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People hold placards with Emanuela Orlandi's portrait at the end of Pope's Angelus prayer in St. Peter's Square at the Vatican. Image Credit: AFP

Vatican City: Pope Francis offered prayers Sunday for the family of a teenager who went missing 40 years ago this week, an intervention her brother hailed as a sign the Vatican was finally engaging seriously with its most famous cold case.

Emanuela Orlandi, the 15-year-old daughter of a Vatican employee, was last seen leaving a music class in Rome on June 22, 1983.

Decades of speculation followed over what happened to her, with suggestions that mobsters, the secret services or a Vatican conspiracy were to blame - theories which sparked a hit Netflix series.

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After his weekly Angelus prayer at the Vatican, Pope Francis said he wanted to use the anniversary "to once again express my closeness to the family, above all her mother, and assure them of my prayers".

"I extend my remembrance to all the families who bear the pain of a loved one who has disappeared," he added.

Orlandi's family have for years campaigned for the truth and in January the Vatican's chief prosecutor opened a file into the case.

On Thursday's anniversary, the Vatican revealed he had forwarded his findings to the Rome prosecutor's office, which is conducting its own probe.

There had been "some lines of inquiry worthy of further investigation", the Vatican said in a statement, without giving further details.

But it said it had collected evidence from Vatican institutions and accounts from senior officials at the time.

The Vatican has been accused of obstructing investigation efforts over the decades, but Orlandi's brother Pietro expressed hope Sunday that some progress might finally be made.

"The Emanuela Orlandi taboo has finally been broken," he told reporters after leading a sit-in near the Vatican and then going to listen to the pope.

"The fact of praying is a sign of hope of reaching the truth."

Pietro Orlandi told AFP "these words are already a big step that we had been asking for for years and years and it had never happened".

But he added: "We expect acts after these words."

Italy's lower chamber of parliament agreed in March to set up a commission to investigate Orlandi's case and that of another Vatican teenager, Mirella Gregori, who disappeared a few weeks earlier.

But it remains under discussion in the upper chamber, the Senate.