This was a retrospective, observational, case series of patients who underwent combined MARK + CXL intervention performed by the same surgeon (MA) with the same instruments in two different centers who were followed-up for several years. Clinical selection criteria included progressive stage I and II KC (Amsler-Krumeich classification) and contact lens intolerance. Patients with any chronic or recurrent ocular infections were excluded. All patients underwent a complete clinical examination prior to the intervention. Ethics approval was provided by the director of the Abbondanza Eye Centers (MA), and written informed consent for both procedures was required as a part of our preoperative routine. The research was performed in accordance with the principles of the Declaration of Helsinki.

For the purposes of this study, best spectacle-corrected visual acuity (BSCVA), mean pachymetry, and mean keratometry (Kavg) were recorded with a Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany) preoperatively and at least 1, 3, and 5 years following the last of the combined operations (CXL). Steady and/or improved pachymetric and keratometric values have been used as indicators of successful KC stabilization, while an increase in BSCVA is a standard indicator of improved visual acuity.

Among all patients that underwent the MARK + CXL combined procedure, fifteen eyes of 12 patients were selected due to availability of a minimum of 5 years of follow-up data after the last intervention. Mean follow-up was 6.9 years. The cohort of patients comprised eight males and four females with a mean age of 34.8 years. No patients required corneal transplantation. The first parameter we employed to evaluate effective KC halting, namely mean keratometry, showed considerable improvements over time. Kavg improved in 87% of patients after a mean of 6.9 years of observation, from 48.82 ± 5.00 to 43.25 ± 3.58 diopters (p = 0.008) (Fig. 3).

Corneal thickness also improved noticeably; mean pachymetry increased in 93% of patients from 442.80 ± 61.02 to 464.50 ± 62.72 µm (p = 0.003) (Fig. 4, 5). Lastly, postoperative visual acuity as measured by BSCVA improved in all patients from 0.46 ± 0.69 logMAR (20 / 60) to 0.15 ± 0.69 logMAR (20 / 30, p = 0.0006) (Fig. 6). Aggregate preoperative and postoperative data with relevant p-values are presented in Table 1, while key indicators for each patient are shown in Table 2. The original dataset is available upon request from the corresponding author.

Four main conclusions can be drawn from our study. First, combined MARK and CXL appeared to be effective in treating both progressive KC (mean keratometry and pachymetry improved) and improving patients' visual acuity (BSCVA increased). Second, the combined protocol appeared to provide predictable outcomes, as mean keratometry, mean pachymetry, and visual acuity improved in 87%, 93%, and 100% of cases respectively. Third, the protocol proved to be safe—no intraoperative or postoperative complications occurred. Fourth, our long-term follow-up data (a minimum of 5 years and an average of 6.9 years) indicate that the effects of the intervention are durable.

Some notes of caution are also needed to clarify the generalizability of these results. It is important to acknowledge the fact that a larger cohort of patients would support the validity of these findings, while a randomized controlled trial would further strengthen internal validity. Moreover, it is also necessary to acknowledge that while CXL is a standardized procedure, MARK is not because it involves customized mini-incisions whose number, position, length, and depth change with every patient. As a corollary, an ophthalmic surgeon with experience in incisional (both manual and laser) surgery is a prerequisite for this combined procedure.

The general availability of more accurate instruments for the diagnosis of KC is increasing, as well as awareness of this condition by the general public, which has resulted in diagnosis of a growing number of patients with KC. However, while medical research is progressing at an impressive pace a nd C XL a lone is a ble to halt c orneal e ctasia, a s showed by Snibson's review [22], the patient's visual acuity still needs to be improved, which justifies the ‘CXL Plus’ approach. Because every CXL-combined protocol has precise indications and limitations, as outlined by Mastropasqua [23], one can conclude that the more options the ophthalmic surgeon has, the better it is for their patients.

The rationale for combination of MARK and CXL is that the combined procedure can offer both corneal reinforcement and regularization, with the advantage of avoiding corneal thinning (PRK/FemtoLASIK) or intracorneal surgery (ICRS). Limitations include likely requiring glasses or contact lenses after surgery as well as very careful patient selection, as MARK is indicated only within the parameters that have been outlined previously. Rigorous inclusion criteria are essential to prevent possible unwanted complications deriving from inappropriate surgery, a number of which have been described in the literature and summarized by Lovisolo et al. [24].

With the positive outcomes and limitations of the Rome protocol outlined, it is possible to contextualize this research, as other CXL-combined procedures showed mixed results. Kanellopoulos and Asimellis [15] reported improved visual acuity and mean keratometry after performing PRK combined with CXL, but also decreased corneal thickness due to surface ablation. Similar findings were reported for the combination of LASIK and CXL by Kanellopoulos and Pamel [16]. El-Raggal [17], moreover, described improved vision and keratometry with ICRS combined with CXL, but did not discuss pachymetric changes. Toric phakic intraocular lenses, when implanted after CXL, also improved visual acuity and mean keratometry, while pachymetric values were relatively stable according to Fadlallah et al. [18]. Lastly, CKP followed by CXL was described as producing results no different from those with CXL alone [19]. The current literature on CXL-combined procedures, excluding CKP, therefore confirms significant gains in terms of visual acuity and mean keratometry, but also outlines varying outcomes relating to corneal thickness. MARK differs in this respect since it does not result in corneal thinning because there is no ablation and because post-keratotomy fibrotic cellular responses produce thicker collagen fibrils over the incisions along with corneal f lattening, a process that has been widely discussed in the literature [25], without compromising the patient's vision due to the incisions' distance from the optical zone.

Lastly, some final considerations concerning MARK surgery are required for greater conceptual clarity. The differences between MARK mini-incisions and standard RK incisions are particularly significant when treating KC, mainly due to the fact that MARK surgery: i) uses very short incisions (approximately 2 mm) compared to full-length RK incisions; ii) applies less deep incisions (80% of corneal thickness) than RK incisions; iii) requires few (3 to 5) customized mini-incisions that involve only a limited angular span of the cornea, as opposed to the full angular span involved with RK; and iv) does not preclude future surgical options such as penetrating keratoplasty, due to the fact MARK mini-incisions do not extend beyond a corneal diameter of 8 mm peripherally, which means that they would be included in the diameter of corneal tissue to be removed and substituted with the corneal graft. These are significant differences that are bound to affect long-term stability and safety.

We showed that the combined intervention of MARK and CXL (the Rome protocol) is effective at treating progressive KC and improving visual acuity based on analyses of long-term follow-up data (a minimum of 5 years and an average of 6.9 years). Mean keratometry and mean pachymetry improved in 87% and 93% of cases, respectively, while best corrected visual acuity increased in all cases. As mentioned previously, further studies with larger cohorts of patients are needed to confirm these results, and we also acknowledge the need for careful patient selection as well as experience with incisional surgery.

Surgical and parasurgical options for the treatment of KC keep increasing in number due to the need to comprehensively treat keratoconic patients, which is reassuring news for patients as well as for the medical and scientific community. In the wider context, it cannot be stressed enough that prevention is the best strategy for the treatment of this pathology, as an early diagnosis will likely result in early-stage CXL, which would probably prevent the need for further surgery. Moreover, 10 years' worth of follow-up data for CXL is available due to the study of Raiskup et al. [26], and this data further confirms the importance of treating progressive KC early and effectively. When this is not the case, however, the availability of multiple surgical options, such as the MARK + CXL procedure, as well as those outlined previously provides a wider treatment spectrum for the ophthalmic surgeon who can then perform the most appropriate one taking each patient's characteristics into consideration.