Correspondence cavitations in enhanced depth imaging spectral-domain OCT (Spectralis). The cystoid spaces at the margin of choroidal colobomas could create the communication between spaces and could develop subclinical retinal detachment. In our opinion, comparable OCTmorphologic changes at the border of colobomas and PCC are different stages of the same disorder. Pathogenesis of colobomas is associated with genetic abnormalities, such as mutations of different genes during the first weeks of embryogenesis. Among 27 well–known coloboma-associated genes some have been implicated particularly often, for example, the paired box homeotic gene 2 (PAX2).3 Most of these mutations are autosomal recessive and therefore may cause incomplete phenotypic changes. Few mutations are autosomal dominant, for example, ATP-binding cassette (ABC) transporter ABCB6.3 Associations of colobomas with environmental causes remain somewhat speculative. Genotoxic compounds, maternal infections, and ionizing radiation have been associated with development of coloboma.4 Interestingly, maternal vitamin A deficiency can cause coloboma.4 In addition, the incidence of colobomas in China is 7 times higher than in Europe.4 Furthermore, the development of colobomas depends on changing of structural connections between cells. The cellecell adhesion is regulated through cell adhesion molecules (CAM). One of the calcium-dependent CAMs, cadhedrin, is essential for the optic fissure closure.5 According to Chen et al,5 mutations of cadhedrin can produce certain coloboma cases in humans. It is possible that cadhedrin or another CAMs may play some important role in the formation of PCCs.5 The similarity of morphologic features at the borders of optic disc colobomas and PCC allows us to create some suggestions about pathogenesis. The prevalence of PCC in elderly patients may be dependent on environmental causes, local disorders of cellecell adhesion following different CAMs pathologies, or some recessive mutations. Unfortunately, Yeh et al1 gathered only few important anamnestic data from 83 investigated patients. It would be interesting if data would be further analyzed with regard to common nutritional conditions, accompanying diseases and medications in elderly patients, contact with genotoxic substances, and so on. The statistical analysis of these data could help the authors to find some pathogenetic synthesis. We are looking forward to their conclusions about the pathogenesis of PCC.

SOPHIE ANNA HOLAK, MD NIKOLAI HOLAK, MD HEINRICH MARKUS HOLAK, MD Augenklinik Salzgitter, Salzgitter, Germany

References 1. Yeh SI, Chang WCh, Wu ChS, et al. Characteristics of peripapillary choroidal cavitation detected by optical coherence tomography. Ophthalmology 2013;120:544–52. 2. Freund KB, Mukkumala SK, Cooney MJ. Peripapillary choroidal thickening and cavitation. Arch Ophthalmol 2011;129: 1096–7. 3. Wang L, He B, Bu J, et al. ABCB6 mutations cause ocular coloboma. Am J Hum Genet 2012;90:40–8. 4. Gregory-Evans CY, Williams MJ, Halford S, Gregory-Evans K. Ocular coloboma: a reassessment in the age of molecular neuroscience. J Med Gen 2004;41:881–91.

5. Chen S, Lewis B, Moran A, Xie T. Cadherin-mediated cell adhesion is critical for the closing of the mouse optic fissure. PloS One 2012;7:51705.

