to identify the success rates for each subgroup according to T stage, primary or non-primary treatment and subsites. In total, 170 patients with 226 lesions are treated with PDT. From these lesions, 95 are primary neoplasms, 131 were non-primaries (recurrences and multiple primaries). The overall response rate is 90.7% with a complete response rate of 70.8%. Subgroup analysis identified oral tongue, floor of mouth sites with more favorable outcome. PDT has more favorable results with certain subsites and with previously untreated lesions. However, PDT can find its place for treating lesions in previously treated areas with acceptable results.

Sentinel node detection in head and neck malignancies: innovations in radioguided surgery.

Sentinel node mapping is becoming a routine procedure for staging of various malignancies, because it can determine lymph node status more precisely. Due to anatomical problems, localizing sentinel nodes in the head and neck region on the basis of conventional images can be difficult. New diagnostic tools can provide better visualization of sentinel nodes. In an attempt to keep up with possible scientific progress, this article reviews new and innovative tools for sentinel node localization in this specific area. The overview comprises a short introduction of the sentinel node procedure as well as indications in the head and neck region. Then the results of SPECT/CT for sentinel node detection are described. Finally, a portable gamma camera to enable intraoperative real-time imaging with improved sentinel node detection is described.

Ventricular fibrillation caused by electrocoagulation during laparoscopic surgery.

A 35-year-old man with morbid obesity was admitted to our hospital to undergo gastric banding gastroplasty by the laparoscopic approach. Aside from his morbid adiposity, with a body mass index (BMI) of 49.9 kg/m2, the patient was healthy. During the procedure, he developed ventricular fibrillation (VF) while a diathermic knife was being used. After defibrillation, his heart rate returned to normal. The postoperative clinical course was uneventful, and there was no evidence of permanent heart failure. Although the VF could have been caused by patient- or material-related variables, it was most likely the result of unwanted electrical effects. Specifically, the occurrence of an arc between the patient's tissue and the tip of the electrode during cutting in the coagulation mode can lead to low-frequency current. The modified low-frequency current may produce arrhythmias. Thus, the use of the coagulation mode to cut tissue in the cardiac region during laparoscopic procedures could increase the risk for arrhythmias. An understanding of the physical principles of electrosurgery, as well as familiarity with the equipment and its various functions, is essential for the patient's safety. In addition, cardioversion equipment should be readily available on every surgical unit.