Does Intra-arterial Chemotherapy Improve Survival for Adenoid Cystic Carcinoma? Dear Editor: Tse et al1 summarize the long-term outcomes in 19 patients with adenoid cystic carcinoma of lacrimal gland who underwent treatment on an investigational protocol that entailed receiving intraarterial chemotherapy (IAC) followed by orbital exenteration followed by postoperative adjuvant chemoradiation; 19 patients were enrolled in 24 years.1 The authors conclude that the prescribed protocol led to a “significantly higher disease-free survival in the 7 patients who had an intact lacrimal artery (group 1) compared with the 11 patients who did not have an intact lacrimal artery (group 2) and also compared with historical controls.” Clarification of several issues would be appreciated. First, the assessment of lacrimal artery status (whether intact or not) was not clearly defined. Was this done via angiography before IAC? Furthermore, how do the authors explain the “radiographic response” of tumor (i.e., shrinkage of lacrimal gland carcinoma) after IAC in all 11 patients in group 2 (in Table 1) who were reported to have had a nonintact lacrimal artery? Second, from reading previous publications by the same authors reporting the results of IAC protocoldthere was no prospective intent to stratify the 19 patients in this protocol into groups 1 and 2. Could the authors explain the rationale for this retroactive stratification strategy, especially in light of the observation that all 11 patients without an intact lacrimal artery experienced radiographic response to IAC? Third, the definition of “tumor resection” versus “biopsy” was confusing. The authors stated (page 2): “Group 2 comprised 11 patients who had (total?) tumor resection before the IAC and were thus without an intact lacrimal artery,” yet subsequently it is stated (page 3): “Gross residual orbital disease or positive tumor margins of the resected mass were present in all 10 cases.” Was there or was there not gross residual disease in group 2 patients? Because the status of lacrimal artery is stated to be a function of the amount of disruption to the lacrimal gland, how should one biopsy a lacrimal gland carcinoma without threatening the lacrimal artery? Especially for the majority of lacrimal gland carcinomas that are not limited to the palpebral lobe, is there a percentage of the mass to biopsy to leave the lacrimal artery intact? Do the authors recommend preoperative or intraoperative angiography to try to preserve the lacrimal artery? Fourth, the size of the lacrimal gland carcinomas at presentation (before any intervention) is an important prognostic feature that is not reported in the current report. Ahmad et al,2 in a series of 53 patients with lacrimal gland adenoid cystic carcinoma, found that tumor size >2.5 cm in greatest dimension correlated with significantly worse disease-free survival compared with smaller tumors. Is it possible that group 2 patients in the current report simply had larger tumors at presentation and thus a worse outcome? What was the relationship between size and histologic type of tumor at presentation and disease-free survival in the 19 patients and between the 2 groups of patients?

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Fifth, 5 of 11 patients in group 2 had local and/or distant recurrence. This rate of recurrence is similar to previously reported series of adenoid cystic carcinoma of lacrimal gland. The authors compared the current series with a reported cohort from MD Anderson by Esmaeli et al.3 However, there is a more recent report from MD Anderson describing outcomes in a larger cohort of 18 patients and with longer follow-up that demonstrated about 40% cause-specific mortality,3 similar to the survival outcomes for patients in group 2. It would have been easier to interpret the authors’ data and compare with the previously reported series if disease-specific survival could be reported for all 19 patients treated on the IAC protocol rather than the retrospective stratification of the patients into groups 1 and 2. Sixth, the disease-specific mortality between groups 1 and 2 patients did not show statistical significance (Figure 4). Is “IAC as designed” referring to group 1 and “IAC protocol deviation” to group 2? If so, the graph does not show a significant difference in disease-specific mortality between the 2 groups. Seventh, the authors highlight 6 patients (cases 1, 4, 19, 8, 9, and 11) as having had excellent response and shrinkage of the extraorbital extension of tumor and “downstaging the disease to an intraorbital process” (page 7); yet 4 of these 6 highlighted patients developed a recurrence or metastasis. It seems that downstaging did not change survival outcomes. Eighth, review of the patient highlighted in Figure 1 suggests that this patient progressed to have surgically unresectable cavernous sinus disease while receiving IAC, whereas his disease before administration of IAC seems to have been surgically resectable. Could the authors comment on the potential risk of progression to a surgically unresectable stage while patients receive IAC? Ninth, the authors suggest that a lateral orbitotomy somehow causes “tumor seeding” whereas an anterior orbitotomy may not. Are there any anatomic reasons or evidence to support this assertion? Tenth, the authors state that, “In patients whose tumors has breached the lateral wall with extensions into the temporalis muscle, a head/neck surgeon should be consulted for possible regional neck dissection” (page 8). This recommendation is not supported by the literature as the risk of nodal metastasis from lacrimal gland adenoid cystic carcinoma is quite low. Eleventh, the historical control group used in this report did particularly poorly in that 100% of patients died of disease. This is worse than any previously published report and has the unintended effect of making the IAC treated group seem better in comparison. Despite the tremendous respect that is justified for the carefully executed protocol led by Dr Tse, the current report may have raised more questions than answers. We are grateful to Dr Tse and his colleagues for their important work and look forward to reading the authors’ responses to the above queries.

BITA ESMAELI, MD Orbital Oncology & Ophthalmic Plastic Surgery Program, Department of Plastic Surgery, MD Anderson Cancer Center, Houston, Texas

References 1. Tse DT, Kossler AL, Feuer WJ, et al. Long-term outcomes of neoadjuvant intra-arterial cytoreductive chemotherapy for lacrimal gland adenoid cystic carcinoma. Ophthalmology 2013;120:1313–23.

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2. Ahmad SM, Esmaeli B, Williams M, et al. American Joint Committee on Cancer classification predicts outcome of patients with lacrimal-gland adenoid cystic carcinoma. Ophthalmology 2009;116:1210–5. 3. Williams MD, Al-Zubidi N, Debnam JM, et al. Bone invasion by adenoid cystic carcinoma of the lacrimal gland: preoperative imaging assessment and surgical considerations. Ophthalmol Plast Reconstr Surg 2010;26:403–8.

Author reply Dear Editor: Esmaeli’s request for clarification of issues regarding our study1 involves 11 points related to both the intra-arterial cytoreductive chemotherapy (IACC) protocol design and our analysis. First, the introductory quotation attributed to us was not a statement made in our manuscript. Eight patients were in group 1, not 7, and the characterization of group 2 patients as only those without an intact lacrimal artery is inaccurate. We address each query sequentially. Second, group 1 was composed of 8 patients with an intact lacrimal artery who completed the IACC treatment protocol in sequential order and within a timeframe of implementation. None had surgical disruption of bone. Group 2 comprised patients who deviated from the protocol design or presented without an intact lacrimal artery. Ten patients had excisional biopsy by a lateral orbitotomy with bone take-down, and thus intra-arterial chemotherapy was delivered to the orbit through altered lacrimal artery anatomy. One patient, case 8, as reported in our 2006 study (cited in reference 1) had a dramatic radiographic response after 2 cycles of intra-arterial chemotherapy delivered through an intact lacrimal artery. This patient was included in group 2 because she refused exenteration, and the remaining 4 cycles of the intravenous chemotherapy, and thus deviated from the prescribed protocol. Disruption of the lacrimal artery was defined clinically. The major flow to the lacrimal gland should occur through the lacrimal artery so an intact artery would deliver the greatest drug concentration to the tumor. Although resection of the lacrimal gland mass severs the glandular branches of the lacrimal artery from the main trunk, the proximal lacrimal artery stump, through collateral vessels (facial, maxillary, and superficial temporal arteries) from the external carotid artery, can still deliver the drug to the intraorbital tumor and surrounding structures harboring microscopic tumor cells. The lacrimal artery also gives off 1 zygomatic branch passing through the zygomaticotemporal foramen to reach the temporal fossa, a site of potential tumor seeding. Thus, blood supply to the orbital tissues is not dependent solely on the lacrimal artery. Third, this treatment program began as an exploratory regimen to remedy the shortcoming of conventional treatments in addressing occult metastases after achieving local disease control with surgery and radiation therapy. Our original papers described our experience with small numbers of patients. In fact, we always intended to stratify patients into those receiving IACC as designed and those who did not. Our larger cohort made this possible.1 Parenthetically, Table 1 includes individual case data, so anyone wishing to regroup the patients can easily do so with KaplaneMeier analysis. Separating groups 1 and 2 underscores that the benefits of IACC will be optimal for patients with intact lacrimal arteries who receive the full course of treatment.